tag:blogger.com,1999:blog-5698923857141181272024-03-16T06:40:17.917+05:30World Drug TrackerTracks information on drugs on worldwide basis by Dr Anthony Melvin Crasto, helping millions with websites, 9 million hits on google, 2.5 lakh connections worldwide, P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.comBlogger886125tag:blogger.com,1999:blog-569892385714118127.post-19639111202526878552023-03-10T08:20:00.002+05:302023-03-10T08:20:29.618+05:30SMARTCHEM BY ROW2 TECHNOLOGIES<p> </p>
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</div><div><br /></div><div class="separator" style="clear: both; text-align: center;"><iframe allowfullscreen='allowfullscreen' webkitallowfullscreen='webkitallowfullscreen' mozallowfullscreen='mozallowfullscreen' width='563' height='468' src='https://www.blogger.com/video.g?token=AD6v5dzw1dTTzsjwu1qNE10MsQYYMsths6n6svbkfzRUBodkm3cZbsSAXCiNQm-VPoi_QvQJSuPshTNYeCFVvvbE9Q' class='b-hbp-video b-uploaded' frameborder='0'></iframe></div><br /><div><br /></div>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-37617004105267825452020-11-13T14:14:00.002+05:302020-11-13T14:14:36.107+05:30REPROXALAP<p> <img alt="2-(3-Amino-6-chloroquinolin-2-yl)propan-2-ol.png" scale="0" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=16088030&t=l" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">REPROXALAP</p><p><br /></p><p><a href="https://newdrugapprovals.org/2020/11/13/reproxalap/">https://newdrugapprovals.org/2020/11/13/reproxalap/</a></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com16tag:blogger.com,1999:blog-569892385714118127.post-51549551531933665842020-09-15T09:08:00.002+05:302020-09-15T09:08:24.517+05:30Somapacitan<p> <span style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px;">FPTIPLSRLF DNAMLRAHRL HQLAFDTYQE FEEAYIPKEQ KYSFLQNPQT SLCFSESIPT</span></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">PSNREETQQK SNLELLRISL LLIQSWLEPV QFLRSVFANS CVYGASDSNV YDLLKDLEEG<br />IQTLMGRLED GSPRTGQIFK QTYSKFDTNS HNDDALLKNY GLLYCFRKDM DKVETFLRIV<br />QCRSVEGSCG F<br />(Disulfide bridge: 53-165, 182-189)</p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="Somapacitan.png" scale="0" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=129894493&t=l" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;"><img alt="2D chemical structure of 1338578-34-9" scale="0" src="https://chem.nlm.nih.gov/chemidplus/structure/1338578-34-9" style="border: 4px solid rgb(238, 238, 238); box-sizing: border-box; height: auto; max-width: 100%; vertical-align: middle;" /></p><p style="background-color: white; color: #333333; font-family: Helvetica, Arial, Tahoma, sans-serif; font-size: 14px; margin: 0px 0px 10px;">Somapacitan</p><p><br /></p><p>READ AT</p><p>https://newdrugapprovals.org/2020/09/15/somapacitan-%e3%82%bd%e3%83%9e%e3%83%91%e3%82%b7%e3%82%bf%e3%83%b3/</p><p><br /></p>DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com26tag:blogger.com,1999:blog-569892385714118127.post-25247755995080006302018-05-22T14:49:00.000+05:302018-05-23T06:46:46.959+05:30Mesothelioma Cancer<div dir="ltr" style="text-align: left;" trbidi="on">
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Mesothelioma is a rare form of cancer that’s most often caused by asbestos exposure. It usually forms in the lungs of those who have been exposed to this deadly toxin, but sometimes occurs in the abdominal area or the area around the heart. There are a number of therapies available that can help prolong survival and minimize symptoms and discomfort, but in most cases the cancer is too aggressive and too advanced at the time of diagnosis to be cured. This disease specifically impacts a thin membrane that protects the lungs, heart and organs within the abdominal cavity and enables them to function properly. This is called the mesothelium and the majority of cases of this type of cancer affect the pleura, the mesothelium that lines the lungs.</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com42tag:blogger.com,1999:blog-569892385714118127.post-8071323534355596912017-12-24T16:42:00.002+05:302017-12-24T16:42:50.230+05:30Strigolactones: a plant phytohormone as novel anti-inflammatory agents<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="http://feeds.rsc.org/~r/rss/MD/~3/DN8SIaCpuXU/C7MD00461C" style="color: #000099; text-decoration-line: none;">Strigolactones: a plant phytohormone as novel anti-inflammatory agents</a></h4>
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<i><b>Med. Chem. Commun.</b></i>, 2018, Advance Article<br /><b>DOI</b>: 10.1039/C7MD00461C, Research Article</div>
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Jun-Xia Zheng, Yu-Shui Han, Jin-Cai Wang, Hui Yang, Hao Kong, Kang-Jia Liu, Si-Yu Chen, Yi-Rui Chen, Yi-Qun Chang, Wei-Min Chen, Jia-Liang Guo, Ping-Hua Sun<br />Strigolactones (SLs), a representative SL, GR24 and its reductive products of D-ring were synthesized and their anti-inflammatory activities were fully evaluated on both <em>in vitro</em> and <em>in vivo</em> models</div>
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<span style="color: rgba(0, 0, 0, 0.749019607843137); font-family: MuseoSlab700Regular, museo-slab;"><span style="letter-spacing: -0.02em;">Strigolactones: a plant phytohormone as novel anti-inflammatory agents</span></span><br /><br /><span style="color: rgba(0, 0, 0, 0.749019607843137); font-family: MuseoSlab700Regular, museo-slab; font-size: small;"><span style="letter-spacing: -0.48px;"><a href="http://pubs.rsc.org/en/Content/ArticleLanding/2018/MD/C7MD00461C?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract">http://pubs.rsc.org/en/Content/ArticleLanding/2018/MD/C7MD00461C?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract</a></span></span></h2>
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<span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AJun-Xia%20Zheng" style="color: #2d7ea9;">Jun-Xia Zheng</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">a</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AYu-Shui%20Han" style="color: #2d7ea9;">Yu-Shui Han</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AJin-Cai%20Wang" style="color: #3dabdc;">Jin-Cai Wang</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AHui%20Yang" style="color: #2d7ea9;">Hui Yang</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AHao%20Kong" style="color: #2d7ea9;">Hao Kong</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AKang-Jia%20Liu" style="color: #2d7ea9;">Kang-Jia Liu</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3ASi-Yu%20Chen" style="color: #2d7ea9;">Si-Yu Chen</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AYi-Rui%20Chen" style="color: #2d7ea9;">Yi-Rui Chen</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">b</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AYi-Qun%20Chang" style="color: #2d7ea9;">Yi-Qun Chang</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AWei-Min%20Chen" style="color: #2d7ea9;">Wei-Min Chen</a>,<span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3AJia-Liang%20Guo" style="color: #2d7ea9;">Jia-Liang Guo</a><span style="font-size: 16px;">*</span><span style="position: relative; top: -0.4em; vertical-align: baseline;">b</span> and </span><span class="article__author-link" style="font-size: 14px; line-height: 20px;"><a href="http://pubs.rsc.org/en/results?searchtext=Author%3APing-Hua%20Sun" style="color: #2d7ea9;">Ping-Hua Sun</a><span style="font-size: 16px;">*</span><span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span> </span></div>
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<span style="display: table-cell; padding-left: 4px; width: 7px;"><span style="position: relative; top: -0.4em; vertical-align: baseline;">a</span></span><span style="display: table-cell; padding-left: 12px;">School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, PR China</span></div>
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<span style="display: table-cell; padding-left: 4px; width: 8px;"><span style="position: relative; top: -0.4em; vertical-align: baseline;">b</span></span><span style="display: table-cell; padding-left: 12px;">School of Stomatology and Medicine, Foshan University, Foshan, PR China<br /><b>E-mail:</b> <a href="mailto:janalguo@126.com" style="color: #9d3d99;" title="janalguo@126.com">janalguo@126.com</a><br /><b>Tel:</b> +86 2085224497</span></div>
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<span style="display: table-cell; padding-left: 4px; width: 7px;"><span style="position: relative; top: -0.4em; vertical-align: baseline;">c</span></span><span style="display: table-cell; padding-left: 12px;">College of Pharmacy, Jinan University, Guangzhou, PR China</span></div>
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Abstract</h3>
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Strigolactones (SLs) are a novel class of plant hormones with enormous potential for the prevention and treatment of inflammation. To further investigate the anti-inflammatory activities of SLs, a representative SL, GR24, and the reductive products of its D-ring were synthesized and their anti-inflammatory activities were fully evaluated on both <em>in vitro</em>and <em>in vivo</em> models. Among these compounds, the two most active optical isomers (<span style="font-weight: 700;">2a</span>and <span style="font-weight: 700;">6a</span>) demonstrated strong inhibitory activity on the release of inflammatory cytokines, including nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) by blocking the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways; they also greatly inhibited the migration of neutrophils and macrophages in fluorescent protein labeled zebrafish larvae. These results identified the promising anti-inflammatory effects of SLs, and suggested that both the absolute configuration of SL and the α,β-unsaturated D-ring structure are essential for the observed anti-inflammatory activity.</div>
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<a href="http://www.rsc.org/suppdata/c7/md/c7md00461c/c7md00461c1.pdf">////////</a>///////Strigolactones, phytohormone, anti-inflammatory agents</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com5tag:blogger.com,1999:blog-569892385714118127.post-5114354326758706502016-10-14T12:31:00.001+05:302016-10-15T07:19:24.344+05:30Register Today for the ACS Symposium in India on Recent Advances in Drug Development, 11-12 November 2016 in Hyderabad, India<div dir="ltr" style="text-align: left;" trbidi="on">
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<span data-mce-style="color: #ff0000;" style="color: red;">Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India</span></h1>
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/////// ACS Symposium, Recent Advances in Drug Development, 11-12 November 2016, Hyderabad, India, dr reddys, cas</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com5tag:blogger.com,1999:blog-569892385714118127.post-43588909742895139152016-08-02T09:10:00.001+05:302016-08-02T09:10:36.625+05:30Biafungin, CD 101, a Novel Echinocandin for Vulvovaginal candidiasis<div dir="ltr" style="text-align: left;" trbidi="on">
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-4.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-4.jpg" rel="attachment wp-att-8069"><img alt="STR1" class="alignnone wp-image-8069" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-4.jpg" height="704" src="http://www.allfordrugs.com/wp-content/uploads/2016/08/STR1-4.jpg" style="height: auto; max-width: 100%;" width="656" /></a></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2016/07/str14.jpg" href="https://newdrugapprovals.files.wordpress.com/2016/07/str14.jpg"><img alt="str1" class="alignnone wp-image-19298" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/str14.jpg?w=300" height="414" src="https://newdrugapprovals.files.wordpress.com/2016/07/str14.jpg?w=300" style="height: auto; max-width: 100%;" width="578" /></a></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2016/07/str1.gif" href="https://newdrugapprovals.files.wordpress.com/2016/07/str1.gif"><img alt="str1" class="alignnone size-medium wp-image-19300" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/str1.gif?w=300" height="233" src="https://newdrugapprovals.files.wordpress.com/2016/07/str1.gif?w=300" style="height: auto; max-width: 100%;" width="300" /></a>as CH3COOH salt</div>
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<img alt="UNII-W1U1TMN677.png" class="" data-mce-src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=92135634&t=l" height="738" src="https://pubchem.ncbi.nlm.nih.gov/image/imgsrv.fcgi?cid=92135634&t=l" style="height: auto; max-width: 100%;" width="738" /></h1>
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<span data-mce-style="color: #ff0000;" style="color: red;">CD 101</span></h1>
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Several structural representations above</div>
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Biafungin™; CD 101 IV; CD 101 Topical; CD101; SP 3025, Biafungin acetate, Echinocandin B</div>
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UNII-G013B5478J FRE FORM,</div>
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CAS 1396640-59-7 FREE FORM</div>
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MF, C63-H85-N8-O17, MW, 1226.4035</div>
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<i id="yui_3_5_0_3_1469938944002_425">Echinocandin B,</i></h4>
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<i id="yui_3_5_0_3_1469938944002_425">1-((4R,5R)-4-hydroxy-N2-((4''-(pentyloxy)(1,1':4',1''-terphenyl)-4-yl)carbonyl)-5-(2-(trimethylammonio)ethoxy)-L-ornithine)-4-((4S)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine)-</i></h4>
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<tr><td style="font-family: inherit; font-size: inherit;">Treat and prevent invasive fungal infections; Treat and prevent systemic Candida infections; Treat candidemia</td></tr>
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<img alt="2D chemical structure of 1631754-41-0" class="" data-mce-src="http://chem.sis.nlm.nih.gov/chemidplus/structure/1631754-41-0" height="400" src="http://chem.sis.nlm.nih.gov/chemidplus/structure/1631754-41-0" style="height: auto; max-width: 100%;" width="400" /></div>
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Biafungin acetate</div>
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CAS 1631754-41-0 ACETATE, Molecular Formula, C63-H85-N8-O17.C2-H3-O2, Molecular Weight, 1285.4472,</div>
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C<sub>63</sub> H<sub>85</sub> N<sub>8</sub> O<sub>17</sub> . C<sub>2</sub> H<sub>3</sub> O<sub>2</sub></div>
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1-[(4<em>R</em>,5<em>R</em>)-4-hydroxy-<em>N</em><sup>2</sup>-[[4''-(pentyloxy)[1,1':4',1''-terphenyl]-4-yl]carbonyl]-5-[2-(trimethylammonio)ethoxy]-L-ornithine]-4-[(4<em>S</em>)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine]-, acetate (1:1)</div>
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<span id="yui_3_5_0_3_1469939107022_415">UNII: W1U1TMN677</span></div>
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CD101 – A novel echinocandin antifungal C. albicans (n=351) MIC90 = 0.06 µg/mL C. glabrata (n=200) MIC90 = 0.06 µg/mL Echinocandins have potent fungicidal activity against Candida species</div>
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<li class="data-list__property" id="at-a-glance_origniator"><strong class="data-list__property-key">Originator </strong><span class="data-list__property-value">Seachaid Pharmaceuticals</span></li>
<li class="data-list__property" id="at-a-glance_developer"><strong class="data-list__property-key">Developer </strong><span class="data-list__property-value">Cidara Therapeutics</span></li>
<li class="data-list__property" id="at-a-glance_class"><strong class="data-list__property-key">Class </strong><span class="data-list__property-value">Antifungals; Echinocandins; Small molecules</span></li>
<li class="data-list__property" id="at-a-glance_mechanismOfAction"><strong class="data-list__property-key">Mechanism of Action </strong><span class="data-list__property-value">Glucan synthase inhibitors</span></li>
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<li class="data-list__property"><strong class="data-list__property-key show-tooltip">Orphan Drug Status </strong><span class="data-list__property-value">Yes - Candidiasis</span></li>
<li class="data-list__property" id="at-a-glance_onFastTrack"><strong class="data-list__property-key show-tooltip">On Fast track </strong><span class="data-list__property-value">Candidiasis; Vulvovaginal candidiasis</span></li>
<li class="data-list__property"><strong class="data-list__property-key">Phase II </strong><span class="data-list__property-value">Candidiasis; Vulvovaginal candidiasis</span></li>
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Most Recent Events</h3>
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<li class="data-list__property"><strong class="data-list__property-key">01 Jun 2016 </strong><span class="data-list__property-value property-value--event-details">Phase-II clinical trials in Vulvovaginal candidiasis in USA (Topical) (9197627; NCT02733432)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">31 May 2016 </strong><span class="data-list__property-value property-value--event-details">CD 101 receives Qualified Infectious Disease Product status for Vulvovaginal candidiasis in USA</span></li>
<li class="data-list__property"><strong class="data-list__property-key">31 May 2016 </strong><span class="data-list__property-value property-value--event-details">CD 101 receives Fast Track designation for Vulvovaginal candidiasis [Topical] in USA</span></li>
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<span class="message__heading">Restricted Access</span></div>
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POSTER......</div>
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<a data-mce-href="https://www.jmilabs.com/data/posters/ICAAC2014/M-1082.PDF" href="https://www.jmilabs.com/data/posters/ICAAC2014/M-1082.PDF">https://www.jmilabs.com/data/posters/ICAAC2014/M-1082.PDF</a></div>
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<a data-mce-href="http://www.cidara.com/wp-content/uploads/2014/12/A-694.-Biafungin-CD101-a-Novel-Echinocandin-Displays-a-Long-Half-life-in-the-Chimpanzee-Suggesting-a-Once-Weekly-IV-Dosing-Option.pdf" href="http://www.cidara.com/wp-content/uploads/2014/12/A-694.-Biafungin-CD101-a-Novel-Echinocandin-Displays-a-Long-Half-life-in-the-Chimpanzee-Suggesting-a-Once-Weekly-IV-Dosing-Option.pdf">http://www.cidara.com/wp-content/uploads/2014/12/A-694.-Biafungin-CD101-a-Novel-Echinocandin-Displays-a-Long-Half-life-in-the-Chimpanzee-Suggesting-a-Once-Weekly-IV-Dosing-Option.pdf</a></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2016/07/str16.jpg" href="https://newdrugapprovals.files.wordpress.com/2016/07/str16.jpg"><img alt="str1" class="alignnone size-medium wp-image-19311" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/str16.jpg?w=300" height="247" src="https://newdrugapprovals.files.wordpress.com/2016/07/str16.jpg?w=300" style="height: auto; max-width: 100%;" width="300" /></a>CLIPPED IMAGE FROM FILE ABOVE</div>
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<em><span data-mce-style="color: #ff0000;" style="color: red;"> <img alt="" class="" data-mce-src="http://chem.sis.nlm.nih.gov/chemidplus/structure/1396640-59-7?maxscale=30&width=300&height=300" height="435" src="http://chem.sis.nlm.nih.gov/chemidplus/structure/1396640-59-7?maxscale=30&width=300&height=300" style="height: auto; max-width: 100%;" width="435" /></span></em></h1>
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BIAFUNGIN, CD 101</h1>
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<em><span data-mce-style="color: #ff0000;" style="color: red;">Watch this space as I add more info................</span></em></h1>
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U.S. - Fast Track (Treat candidemia);<br />U.S. - Fast Track (Treat and prevent invasive fungal infections);<br />U.S. - Orphan Drug (Treat and prevent invasive fungal infections);<br />U.S. - Orphan Drug (Treat candidemia);<br />U.S. - Qualified Infectious Disease Program (Treat candidemia);<br />U.S. - Qualified Infectious Disease Program (Treat and prevent invasive fungal infections)</div>
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Fungal infections have emerged as major causes of human disease, especially among the immunocompromised patients and those hospitalized with serious underlying disease. As a consequence, the frequency of use of systemic antifungal agents has increased significantly and there is a growing concern about a shortage of effective antifungal agents. Although resistance rates to the clinically available antifungal agents remains low, reports of breakthrough infections and the increasing prevalence of uncommon fungal species that display elevated MIC values for existing agents is worrisome. Biafungin (CD101, previously SP 3025) is a novel echinocandin that displays chemical stability and long-acting pharmacokinetics that is being developed for once-weekly or other intermittent administration (see posters #A-693 and A- 694 for further information). In this study, we test biafungin and comparator agents against a collection of common Candida and Aspergillus species, including isolates resistant to azoles and echinocandins.</div>
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The echinocandins are an important class of antifungal agents, but are administered once daily by intravenous (IV) infusion. An echinocandin that could be administered once weekly could facilitate earlier hospital discharges and could expand usage to indications where daily infusions are impractical. Biafungin is a highly stable echinocandin for once-weekly IV administration. The compound was found to have a spectrum of activity and potency comparable to other echinocandins. In chimpanzees single dose pharmacokinetics of IV and orally administered biafungin were compared to IV anidulafungin, which has the longest half-life (T1/2 ) of the approved echinocandins.</div>
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Background Vulvovaginal candidiasis (VVC) is a highly prevalent mucosal infection VVC is caused by Candida albicans (~85%) and non-albicans (~15%) 5-8% of women have recurrent VVC (RVVC) which is associated with a negative impact on work/social life Oral fluconazole prescribed despite relapse, potential DDIs and increased risk to pregnant women No FDA-approved therapy for RVVC and no novel agent in >20 years</div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2016/07/str15.jpg" href="https://newdrugapprovals.files.wordpress.com/2016/07/str15.jpg"><img alt="str1" class="alignnone size-medium wp-image-19299" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/str15.jpg?w=300" height="138" src="https://newdrugapprovals.files.wordpress.com/2016/07/str15.jpg?w=300" style="height: auto; max-width: 100%;" width="300" /></a></div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2016/07/str15.jpg" href="https://newdrugapprovals.files.wordpress.com/2016/07/str15.jpg">Cidara Therapeutics 6310 Nancy Ridge Drive, Suite 101 San Diego, CA 92121</a></div>
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The incidence of invasive fungal infections, especially those due to <em>Aspergillus</em> spp. and <em>Candida</em> spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due <em>Candida</em> spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to <em>Aspergillus</em> spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains of<em>Candida</em>, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents.</div>
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<b>Echinocandins</b> are a new class of <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Antifungal_drug" href="https://en.wikipedia.org/wiki/Antifungal_drug" title="Antifungal drug">antifungal drugs</a><sup class="reference" id="cite_ref-pmid12039879_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid12039879-1" href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid12039879-1">[1]</a></sup> that inhibit the synthesis of <a data-mce-href="https://en.wikipedia.org/wiki/Glucan" href="https://en.wikipedia.org/wiki/Glucan" title="Glucan">glucan</a> in the <a data-mce-href="https://en.wikipedia.org/wiki/Cell_wall" href="https://en.wikipedia.org/wiki/Cell_wall" title="Cell wall">cell wall</a>, via <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Noncompetitive_inhibition" href="https://en.wikipedia.org/wiki/Noncompetitive_inhibition" title="Noncompetitive inhibition">noncompetitive inhibition</a> of the <a data-mce-href="https://en.wikipedia.org/wiki/Enzyme" href="https://en.wikipedia.org/wiki/Enzyme" title="Enzyme">enzyme</a> <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/1,3-%CE%B2_glucan_synthase" href="https://en.wikipedia.org/wiki/1,3-%CE%B2_glucan_synthase" title="1,3-β glucan synthase">1,3-β glucan synthase</a><sup class="reference" id="cite_ref-pmid16960253_2-0"><a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid16960253-2" href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid16960253-2">[2]</a></sup><sup class="reference" id="cite_ref-pmid16990627_3-0"><a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid16990627-3" href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid16990627-3">[3]</a></sup> and are thus called "penicillin of antifungals"<sup class="reference" id="cite_ref-JenniferLong2003_4-0"><a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-JenniferLong2003-4" href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-JenniferLong2003-4">[4]</a></sup> (a property shared with papulacandins) as penicillin has a similar mechanism against bacteria but not fungi. Beta glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components (The bacterial equivalent is <a data-mce-href="https://en.wikipedia.org/wiki/Peptidoglycan" href="https://en.wikipedia.org/wiki/Peptidoglycan" title="Peptidoglycan">peptidoglycan</a>). Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.<sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-5" href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-5">[5]</a></sup></div>
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<a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin_B" href="https://en.wikipedia.org/wiki/Echinocandin_B" title="Echinocandin B">Echinocandin B</a></div>
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<a data-mce-href="https://en.wikipedia.org/wiki/Caspofungin" href="https://en.wikipedia.org/wiki/Caspofungin" title="Caspofungin">Caspofungin</a></div>
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List of echinocandins:<sup class="reference" id="cite_ref-pmid18360617_17-0"><a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid18360617-17" href="https://en.wikipedia.org/wiki/Echinocandin#cite_note-pmid18360617-17">[17]</a></sup></div>
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<li><a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=Pneumocandin&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=Pneumocandin&action=edit&redlink=1" title="Pneumocandin (page does not exist)">Pneumocandins</a> (cyclic hexapeptides linked to a long-chain fatty acid)</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin_B" href="https://en.wikipedia.org/wiki/Echinocandin_B" title="Echinocandin B">Echinocandin B</a> not clinically used, risk of hemolysis</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Cilofungin" href="https://en.wikipedia.org/wiki/Cilofungin" title="Cilofungin">Cilofungin</a> withdrawn from trials due to solvent toxicity</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Caspofungin" href="https://en.wikipedia.org/wiki/Caspofungin" title="Caspofungin">Caspofungin</a> (trade name Cancidas, by Merck)</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Micafungin" href="https://en.wikipedia.org/wiki/Micafungin" title="Micafungin">Micafungin</a> (FK463) (trade name Mycamine, by Astellas Pharma.)</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin" href="https://en.wikipedia.org/wiki/Anidulafungin" title="Anidulafungin">Anidulafungin</a> (VER-002, V-echinocandin, LY303366) (trade name Eraxis, by Pfizer)</li>
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<span class="mw-headline" id="History">History</span></h2>
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<a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin" href="https://en.wikipedia.org/wiki/Anidulafungin" title="Anidulafungin">Anidulafungin</a></div>
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Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of <i>Papularia sphaerosperma</i> (Pers.), which were liposaccharide - i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase - and had action only on <i>Candida</i> spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins, a new group of antifungals with broad-range activity against <i>Candida</i> spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first approved of these newer echinocandins was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations so far have low oral bioavailability, so must be given intravenously only. Echinocandins have now become one of the first-line treatments for <i>Candida</i> before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.</div>
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CIDARA THERAPEUTICS DOSES FIRST PATIENT IN PHASE 2 TRIAL OF CD101 TOPICAL TO TREAT VULVOVAGINAL CANDIDIASIS</div>
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SAN DIEGO--(BUSINESS WIRE)--Jun. 9, 2016-- Cidara Therapeutics, Inc. (Nasdaq:CDTX), a biotechnology company developing novel anti-infectives and immunotherapies to treat fungal and other infections, today announced that the first patient has been dosed in RADIANT, a Phase 2 clinical trial comparing the safety and tolerability of the novel echinocandin, CD101, to standard-of-care fluconazole for the treatment of acute vulvovaginal candidiasis (VVC). RADIANT will evaluate two topical formulations of CD101, which is Cidara’s lead antifungal drug candidate.</div>
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“There have been no novel VVC therapies introduced for more than two decades, so advancing CD101 topical into Phase 2 is a critical step for women with VVC and for Cidara,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “Because of their excellent safety record and potency against <i>Candida</i>, echinocandin antifungals are recommended as first line therapy to fight systemic <i>Candida</i> infections. CD101 topical will be the first echinocandin tested clinically in VVC and we expect to demonstrate safe and improved eradication of <i>Candida</i> with rapid symptom relief for women seeking a better option over the existing azole class of antifungals.”</div>
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RADIANT is a Phase 2, multicenter, randomized, open-label, active-controlled, dose-ranging trial designed to evaluate the safety and tolerability of CD101 in women with moderate to severe episodes of VVC. The study will enroll up to 125 patients who will be randomized into three treatment cohorts. The first cohort will involve the treatment of 50 patients with CD101 Ointment while a second cohort of 50 patients will receive CD101 Gel. The third cohort will include 25 patients who will be treated with oral fluconazole.</div>
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The primary endpoints of RADIANT will be the safety and tolerability of a single dose of CD101 Ointment and multiple doses of CD101 Gel in patients with acute VVC. Secondary endpoints include therapeutic efficacy in acute VVC patients treated with CD101. Treatment evaluations and assessments will occur on trial days 7, 14 and 28.</div>
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The RADIANT trial will be conducted at clinical trial centers across the United States. More information about the trial is available at <a data-mce-href="http://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.clinicaltrials.gov&esheet=51358935&newsitemid=20160609005334&lan=en-US&anchor=www.clinicaltrials.gov&index=1&md5=c4ec4dffbb972b6270d476b8e0c352c6" href="http://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.clinicaltrials.gov&esheet=51358935&newsitemid=20160609005334&lan=en-US&anchor=www.clinicaltrials.gov&index=1&md5=c4ec4dffbb972b6270d476b8e0c352c6" rel="nofollow">www.clinicaltrials.gov</a>, identifier NCT02733432.</div>
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<b>About VVC and RVVC</b></div>
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Seventy-five percent of women worldwide suffer from VVC in their lifetime, and four to five million women in the United Statesalone have the recurrent form of the infection, which is caused by <i>Candida</i>. Many women will experience recurrence after the completion of treatment with existing therapies. Most VVC occurs in women of childbearing potential (the infection is common in pregnant women), but it affects women of all ages. In a recent safety communication, the U.S. Food and Drug Administration(FDA) advised caution in the prescribing of oral fluconazole for yeast infections during pregnancy based on a published study concluding there is an increased risk of miscarriage. The Centers for Disease Control and Prevention (CDC) guidelines recommend using only topical antifungal products to treat pregnant women with vulvovaginal yeast infections. Vaginal infections are associated with a substantial negative impact on day-to-day functioning and adverse pregnancy outcomes including preterm delivery, low birth weight, and increased infant mortality in addition to predisposition to HIV/AIDS. According to the CDC, certain species of <i>Candida</i> are becoming increasingly resistant to existing antifungal medications. This emerging resistance intensifies the need for new antifungal agents.</div>
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<b>About CD101 Topical</b></div>
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CD101 topical is the first topical agent in the echinocandin class of antifungals and exhibits a broad spectrum of fungicidal activity against <i>Candida</i> species. In May 2016, the FDA granted Qualified Infectious Disease Product (QIDP) and Fast Track Designation to CD101 topical for the treatment of VVC and the prevention of RVVC.</div>
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<b>About Cidara Therapeutics</b></div>
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Cidara is a clinical-stage biotechnology company focused on the discovery, development and commercialization of novel anti-infectives for the treatment of diseases that are inadequately addressed by current standard-of-care therapies. Cidara's initial product portfolio comprises two formulations of the company's novel echinocandin, CD101. CD101 IV is being developed as a once-weekly, high-exposure therapy for the treatment and prevention of serious, invasive fungal infections. CD101 topical is being developed for the treatment of vulvovaginal candidiasis (VVC) and the prevention of recurrent VVC (RVVC), a prevalent mucosal infection. In addition, Cidara has developed a proprietary immunotherapy platform, Cloudbreak™, designed to create compounds that direct a patient's immune cells to attack and eliminate pathogens that cause infectious disease. Cidara is headquartered inSan Diego, California. For more information, please visit <a data-mce-href="http://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.cidara.com&esheet=51358935&newsitemid=20160609005334&lan=en-US&anchor=www.cidara.com&index=2&md5=61fe3e446ae026d996534f87f499340e" href="http://cts.businesswire.com/ct/CT?id=smartlink&url=http%3A%2F%2Fwww.cidara.com&esheet=51358935&newsitemid=20160609005334&lan=en-US&anchor=www.cidara.com&index=2&md5=61fe3e446ae026d996534f87f499340e" rel="nofollow">www.cidara.com</a>.</div>
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REF <a data-mce-href="http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2176474" href="http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2176474">http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2176474</a></div>
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CLIP</div>
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<a data-mce-href="https://yixiblog.wordpress.com/2015/02/12/cidara-therapeutics-raises-42-million-to-develop-once-weekly-anti-fungal-therapy/" href="https://yixiblog.wordpress.com/2015/02/12/cidara-therapeutics-raises-42-million-to-develop-once-weekly-anti-fungal-therapy/" rel="bookmark">Cidara Therapeutics raises $42 million to develop once-weekly anti-fungal therapy</a></h2>
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Cidara Therapeutics (formerly K2 Therapeutics) grabbed $42 million in a private Series B funding round Wednesday to continue developing its once-weekly anti-fungal therapy. Just in June 2014, the company completed a $32 million Series A financing led by 5AM Ventures, Aisling Capital, Frazier Healthcare and InterWest Partners, which was the fourth largest A round in 2014 for innovative startups[1]. FierceBiotech named the company as one of <a data-mce-href="http://www.fiercebiotech.com/special-reports/fiercebiotechs-2014-fierce-15" href="http://www.fiercebiotech.com/special-reports/fiercebiotechs-2014-fierce-15">2014 Fierce 15</a> biotech startups.<br />
Cidara has an impressive executive team. The company was co-founded by Kevin Forrest, former CEO of Achaogen (NASDAQ: AKAO), and Shaw Warren. Jeffrey Stein, former CEO of Trius Therapeutics (NASDAQ: TSRX) and Dirk Thye, former president of Cerexa, have joined Cidara as CEO and CMO, respectively. Trius successfully developed antibiotic tedizolid and was acquired in 2013 by Cubist Pharmaceuticals (NASDAQ: CBST) for $818 million.<br />
Cidara’s lead candidate, biafungin (SP3025), was acquired from Seachaid Pharmaceuticals for $6 million. Biafungin’s half-life is much longer than that of similar drugs known as echinocandins (e.g., caspofungin, micafungin, anidulafungin), which may allow it to be developed as a once-weekly therapy, instead of once daily. The company is also developing a topical formulation of biafungin, namely topifungin. Cidara intends to file an IND and initiate a Phase I clinical trial in the second half of 2015.<br />
Merck’s Cancidas (caspofungin), launched in 2001, was the first of approved enchinocandins. The drug generated annual sales of $596 million in 2008. The approved echinocandins must be administered daily by intravenous infusion. Biafungin with improved pharmacokinetic characteristics has the potential to bring in hundreds of millions of dollars per year.<br />
[1] Nat Biotechnol. 2015, 33(1), 18.</div>
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CLIP</div>
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Biafungin is a potent and broad-spectrum antifungal agent with excellent activity against wild-type and troublesome azole- and echinocandin-resistant strains of Candida spp. The activity of biafungin is comparable to anidulafungin. • Biafungin was active against both wild-type and itraconazole-resistant strains of Aspergillus spp. from four different species. • In vitro susceptibility testing of biafungin against isolates of Candida and Aspergillus may be accomplished by either CLSI or EUCAST broth microdilution methods each providing comparable results. • The use of long-acting intravenous antifungal agents that could safely be given once a week to select patients is desirable and might decrease costs with long-term hospitalizations. Background: A novel echinocandin, biafungin, displaying long-acting pharmacokinetics and chemical stability is being developed for once-weekly administration. The activities of biafungin and comparator agents were tested against 173 fungal isolates of the most clinically common species. Methods: 106 CAN and 67 ASP were tested using CLSI and EUCAST reference broth microdilution methods against biafungin (50% inhibition) and comparators. Isolates included 27 echinocandin-resistant CAN (4 species) with identified fks hotspot (HS) mutations and 20 azole nonsusceptible ASP (4 species). Results: Against C. albicans, C. glabrata and C. tropicalis, the activity of biafungin (MIC50, 0.06, 0.12 and 0.03 μg/ml, respectively by CLSI method) was comparable to anidulafungin (AND; MIC50, 0.03, 0.12 and 0.03 μg/ml, respectively) and caspofungin (CSP; MIC50, 0.12, 0.25 and 0.12 μg/ml, respectively; Table). C. krusei strains were very susceptible to biafungin, showing MIC90 values of 0.06 μg/ml by both methods. Biafungin (MIC50/90, 1/2 μg/ml) was comparable to AND and less potent than CSP against C. parapsilosis using CLSI methodology. CLSI and EUCAST methods displayed similar results for most species, but biafungin (MIC50, 0.06 μg/ml) was eight-fold more active than CSP (MIC50, 0.5 μg/ml) against C. glabrata using the EUCAST method. Overall, biafungin was two- to four-fold more active against fks HS mutants than CSP and results were comparable to AND. Biafungin was active against A. fumigatus (MEC50/90, ≤0.008/0.015 μg/ml), A. terreus (MEC50/90, 0.015/0.015 μg/ml), A. niger (MEC50/90, ≤0.008/0.03 μg/ml) and A. flavus (MEC50/90, ≤0.008/≤0.008 μg/ml) using CLSI method. EUCAST results for ASP were also low for all echinocandins and comparable to CLSI results. Conclusions: Biafungin displayed comparable in vitro activity with other echinocandins against common wild-type CAN and ASP and resistant subsets that in combination with the long-acting profile warrants further development of this compound. 1. Arendrup MC, Cuenca-Estrella M, Lass-Florl C, Hope WW (2013). Breakpoints for antifungal agents: An update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp. Drug Resist Updat 16: 81-95. 2. Castanheira M, Woosley LN, Messer SA, Diekema DJ, Jones RN, Pfaller MA (2014). Frequency of fks mutations among Candida glabrata isolates from a 10-year global collection of bloodstream infection isolates. Antimicrob Agents Chemother 58: 577-580. 3. Clinical and Laboratory Standards Institute (2008). M27-A3. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: third edition. Wayne, PA: CLSI. 4. Clinical and Laboratory Standards Institute (2008). M38-A2. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Second Edition. Wayne, PA: CLSI. 5. Clinical and Laboratory Standards Institute (2012). M27-S4. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: 4th Informational Supplement. Wayne, PA: CLSI. 6. European Committee on Antimicrobial Susceptibility Testing (2014). Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0, January 2014. Available at: http://www.eucast.org/clinical_breakpoints/. Accessed January 1, 2014. 7. Pfaller MA, Diekema DJ (2010). Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36: 1-53. 8. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS (2011). Clinical breakpoints for the echinocandins and Candida revisited: Integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14: 164-176. ABSTRACT Activity of a Novel Echinocandin Biafungin (CD101) Tested against Most Common Candida and Aspergillus Species, Including Echinocandin- and Azole-resistant Strains M CASTANHEIRA, SA MESSER, PR RHOMBERG, RN JONES, MA PFALLER JMI Laboratories, North Liberty, Iowa, USA C</div>
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PATENT</h1>
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<a data-mce-href="https://www.google.com/patents/WO2015035102A2?cl=en" href="https://www.google.com/patents/WO2015035102A2?cl=en">https://www.google.com/patents/WO2015035102A2?cl=en</a></div>
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<span data-mce-style="color: #ff0000;" style="color: red;">BIAFUNGIN ACETATE IS USED AS STARTING MATERIAL</span></div>
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Example 30b: Synthesis of Compound 31</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000124_0001.gif" height="123" id="imgf000124_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000124_0001.gif" style="height: auto; max-width: 100%;" width="181" /></div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000124_0002.gif" height="172" id="imgf000124_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000124_0002.gif" style="height: auto; max-width: 100%;" width="467" /></div>
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Step a. Nitration of Biafungin Acetate</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000124_0003.gif" height="136" id="imgf000124_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000124_0003.gif" style="height: auto; max-width: 100%;" width="198" /></div>
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To a stirring solution of biafungin (1 00 mg, 0.078 mmol) in glacial acetic acid(1 .5 ml_) was added sodium nitrite (1 1 mg, 0.159 mmol) and the reaction was stirred at ambient temperature for 20 hours. The mixture was applied directly to reversed phase H PLC (Isco CombiFlash Rf; 50g RediSep C1 8 column, 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 85 mg of the desired product as a light yellow solid, formate salt. <sup>1</sup> H-NMR (300 M Hz, Methanol-d4) δ 8.58 (d, 1 H, J = 1 1 .7 Hz), 8.47 (t, 2H, J = 8.7Hz), 8.05 (d, 1 H, J = 2.1 Hz), 7.99 (d, 2H, J = 9.3 Hz), 7.82 (d, 2H, J = 8.7 Hz), 7.79-7.60 (m, 12H), 7.1 7 (d, 1 H, J = 8.7 Hz), 7.03 (d, 2H, J = 9 Hz), 5.48 (d, 1 H, J = 6 Hz), 5.08 (dd, 1 H, J = 1 .2, 5.7 Hz), 4.95-4.73 (m, 5H), 4.68-4.56 (m, 2H), 4.53 (d, 1 H, J = 5.7 Hz), 4.48-4.39 (m, 2H), 4.31 -3.79 (m, 6H), 4.04 (t, 2H, J = 5.7 Hz), 3.72-3.44 (m,3H), 3.1 8 (s, 9H), 2.60-1 .99 (m, 5H), 1 .83 (m, 2H, J = 8.7 Hz), 1 .56-1 .35 (m, 5H), 1 .28 (d, 6H, J = 4.2 Hz), 1 .09 (d, 3H, J = 1 0.2 Hz), 0.99 (t, 3H, J = 8.7 Hz) ; LC/MS, [M/2+H]+: 635.79, 635.80 calculated.</div>
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Step b. Reduction of Nitro-Biafungin To Amino-Biafungin</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000125_0001.gif" height="136" id="imgf000125_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000125_0001.gif" style="height: auto; max-width: 100%;" width="198" /></div>
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To a stirring solution of Nitro-Biafungin (1 00 mg, 0.075 mmol) in glacial acetic acid(1 .5 ml_) was added zinc powder (50 mg, 0.77 mmol) and the reaction was stirred at ambient temperature for 1 hour. The mixture was filtered and applied directly to reversed phase HPLC (Isco CombiFlash Rf, 50g Redisep C18 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 55 mg of the desired product as a white solid, formate salt. <sup>1</sup> H-NMR (300 MHz, Methanol-d4) 5 8.47 (bs, 1 H), 7.99 (d, 2H, J = 1 0.8Hz), 7.82 (d, 2H, J = 7.5 Hz), 7.80-7.67 (m, 6H), 7.62 (d, 2H, J = 8.7 Hz), 7.03 (d, 2H, J = 7.5 Hz), 6.77 (d, 1 H, J = 1 .9 Hz), 6.68 (d, 1 H, J = 8.2 Hz), 6.55 (dd, 2H, J = 8.2, 1 .9 Hz), 5.43 (d, 1 H, J = 2.5 Hz), 5.05 (d, 1 H, J = 3 Hz), 4.83-4.73 (m, 2H), 4.64- 4.56 (m, 2H), 4.43-4.34 (m, 2H), 4.31 -4.15 (m, 4H), 4.03-4.08 (m, 1 H), 4.1 1 -3.89 (m, 8H), 3.83 (d, 1 H, J = 1 0.8 Hz), 3.68-3.47 (m, 3H), 3.1 7 (s, 9H), 2.57-2.42 (m, 2H), 2.35-2.27 (m, 1 H), 2.14-1 .98 (m, 2H), 1 .83 (m, 2H, J = 6 Hz), 1 .56-1 .38 (m, 4H), 1 .28 (dd, 6H, J = 6.5, 2 Hz), 1 .09 (d, 3H, J = 7 Hz), 0.986 (t, 3H, J = 7 Hz); High Res LC/MS: [M+H]+ 1241 .61 63; 1241 .6136 calculated.</div>
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Step c. Reaction of Amino-Biafungin with lnt-2 to Produce Compound 31</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000125_0002.gif" height="158" id="imgf000125_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000125_0002.gif" style="height: auto; max-width: 100%;" width="199" /></div>
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To a stirring solution of Amino-Biafungin (50 mg, 0.04 mmol) in DM F (1 ml_) was added formyl-Met-Leu-Phe- -Ala-OSu (lnt-2) (36 mg, 0.06 mmol) and DI PEA (7 uL, 0.04 mmol). The reaction was stirred at ambient temperature for 1 8 hours. The mixture was applied directly to reversed phase HPLC (Isco CombiFlash Rf; 50g Redisep C1 8 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 26 mg of a white solid as a formate salt. <sup>1</sup> H-NMR (300 M Hz, Methanol-d4) 5 8.55 (bs, 1 H), 8.44 (t, 1 H, J = 10 Hz), 8.1 8 (d, 1 H, J = 6 Hz), 8.1 1 (s, 1 H), 7.99 (d, 2H, J = 1 0 Hz), 7.84-7.70 (m, 6H), 7.63 (d, 2H, J = 7.8 Hz), 7.32-7.1 9 (m, 6H), 7.03 (d, 4H, J = 9 Hz), 6.87 (d, 1 H, J = 8.1 Hz), 5.44 (d, 1 H, J = 1 0.5 Hz), 5.05 (d, 1 H, J = 4.5 Hz), 4.83-4.74 (m, 2H), 4.66-4.50 (m, 6H), 4.45-4.29 (m, 10H), 4.1 9-3.82 (m, 1 0H), 3.67-3.57 (m, 6H), 3.1 7 (s, 9H), 2.64-2.46 (m, 6 H), 2.14-1 .92 (m, 6H), 1 .84 (m, 4H, J = 6 Hz), 1 .62-1 .40 (m, 8H), 1 .32-1 .22 (m, 6H), 1 .09 (d, 3H, J = 9 Hz), 0.99 (t, 3H, J = 7.5 Hz), 0.88 (m, 6H, J = 6.8 Hz) ; High Res LC/MS, [M/2+H]+ 865.4143, 865.4147 calculated.</div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">REFERENCES</span></em></strong></h1>
<ol class="references" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li id="cite_note-pmid12039879-1"><span class="reference-text"><cite class="citation journal">Denning, DW (June 2002). "Echinocandins: a new class of antifungal.". <i>The Journal of antimicrobial chemotherapy</i> <b>49</b> (6): 889–91. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1093%2Fjac%2Fdkf045" href="https://dx.doi.org/10.1093%2Fjac%2Fdkf045" rel="nofollow">10.1093/jac/dkf045</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/12039879" href="https://www.ncbi.nlm.nih.gov/pubmed/12039879" rel="nofollow">12039879</a>.</cite></span></li>
<li id="cite_note-pmid16960253-2"> <span class="reference-text"><cite class="citation journal">Morris MI, Villmann M (September 2006). <a class="external text" data-mce-href="http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16960253" href="http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16960253" rel="nofollow">"Echinocandins in the management of invasive fungal infections, part 1"</a>. <i>Am J Health Syst Pharm</i> <b>63</b> (18): 1693–703.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.2146%2Fajhp050464.p1" href="https://dx.doi.org/10.2146%2Fajhp050464.p1" rel="nofollow">10.2146/ajhp050464.p1</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/16960253" href="https://www.ncbi.nlm.nih.gov/pubmed/16960253" rel="nofollow">16960253</a>.</cite></span></li>
<li id="cite_note-pmid16990627-3"><span class="reference-text"><cite class="citation journal">Morris MI, Villmann M (October 2006). <a class="external text" data-mce-href="http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16990627" href="http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16990627" rel="nofollow">"Echinocandins in the management of invasive fungal infections, Part 2"</a>. <i>Am J Health Syst Pharm</i> <b>63</b> (19): 1813–20.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.2146%2Fajhp050464.p2" href="https://dx.doi.org/10.2146%2Fajhp050464.p2" rel="nofollow">10.2146/ajhp050464.p2</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/16990627" href="https://www.ncbi.nlm.nih.gov/pubmed/16990627" rel="nofollow">16990627</a>.</cite></span></li>
<li id="cite_note-JenniferLong2003-4"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_ref-JenniferLong2003_4-0" href="https://en.wikipedia.org/wiki/Echinocandin#cite_ref-JenniferLong2003_4-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin#cite_ref-JenniferLong2003_4-1" href="https://en.wikipedia.org/wiki/Echinocandin#cite_ref-JenniferLong2003_4-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2003/antifungal.htm" href="http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2003/antifungal.htm" rel="nofollow">"Pharmacotherapy Update - New Antifungal Agents: Additions to the Existing Armamentarium (Part 1)"</a>.</cite></span></li>
<li id="cite_note-5"> <span class="reference-text"><cite class="citation journal">Debono, M; Gordee, RS (1994). "Antibiotics that inhibit fungal cell wall development".<i>Annu Rev Microbiol</i> <b>48</b>: 471–497. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1146%2Fannurev.mi.48.100194.002351" href="https://dx.doi.org/10.1146%2Fannurev.mi.48.100194.002351" rel="nofollow">10.1146/annurev.mi.48.100194.002351</a>.</cite></span></li>
</ol>
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17 Eschenauer, G; Depestel, DD; Carver, PL (March 2007). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936290" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936290" rel="nofollow">"Comparison of echinocandin antifungals."</a>. <i>Therapeutics and clinical risk management</i> <b>3</b> (1): 71–97. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936290" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936290" rel="nofollow">1936290</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/18360617" href="https://www.ncbi.nlm.nih.gov/pubmed/18360617" rel="nofollow">18360617</a>.</div>
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///////////Biafungin™, CD 101 IV, CD 101 Topical, CD101, SP 3025, PHASE 2, CIDARA, Orphan Drug, Fast Track Designation, Seachaid Pharmaceuticals, Qualified Infectious Disease Product, QIDP, UNII-G013B5478J, 1396640-59-7, 1631754-41-0, Vulvovaginal candidiasis, Echinocandin B, FUNGIN</div>
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FREE FORM</div>
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CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)C(NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C</div>
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AND OF ACETATE</div>
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CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)[C@@H](NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C.CC(=O)[O-]</div>
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Three antifungal drugs approved by the United States Food and Drug Administration, caspofungin, anidulafungin, and micafungin, are known to inhibit β-1 ,3-glucan synthase which have the structures shown below.</div>
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<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000049_0002.gif" height="187" id="imgf000049_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000049_0002.gif" style="height: auto; max-width: 100%;" width="200" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
caspofungin</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000050_0001.gif" height="183" id="imgf000050_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000050_0001.gif" style="height: auto; max-width: 100%;" width="288" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Anidulafungin</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000050_0002.gif" height="209" id="imgf000050_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000050_0002.gif" style="height: auto; max-width: 100%;" width="374" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Other exemplary p-1 ,3-glucan synthase inhibitors include,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000050_0003.gif" height="157" id="imgf000050_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000050_0003.gif" style="height: auto; max-width: 100%;" width="204" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
echinocandin B</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000051_0001.gif" height="163" id="imgf000051_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000051_0001.gif" style="height: auto; max-width: 100%;" width="236" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
cilofungin</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000051_0002.gif" height="147" id="imgf000051_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000051_0002.gif" style="height: auto; max-width: 100%;" width="168" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
pneumocandin A<sub>0</sub></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000051_0003.gif" height="147" id="imgf000051_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000051_0003.gif" style="height: auto; max-width: 100%;" width="165" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
pneumocandin B<sub>0</sub></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000052_0001.gif" height="163" id="imgf000052_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000052_0001.gif" style="height: auto; max-width: 100%;" width="174" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
L-705589</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000052_0002.gif" height="356" id="imgf000052_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000052_0002.gif" style="height: auto; max-width: 100%;" width="362" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
L-733560</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000053_0001.gif" height="152" id="imgf000053_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000053_0001.gif" style="height: auto; max-width: 100%;" width="237" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A-174591 <img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000053_0002.gif" height="155" id="imgf000053_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000053_0002.gif" style="height: auto; max-width: 100%;" width="238" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000053_0003.gif" height="153" id="imgf000053_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000053_0003.gif" style="height: auto; max-width: 100%;" width="243" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000054_0001.gif" height="168" id="imgf000054_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000054_0001.gif" style="height: auto; max-width: 100%;" width="247" /> or a salt thereof,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Biafungin</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000054_0002.gif" height="151" id="imgf000054_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000054_0002.gif" style="height: auto; max-width: 100%;" width="222" /><br />or a salt thereof,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Amino-biafungin</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000054_0003.gif" height="180" id="imgf000054_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000054_0003.gif" style="height: auto; max-width: 100%;" width="228" /><br />or a salt thereof,</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000055_0001.gif" height="205" id="imgf000055_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000055_0001.gif" style="height: auto; max-width: 100%;" width="342" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Amino-AF-053 <img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000055_0002.gif" height="144" id="imgf000055_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000055_0002.gif" style="height: auto; max-width: 100%;" width="177" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000055_0003.gif" height="148" id="imgf000055_0003" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000055_0003.gif" style="height: auto; max-width: 100%;" width="179" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000056_0001.gif" height="150" id="imgf000056_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000056_0001.gif" style="height: auto; max-width: 100%;" width="262" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
ASP9726</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Yet other exemplary p-1 ,3-glucan synthase inhibitors include, without limitation:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000056_0002.gif" height="453" id="imgf000056_0002" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000056_0002.gif" style="height: auto; max-width: 100%;" width="220" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Papulacandin B</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000057_0001.gif" height="757" id="imgf000057_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000057_0001.gif" style="height: auto; max-width: 100%;" width="453" /> <img alt="" data-mce-src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000058_0001.gif" height="110" id="imgf000058_0001" src="https://patentscope.wipo.int/search/docservice_image/WO@@@US2014054164@@@id00000062481471@@@7966343@@@imgf000058_0001.gif" style="height: auto; max-width: 100%;" width="243" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Ergokonin</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
//////////////</div>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com3tag:blogger.com,1999:blog-569892385714118127.post-19190270608274258652016-08-01T12:48:00.001+05:302016-08-01T12:48:17.662+05:30ANIDULAFUNGIN<div dir="ltr" style="text-align: left;" trbidi="on">
<br />
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="Anidulafungin Molecular Structure 2.png" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Anidulafungin_Molecular_Structure_2.png/230px-Anidulafungin_Molecular_Structure_2.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Anidulafungin_Molecular_Structure_2.png/230px-Anidulafungin_Molecular_Structure_2.png" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
OR</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800055h/production/images/medium/op-2008-00055h_0002.gif" height="551" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800055h/production/images/medium/op-2008-00055h_0002.gif" style="height: auto; max-width: 100%;" width="823" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Anidulafungin</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
V-Echinocandin</div>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><tbody>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"> </th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=166663-25-8" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=166663-25-8" rel="nofollow">166663-25-8</a></span></td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<i>N</i>-[(3<i>S</i>,6<i>S</i>,9<i>S</i>,11<i>R</i>,15<i>S</i>,18<i>S</i>,20<i>R</i>,21<i>R</i>,24<i>S</i>,25<i>S</i>,26<i>S</i>)-6-[(1<i>S</i>,2<i>R</i>)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-<i>bis</i>[(1<i>R</i>)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.0<sup>9,13</sup>]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide</div>
<ul style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<li>LY-307853</li>
<li>LY-329960</li>
<li>LY-333006</li>
<li>LY303366</li>
<li>VEC</li>
<li>VER-002</li>
</ul>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>1</sup>H NMR (700 MHz, <i>d</i><sub>6</sub>-DMSO) δ 0.91 (t, 3H), 1.12 (d, 3H), 1.36 (m, 2H), 1.41 (m, 2H), 1.74 (p, 2H), 1.88 and 1.97 (overlapped, 2H), 3.85 (overlapped, 1H), 4.01 (t, 2H), 4.35 (overlapped, 1H), 4.44 (m, 1H), 4.76 (m, 1H), 4.80 (m, 1H), 5.02 (m, 1H), 5.07 (d, 1H), 5.52 (d, 1H), 7.04 (d, 1H), 7.66 (d, 1H), 7.74 (d, 1H), 7.80 (d, 1H), 7.82 (d, 1H), 7.97 (d, 1H), 8.01 (d, 1H), 8.14 (broad s, 1H), 8.60 (d, 1H). IR (cm<sup>−1</sup>)</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
KBr ν<sub>max</sub>; 3450 (O−H), 2932 (C−H), 2871 (C−H), 1632 (C═O), 1517 (Ar), 1488 (Ar), 1248 (C−O), 821 (C−H out-of-plane bending Ar 2 adj H’s).</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>Anidulafungin</b> (brand names: <b>Eraxis</b> (in U.S. and Russia), <b>Ecalta</b> (in Europe)) is a <a data-mce-href="https://en.wikipedia.org/wiki/Semisynthesis" href="https://en.wikipedia.org/wiki/Semisynthesis" title="Semisynthesis">semisynthetic</a> <a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin" href="https://en.wikipedia.org/wiki/Echinocandin" title="Echinocandin">echinocandin</a> used as an<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Antifungal_medication" href="https://en.wikipedia.org/wiki/Antifungal_medication" title="Antifungal medication">antifungal drug</a>. Anidulafungin was originally manufactured and submitted for FDA approval by Vicuron Pharmaceuticals.<sup class="reference" id="cite_ref-1"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-1" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-1">[1]</a></sup> <a data-mce-href="https://en.wikipedia.org/wiki/Pfizer" href="https://en.wikipedia.org/wiki/Pfizer" title="Pfizer">Pfizer</a>acquired the drug upon its acquisition of Vicuron in the fall of 2005.<sup class="reference" id="cite_ref-2"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-2" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-2">[2]</a></sup> Pfizer gained approval by the <a data-mce-href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a>(FDA) on February 21, 2006;<sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-3" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-3">[3]</a></sup> it was previously known as LY303366. Preliminary evidence indicates it has a similar safety profile to<a data-mce-href="https://en.wikipedia.org/wiki/Caspofungin" href="https://en.wikipedia.org/wiki/Caspofungin" title="Caspofungin">caspofungin</a>. Anidulafungin has proven efficacy against esophageal candidiasis, but its main use will probably be in invasive <i><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Candida_(genus)" href="https://en.wikipedia.org/wiki/Candida_(genus)" title="Candida (genus)">Candida</a></i>infection;<sup class="reference" id="cite_ref-4"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-4" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-4">[4]</a></sup><sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-5" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-5">[5]</a></sup><sup class="reference" id="cite_ref-6"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-6" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-6">[6]</a></sup> it may also have application in treating invasive <i><a data-mce-href="https://en.wikipedia.org/wiki/Aspergillus" href="https://en.wikipedia.org/wiki/Aspergillus" title="Aspergillus">Aspergillus</a></i> infection. It is a member of the class of antifungal drugs known as the <a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin" href="https://en.wikipedia.org/wiki/Echinocandin" title="Echinocandin">echinocandins</a>; its mechanism of action is by inhibition of <a data-mce-href="https://en.wikipedia.org/wiki/Beta-glucan" href="https://en.wikipedia.org/wiki/Beta-glucan" title="Beta-glucan">(1→3)-β-<small>D</small>-glucan</a> synthase, an enzyme important to the synthesis of the fungal cell wall.</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Pharmacodynamics_and_pharmacokinetics">Pharmacodynamics and pharmacokinetics</span></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Anidulafungin significantly differs from other antifungals in that it undergoes chemical degradation to inactive forms at body <a data-mce-href="https://en.wikipedia.org/wiki/PH" href="https://en.wikipedia.org/wiki/PH" title="PH">pH</a> and temperature. Because it does not rely on enzymatic degradation or hepatic or renal excretion, the drug is safe to use in patients with any degree of hepatic or renal impairment.<sup class="reference" id="cite_ref-7"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-7" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-7">[7]</a></sup></div>
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Distribution: 30–50 L. Protein binding: 84%.</div>
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Anidulafungin is not evidently metabolized by the liver. This specific drug undergoes slow chemical hydrolysis to an open-ring peptide which lacks antifungal activity. The half-life of the drug is 27 hours. Thirty percent is excreted in the feces (10% as unchanged drug). Less than 1% is excreted in the urine.<sup class="reference" id="cite_ref-8"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-8" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-8">[8]</a></sup><sup class="reference" id="cite_ref-9"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-9" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-9">[9]</a></sup><sup class="reference" id="cite_ref-10"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-10" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-10">[10]</a></sup></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Mechanism_of_action">Mechanism of action</span></h2>
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Anidulafungin inhibits glucan synthase, an enzyme important in the formation of (1→3)-β-<small>D</small>-glucan, a major fungal cell wall component. Glucan synthase is not present in mammalian cells, so it is an attractive target for antifungal activity.<sup class="reference" id="cite_ref-pmid9421307_11-0"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-pmid9421307-11" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-pmid9421307-11">[11]</a></sup></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Semisynthesis">Semisynthesis</span></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Anidulafungin is manufactured via semisynthesis. The starting material is <a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin_B" href="https://en.wikipedia.org/wiki/Echinocandin_B" title="Echinocandin B">echinocandin B</a> (a <a data-mce-href="https://en.wikipedia.org/wiki/Lipopeptide" href="https://en.wikipedia.org/wiki/Lipopeptide" title="Lipopeptide">lipopeptide</a> fermentation product of<i><a data-mce-href="https://en.wikipedia.org/wiki/Aspergillus_nidulans" href="https://en.wikipedia.org/wiki/Aspergillus_nidulans" title="Aspergillus nidulans">Aspergillus nidulans</a></i> or the closely related species, <i>A. rugulosus</i>), which undergoes deacylation (cleavage of the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Lenoleic_acid" href="https://en.wikipedia.org/wiki/Lenoleic_acid" title="Lenoleic acid">linoleoyl</a> side chain) by the action of a deacylase enzyme from the bacterium <i>Actinoplanes utahensis</i>;<sup class="reference" id="cite_ref-12"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-12" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-12">[12]</a></sup> in three subsequent synthetic steps, including a chemical reacylation, the antifungal drug anidulafungin<sup class="reference" id="cite_ref-pmid9421307_11-1"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-pmid9421307-11" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-pmid9421307-11">[11]</a></sup><sup class="reference" id="cite_ref-urlAnidulafungin_13-0"><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-urlAnidulafungin-13" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_note-urlAnidulafungin-13">[13]</a></sup> is synthesized.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<i>Aspergillus nidulans</i>. Anidulafungin is an echinocandin, a class of <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=9620" href="http://www.rxlist.com/script/main/art.asp?articlekey=9620" rel="dict">antifungal</a> drugs that inhibits the synthesis of 1,3-β-D-glucan, an <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=3332" href="http://www.rxlist.com/script/main/art.asp?articlekey=3332" rel="dict">essential</a> component of fungal cell walls.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
ERAXIS (anidulafungin) is 1-[(4R,5R)-4,5-dihydroxy-N -[[4“-(pentyloxy)[1,1':4',1”-terphenyl]-4-yl]carbonyl]-L-<a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=24649" href="http://www.rxlist.com/script/main/art.asp?articlekey=24649" rel="dict">ornithine</a>]echinocandin B. Anidulafungin is a white to off-white powder that is practically insoluble in water and slightly soluble in ethanol. In addition to the active ingredient, anidulafungin, ERAXIS for Injection contains the following inactive ingredients:</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b>50 mg/vial</b> - <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=20907" href="http://www.rxlist.com/script/main/art.asp?articlekey=20907" rel="dict">fructose</a> (50 mg), mannitol (250 mg), polysorbate 80 (125 mg), tartaric acid (5.6 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.</div>
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<b>100 mg/vial</b> - fructose (100 mg), mannitol (500 mg), polysorbate 80 (250 mg), tartaric acid (11.2 mg), and sodium hydroxide and/or hydrochloric acid for pH adjustment.</div>
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The empirical formula of anidulafungin is C<sub>58</sub>H<sub>73</sub>N<sub>7</sub>O<sub>17</sub> and the formula weight is 1140.3. The structural formula is</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="ERAXIS™ (anidulafung in) Structural Formula Illustration" data-mce-src="http://images.rxlist.com/images/rxlist/eraxis1.gif" src="http://images.rxlist.com/images/rxlist/eraxis1.gif" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Prior to administration, ERAXIS for Injection requires reconstitution with sterile Water for Injection and subsequent dilution with either 5% <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=7040" href="http://www.rxlist.com/script/main/art.asp?articlekey=7040" rel="dict">Dextrose</a>Injection, USP or 0.9% Sodium Chloride Injection, USP (normal <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=16206" href="http://www.rxlist.com/script/main/art.asp?articlekey=16206" rel="dict">saline</a>).</div>
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SYNTHESIS</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
J MED CHEM 1995, 38 3271-3281</div>
<h3 class="r" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/jm00017a012" href="http://pubs.acs.org/doi/abs/10.1021/jm00017a012" target="_blank">Semisynthetic Chemical Modification of the Antifungal Lipopeptide ...</a></h3>
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<div class="f kv _SWb">
<cite class="_Rm">pubs.acs.org/doi/abs/10.1021/jm00017a012</cite><br />
<div class="action-menu ab_ctl">
</div>
</div>
<div class="f slp">
by M Debono - 1995 - <a class="fl" data-mce-href="https://scholar.google.co.in/scholar?safe=active&um=1&ie=UTF-8&lr&cites=4280917584597969790" href="https://scholar.google.co.in/scholar?safe=active&um=1&ie=UTF-8&lr&cites=4280917584597969790" target="_blank">Cited by 113</a> - <a class="fl" data-mce-href="https://scholar.google.co.in/scholar?safe=active&um=1&ie=UTF-8&lr&q=related:fmuvptzfaDtkKM:scholar.google.com/" href="https://scholar.google.co.in/scholar?safe=active&um=1&ie=UTF-8&lr&q=related:fmuvptzfaDtkKM:scholar.google.com/" target="_blank">Related articles</a></div>
<span class="st"><span class="f">Aug 1, 1995 - </span><em>J</em>. <em>Med</em>. <em>Chem</em>. , <em>1995</em>, <em>38</em> (17), pp <em>3271–3281</em>. DOI: 10.1021/jm00017a012 ... <em>Journal</em> of<em>Medicinal Chemistry</em> 2001 44 (16), 2671-2674</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide "nucleus" as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-63.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-63.jpg" rel="attachment wp-att-8018"><img alt="str1" class="alignnone size-full wp-image-8018" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-63.jpg" height="538" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-63.jpg" style="height: auto; max-width: 100%;" width="758" /></a></div>
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PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
US 5965525</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.co.in/patents/US5965525" href="http://www.google.co.in/patents/US5965525">http://www.google.co.in/patents/US5965525</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
US 4293482</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.co.in/patents/US4293482" href="http://www.google.co.in/patents/US4293482">http://www.google.co.in/patents/US4293482</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Paper</div>
<h1 class="articleTitle" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="hlFld-Title">Commercialization and Late-Stage Development of a Semisynthetic Antifungal API: Anidulafungin/<span class="smallcaps">d</span>-Fructose (Eraxis)</span></h1>
<div id="articleMeta" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<div id="authors">
<span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Norris%2C+Timothy" href="http://pubs.acs.org/author/Norris%2C+Timothy" id="authors">Timothy Norris</a></span><a class="ref" data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op800055h#cor1" href="http://pubs.acs.org/doi/abs/10.1021/op800055h#cor1">*</a><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/VanAlsten%2C+John" href="http://pubs.acs.org/author/VanAlsten%2C+John" id="authors">John VanAlsten</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Hubbs%2C+Stephen" href="http://pubs.acs.org/author/Hubbs%2C+Stephen" id="authors">Stephen Hubbs</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Ewing%2C+Marcus" href="http://pubs.acs.org/author/Ewing%2C+Marcus" id="authors">Marcus Ewing</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Cai%2C+Weiling" href="http://pubs.acs.org/author/Cai%2C+Weiling" id="authors">Weiling Cai</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Jorgensen%2C+Matthew+L" href="http://pubs.acs.org/author/Jorgensen%2C+Matthew+L" id="authors">Matthew L. Jorgensen</a></span><span class="NLM_x">, </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Bordner%2C+Jon" href="http://pubs.acs.org/author/Bordner%2C+Jon" id="authors">Jon Bordner</a></span><span class="NLM_x">and </span></span><span class="hlFld-ContribAuthor"><span class="hlFld-ContribAuthor"><a data-mce-href="http://pubs.acs.org/author/Jensen%2C+Grace+O" href="http://pubs.acs.org/author/Jensen%2C+Grace+O" id="authors">Grace O. Jensen</a></span></span></div>
<div class="affiliations">
Chemical Research and Development, Pfizer Inc. Global Research and Development Laboratories, Eastern Point Road, Groton, Connecticut 06340, U.S.A.</div>
<div id="citation">
<cite>Org. Process Res. Dev.</cite>, <span class="citation_year">2008</span>, <span class="citation_volume">12</span> (3), pp 447–455</div>
<div id="doi">
<strong>DOI: </strong>10.1021/op800055h</div>
<div id="pubDate">
</div>
<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/op800055h" href="http://pubs.acs.org/doi/abs/10.1021/op800055h">http://pubs.acs.org/doi/abs/10.1021/op800055h</a><br />
<div id="correspondence">
* Corresponding author. E-mail: <a data-mce-href="mailto:timothy.norris@pfizer.com" href="mailto:timothy.norris@pfizer.com">timothy.norris@pfizer.com</a>. Telephone: <span class="phone">+860 441 4406</span> . Fax: <span class="fax">+860 686 5340</span>.</div>
</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="Abstract Image" data-mce-src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800055h/production/images/medium/op-2008-00055h_0001.gif" src="http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/oprdfk/2008/oprdfk.2008.12.issue-3/op800055h/production/images/medium/op-2008-00055h_0001.gif" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Many years ago anidulafungin <b>1</b> was identified as a potentially useful medicine for the treatment of fungal infections. Its chemical and physical properties as a relatively high molecular weight semisynthetic derived from echinocandin B proved to be a significant hurdle to its final presentation as a useful medicine. It has recently been approved as an intravenous treatment for invasive candidaisis, an increasingly common health hazard that is potentially life-threatening. The development and commercialization of this API, which is presented as a molecular mixture of anidulafungin and <span class="smallcaps">d</span>-fructose is described. This includes, single crystal X-ray structures of the starting materials, the echinocandin B cyclic-peptide nucleus (ECBN·HCl) and the active ester 1-({[4′′-(pentyloxy)-1,1′:4′,1′′-terphenyl-4-yl]carbonyl}oxy)-1<i>H</i>-1,2,3-benzotriazole (TOBt). Details of the structure and properties of starting materials, scale-up chemistry and unusual crystallization phenomena associated with the API formation are discussed.</div>
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<span class="mw-headline" id="References">References</span></div>
<div class="reflist" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<ol class="references">
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<li id="cite_note-2"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_ref-2" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_ref-2"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">PRNewswire. <a class="external text" data-mce-href="http://www2.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/08-15-2005/0004088704&EDATE=" href="http://www2.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/08-15-2005/0004088704&EDATE=" rel="nofollow">Vicuron Pharmaceuticals Stockholders Approve Merger With Pfizer</a> 08-15-2005</span></li>
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<li id="cite_note-5"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_ref-5" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_ref-5"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ (2005). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287823" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287823" rel="nofollow">"In Vitro Activities of Anidulafungin against More than 2,500 Clinical Isolates of Candida spp., Including 315 Isolates Resistant to Fluconazole"</a>. <i>J Clin Microbiol</i> <b>43</b> (11): 5425–7.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1128%2FJCM.43.11.5425-5427.2005" href="https://dx.doi.org/10.1128%2FJCM.43.11.5425-5427.2005" rel="nofollow">10.1128/JCM.43.11.5425-5427.2005</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287823" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1287823" rel="nofollow">1287823</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/16272464" href="https://www.ncbi.nlm.nih.gov/pubmed/16272464" rel="nofollow">16272464</a>.</cite></span></li>
<li id="cite_note-6"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Anidulafungin#cite_ref-6" href="https://en.wikipedia.org/wiki/Anidulafungin#cite_ref-6"><span class="cite-accessibility-label">J</span></a></b></span> <span class="reference-text"><cite class="citation journal">Pfaller MA, Diekema DJ, Boyken L, Messer SA, Tendolkar S, Hollis RJ, Goldstein BP (2005). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280139" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280139" rel="nofollow">"Effectiveness of anidulafungin in eradicating Candida species in invasive candidiasis"</a>. <i>Antimicrob Agents Chemother</i> <b>49</b> (11): 4795–7. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1128%2FAAC.49.11.4795-4797.2005" href="https://dx.doi.org/10.1128%2FAAC.49.11.4795-4797.2005" rel="nofollow">10.1128/AAC.49.11.4795-4797.2005</a>.<a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280139" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280139" rel="nofollow">1280139</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/16251335" href="https://www.ncbi.nlm.nih.gov/pubmed/16251335" rel="nofollow">16251335</a>.</cite></span></li>
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<li id="cite_note-urlAnidulafungin-13"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000788/WC500020676.pdf" href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000788/WC500020676.pdf" rel="nofollow">"Anidulafungin EMA Europa"</a> (PDF).</cite></span></li>
</ol>
</div>
<table class="infobox mce-item-table" data-mce-style="height: 1165px;" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 1165px; line-height: 24px; width: 839px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Anidulafungin">Anidulafungin</span></caption><tbody>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Anidulafungin_Molecular_Structure_2.png" href="https://en.wikipedia.org/wiki/File:Anidulafungin_Molecular_Structure_2.png"><img alt="Anidulafungin Molecular Structure 2.png" data-file-height="536" data-file-width="278" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Anidulafungin_Molecular_Structure_2.png/230px-Anidulafungin_Molecular_Structure_2.png" height="443" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/4d/Anidulafungin_Molecular_Structure_2.png/230px-Anidulafungin_Molecular_Structure_2.png" srcset="//upload.wikimedia.org/wikipedia/commons/4/4d/Anidulafungin_Molecular_Structure_2.png 1.5x, //upload.wikimedia.org/wikipedia/commons/4/4d/Anidulafungin_Molecular_Structure_2.png 2x" style="height: auto; max-width: 100%;" width="230" /></a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" href="https://en.wikipedia.org/wiki/IUPAC_nomenclature_of_chemistry" title="IUPAC nomenclature of chemistry">Systematic</a> (IUPAC) name</th></tr>
<tr><td colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><i>N</i>-[(3<i>S</i>,6<i>S</i>,9<i>S</i>,11<i>R</i>,15<i>S</i>,18<i>S</i>,20<i>R</i>,21<i>R</i>,24<i>S</i>,25<i>S</i>,26<i>S</i>)-6-[(1<i>S</i>,2<i>R</i>)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-3,15-<i>bis</i>[(1<i>R</i>)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexaazatricyclo[22.3.0.0<sup>9,13</sup>]heptacosan-18-yl]- 4-{4-[4-(pentyloxy)phenyl]phenyl}benzamide</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Eraxis</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" href="https://en.wikipedia.org/wiki/American_Society_of_Health-System_Pharmacists" title="American Society of Health-System Pharmacists">AHFS</a>/<a data-mce-href="https://en.wikipedia.org/wiki/Drugs.com" href="https://en.wikipedia.org/wiki/Drugs.com" title="Drugs.com">Drugs.com</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugs.com"><a class="external text" data-mce-href="https://www.drugs.com/monograph/anidulafungin.html" href="https://www.drugs.com/monograph/anidulafungin.html" rel="nofollow">Monograph</a></span></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Plasma_protein_binding" href="https://en.wikipedia.org/wiki/Plasma_protein_binding" title="Plasma protein binding">Protein binding</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">84 %</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">40–50 hours</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=166663-25-8" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=166663-25-8" rel="nofollow">166663-25-8</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_J02" href="https://en.wikipedia.org/wiki/ATC_code_J02" title="ATC code J02">J02AX06</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=J02AX06" href="http://www.whocc.no/atc_ddd_index/?code=J02AX06" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=166548" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=166548" rel="nofollow">166548</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/DrugBank" href="https://en.wikipedia.org/wiki/DrugBank" title="DrugBank">DrugBank</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.drugbank.ca"><a class="external text" data-mce-href="http://www.drugbank.ca/drugs/DB00362" href="http://www.drugbank.ca/drugs/DB00362" rel="nofollow">DB00362</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.21106258.html" href="http://www.chemspider.com/Chemical-Structure.21106258.html" rel="nofollow">21106258</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=9HLM53094I" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=9HLM53094I" rel="nofollow">9HLM53094I</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/KEGG" href="https://en.wikipedia.org/wiki/KEGG" title="KEGG">KEGG</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.kegg.jp"><a class="external text" data-mce-href="http://www.kegg.jp/entry/D03211" href="http://www.kegg.jp/entry/D03211" rel="nofollow">D03211</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEBI" href="https://en.wikipedia.org/wiki/ChEBI" title="ChEBI">ChEBI</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:55346" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:55346" rel="nofollow">CHEBI:55346</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEMBL" href="https://en.wikipedia.org/wiki/ChEMBL" title="ChEMBL">ChEMBL</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1630215" href="https://www.ebi.ac.uk/chembldb/index.php/compound/inspect/CHEMBL1630215" rel="nofollow">CHEMBL1630215</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>58</sub><span title="Hydrogen">H</span><sub>73</sub><span title="Nitrogen">N</span><sub>7</sub><span title="Oxygen">O</span><sub>17</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1140.24 g/mol</td></tr>
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//////////FUNGIN, ANIDULAFUNGIN, <b>Eraxis</b> , <b>Ecalta, </b> <a data-mce-href="https://en.wikipedia.org/wiki/Semisynthesis" href="https://en.wikipedia.org/wiki/Semisynthesis" title="Semisynthesis">semisynthetic</a> <a data-mce-href="https://en.wikipedia.org/wiki/Echinocandin" href="https://en.wikipedia.org/wiki/Echinocandin" title="Echinocandin">echinocandin,</a> an<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Antifungal_medication" href="https://en.wikipedia.org/wiki/Antifungal_medication" title="Antifungal medication">antifungal drug</a>, FDA 2006, PFIZER, LY-307853, LY-329960, LY-333006, LY303366, VEC, VER-002, 166663-25-8, Eli Lilly and Company Inc.</div>
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CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]6C[C@@H](O)[C@@H](O)NC(=O)C4[C@@H](O)[C@@H](C)CN4C(=O)C(NC(=O)C(NC(=O)C5C[C@@H](O)CN5C(=O)C(NC6=O)[C@@H](C)O)[C@@H](O)[C@H](O)c7ccc(O)cc7)[C@@H](C)O</div>
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<a data-mce-href="http://pubs.acs.org/doi/suppl/10.1021/op800055h" href="http://pubs.acs.org/doi/suppl/10.1021/op800055h">Supporting Info</a></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-569892385714118127.post-28990423866219317692016-07-29T09:38:00.001+05:302016-07-29T09:56:22.557+05:30FDA approves Adlyxin (lixisenatide) 利西拉 to treat type 2 diabetes<div dir="ltr" style="text-align: left;" trbidi="on">
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07/28/2016 07:53 AM EDT</div>
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The U.S. Food and Drug Administration approved Adlyxin (lixisenatide), a once-daily injection to improve glycemic control (blood sugar levels), along with diet and exercise, in adults with type 2 diabetes.</div>
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<a data-mce-href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513602.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery" href="http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm513602.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery">For Immediate Release</a></h2>
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July 28, 2016</div>
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Release</h2>
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The U.S. Food and Drug Administration approved Adlyxin (lixisenatide), a once-daily injection to improve glycemic control (blood sugar levels), along with diet and exercise, in adults with type 2 diabetes.<br />
“The FDA continues to support the development of new drug therapies for diabetes management,” said Mary Thanh Hai Parks, M.D., deputy director, Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “Adlyxin will add to the available treatment options to control blood sugar levels for those with type 2.”<br />
Type 2 diabetes affects more than 29 million people and accounts for more than 90 percent of diabetes cases diagnosed in the United States. Over time, high blood sugar levels can increase the risk for serious complications, including heart disease, blindness and nerve and kidney damage.<br />
Adlyxin is a glucagon-like peptide-1 (GLP-1) receptor agonist, a hormone that helps normalize blood sugar levels. The drug’s safety and effectiveness were evaluated in 10 clinical trials that enrolled 5,400 patients with type 2 diabetes. In these trials, Adlyxin was evaluated both as a standalone therapy and in combination with other FDA-approved diabetic medications, including metformin, sulfonylureas, pioglitazone and basal insulin. Use of Adlyxin improved hemoglobin A1c levels (a measure of blood sugar levels) in these trials.<br />
In addition, more than 6,000 patients with type 2 diabetes at risk for atherosclerotic cardiovascular disease were treated with either Adlyxin or a placebo in a cardiovascular outcomes trial. Use of Adlyxin did not increase the risk of cardiovascular adverse events in these patients.<br />
Adlyxin should not be used to treat people with type 1 diabetes or patients with increased ketones in their blood or urine (diabetic ketoacidosis).<br />
The most common side effects associated with Adlyxin are nausea, vomiting, headache, diarrhea and dizziness. Hypoglycemia in patients treated with both Adlyxin and other antidiabetic drugs such as sulfonylurea and/or basal insulin is another common side effect. In addition, severe hypersensitivity reactions, including <a data-mce-href="https://www.nlm.nih.gov/medlineplus/anaphylaxis.html" href="https://www.nlm.nih.gov/medlineplus/anaphylaxis.html" target="_blank">anaphylaxis</a>, were reported in clinical trials of Adlyxin.<br />
The FDA is requiring the following post-marketing studies for Adlyxin:<br />
<ul>
<li>Clinical studies to evaluate dosing, efficacy and safety in pediatric patients.</li>
<li>A study evaluating the immunogenicity of lixisenatide.</li>
</ul>
Adlyxin is manufactured by Sanofi-Aventis U.S. LLC, of Bridgewater, New Jersey.<br />
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<img data-mce-src="http://www.chemicalbook.com/CAS/GIF/320367-13-3.gif" src="http://www.chemicalbook.com/CAS/GIF/320367-13-3.gif" style="height: auto; max-width: 100%;" /></div>
<table bgcolor="d5d5d5" border="0" cellpadding="2" cellspacing="1" class="mce-item-table" data-mce-style="height: 126px;" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; height: 126px; line-height: 24px; width: 579px;"><tbody>
<tr class="ProdSupplierGN_ProductA_2"><td bgcolor="#FFFFFF" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">lixisenatide;Lixisenatide|Lixisenatide Acetate;Lixisenatide Acetate</td></tr>
<tr class="ProdSupplierGN_ProductA_1"><td class="td1" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CAS:</td><td bgcolor="#fafafa" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.chemicalbook.com/Search_EN.aspx?keyword=320367-13-3" href="http://www.chemicalbook.com/Search_EN.aspx?keyword=320367-13-3"><b>320367-13-3</b></a></td></tr>
<tr class="ProdSupplierGN_ProductA_2"><td bgcolor="#FFFFFF" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MF:</td><td bgcolor="#FFFFFF" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">C215H347N61O65S</td></tr>
<tr class="ProdSupplierGN_ProductA_1"><td class="td1" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MW:</td><td bgcolor="#fafafa" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4858.53</td></tr>
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C<sub>215</sub> H<sub>347</sub> N<sub>61</sub> O<sub>65</sub> S</div>
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L-Lysinamide, L-histidylglycyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-α-glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-seryl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-</div>
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L-Histidylglycyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-α-glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-seryl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysinamide</h3>
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Lixisenatide</div>
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Lixisenatide</div>
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<tr><td class="breakword" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">827033-10-3; Lixisenatide [INN]; UNII-74O62BB01U; DesPro36Exendin-4(1-39)-Lys6-NH2; <a data-mce-href="https://www.ncbi.nlm.nih.gov/pcsubstance/?term=%22DesPro36Exendin-4(1-39)-Lys6-NH2%22%5BCompleteSynonym%5D%20AND%2016139342%5BStandardizedCID%5D" href="https://www.ncbi.nlm.nih.gov/pcsubstance/?term=%22DesPro36Exendin-4(1-39)-Lys6-NH2%22%5BCompleteSynonym%5D%20AND%2016139342%5BStandardizedCID%5D" rel="nofollow">DesPro36Exendin-4(1-39)-Lys6-NH2</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Formula:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C215H347N61O65S&sort=mw&sort_dir=asc" href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C215H347N61O65S&sort=mw&sort_dir=asc" title="Find all compounds with formula C215H347N61O65S">C<sub>215</sub>H<sub>347</sub>N<sub>61</sub>O<sub>65</sub>S</a></td></tr>
<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Molecular Weight:</th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4858.49038 g/mol</td></tr>
</tbody></table>
<div class="section-content-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<h5 class="minor-section-title">
IUPAC Condensed</h5>
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2</div>
<div class="reference" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="btn-text">from PubChem</span></div>
<div class="section-content-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<h5 class="minor-section-title">
LINUCS</h5>
[][L-Lys-NH2]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Ser]{[(1+2)][L-Pro]{[(1+2)][L-Pro]{[(1+2)][L-Ala]{[(1+2)][Gly]{[(1+2)][L-Ser]{[(1+2)][L-Ser]{[(1+2)][L-Pro]{[(1+2)][Gly]{[(1+2)][Gly]{[(1+2)][L-Asn]{[(1+2)][L-Lys]{[(1+2)][L-Leu]{[(1+2)][L-Trp]{[(1+2)][L-Glu]{[(1+2)][L-Ile]{[(1+2)][L-Phe]{[(1+2)][L-Leu]{[(1+2)][L-Arg]{[(1+2)][L-Val]{[(1+2)][L-Ala]{[(1+2)][L-Glu]{[(1+2)][L-Glu]{[(1+2)][L-Glu]{[(1+2)][L-Met]{[(1+2)][L-Gln]{[(1+2)][L-Lys]{[(1+2)][L-Ser]{[(1+2)][L-Leu]{[(1+2)][L-Asp]{[(1+2)][L-Ser]{[(1+2)][L-Thr]{[(1+2)][L-Phe]{[(1+2)][L-Thr]{[(1+2)][Gly]{[(1+2)][L-Glu]{[(1+2)][Gly]{[(1+2)][L-His]{}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}</div>
<div class="reference" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="btn-text">from PubChem</span></div>
<div class="section-content-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<h5 class="minor-section-title">
Sequence</h5>
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK</div>
<div class="reference" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="btn-text">from PubChem</span></div>
<div class="section-content-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<h5 class="minor-section-title">
PLN</h5>
H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-[NH2]</div>
<div class="reference" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="btn-text">from PubChem</span></div>
<div class="section-content-item" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<h5 class="minor-section-title">
HELM</h5>
PEPTIDE1{H.G.E.G.T.F.T.S.D.L.S.K.Q.M.E.E.E.A.V.R.L.F.I.E.W.L.K.N.G.G.P.S.S.G.A.P.P.S.K.K.K.K.K.K.[am]}$$$$</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img data-mce-src="https://www.researchgate.net/profile/Stephen_Bain/publication/263972071/figure/fig3/AS:271701619507205@1441790122312/Figure-2-Peptide-sequence-of-lixisenatide-and-other-GLP-1-receptor-agonists-Peptide.png" src="https://www.researchgate.net/profile/Stephen_Bain/publication/263972071/figure/fig3/AS:271701619507205@1441790122312/Figure-2-Peptide-sequence-of-lixisenatide-and-other-GLP-1-receptor-agonists-Peptide.png" style="height: auto; max-width: 100%;" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<b><br /></b>
<strong style="background-color: white; color: #3d596d; font-family: Merriweather, Georgia, "Times New Roman", Times, serif; font-size: 15px; line-height: 25.5px;"><em><span data-mce-style="color: #800080;" style="color: purple;"><a data-mce-style="color: #800080;" href="https://www.blogger.com/null" style="outline: 0px;">Sanofi</a> (formerly sanofi-aventis, formerly Aventis), under license from <a data-mce-style="color: #800080;" href="https://www.blogger.com/null">Zealand Pharma</a>, has developed and launched lixisenatide</span></em></strong><br />
<b><br /></b>
<b>Lixisenatide</b> (trade name <b>Lyxumia</b>) is a once-daily injectable <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/GLP-1_receptor_agonist" href="https://en.wikipedia.org/wiki/GLP-1_receptor_agonist" title="GLP-1 receptor agonist">GLP-1 receptor agonist</a> for the treatment of <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Diabetes" href="https://en.wikipedia.org/wiki/Diabetes" title="Diabetes">diabetes</a>, discovered by Zealand Pharma A/S of Denmark and licensed and developed by <a data-mce-href="https://en.wikipedia.org/wiki/Sanofi" href="https://en.wikipedia.org/wiki/Sanofi" title="Sanofi">Sanofi</a>.<sup class="reference" id="cite_ref-1"><a data-mce-href="https://en.wikipedia.org/wiki/Lixisenatide#cite_note-1" href="https://en.wikipedia.org/wiki/Lixisenatide#cite_note-1">[1]</a></sup> Lixisenatide was accepted for review by the US FDA on February 19, 2013, and approved by the European Commission on February 1, 2013.<sup class="reference" id="cite_ref-2"><a data-mce-href="https://en.wikipedia.org/wiki/Lixisenatide#cite_note-2" href="https://en.wikipedia.org/wiki/Lixisenatide#cite_note-2">[2]</a></sup> On September 12, 2013, Sanofi delayed the approval process in the US, citing internal data from a cardiovascular risk study. The drug will likely be resubmitted for approval in 2015.</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Lixisenatide is a once-daily injectable GLP-1 receptor agonist discovered by Zealand Pharma A/S of Denmark and licensed and developed by Sanofi. As of September 2010 it is in clinical trials for diabetes. Lixisenatide was accepted for review by the US FDA on February 19, 2013, and approved by the European Commission on February 1, 2013. The drug will likely be resubmitted for approval in 2015.</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Mechanism_of_action">Mechanism of action</span></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
GLP-1 is a naturally-occurring peptide that is released within minutes of eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and stimulate insulin secretion by pancreatic beta cells. GLP-1 receptor agonists are used as an add-on treatment for type 2 diabetes and their use is endorsed by the European Association for the Study of Diabetes, the American Diabetes Association, the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/American_Association_of_Clinical_Endocrinologists_(AACE)" href="https://en.wikipedia.org/wiki/American_Association_of_Clinical_Endocrinologists_(AACE)" title="American Association of Clinical Endocrinologists (AACE)">American Association of Clinical Endocrinologists</a> and the American College of Endocrinology.</div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="mw-headline" id="Physical_and_chemical_properties">Physical and chemical properties</span></h2>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Lixisenatixe has been described as "des-38-proline-exendin-4 (<i>Heloderma suspectum</i>)-(1–39)-peptidylpenta-<small>L</small>-lysyl-<small>L</small>-lysinamide", meaning it is derived from the first 39 amino acids in the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Amino_acid_sequence" href="https://en.wikipedia.org/wiki/Amino_acid_sequence" title="Amino acid sequence">sequence</a> of the peptide <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=Exendin-4&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=Exendin-4&action=edit&redlink=1" title="Exendin-4 (page does not exist)">exendin-4</a>, found in the <a data-mce-href="https://en.wikipedia.org/wiki/Gila_monster" href="https://en.wikipedia.org/wiki/Gila_monster" title="Gila monster">Gila monster</a> (<i>Heloderma suspectum</i>), omitting <a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">proline</a> at position 38 and adding six <a data-mce-href="https://en.wikipedia.org/wiki/Lysine" href="https://en.wikipedia.org/wiki/Lysine" title="Lysine">lysine</a> residues. Its complete sequence is:<sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/Lixisenatide#cite_note-3" href="https://en.wikipedia.org/wiki/Lixisenatide#cite_note-3">[3]</a></sup></div>
<dl style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><dd>H–<a data-mce-href="https://en.wikipedia.org/wiki/Histidine" href="https://en.wikipedia.org/wiki/Histidine" title="Histidine">His</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Glycine" href="https://en.wikipedia.org/wiki/Glycine" title="Glycine">Gly</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Glutamic_acid" href="https://en.wikipedia.org/wiki/Glutamic_acid" title="Glutamic acid">Glu</a>–Gly–<a data-mce-href="https://en.wikipedia.org/wiki/Threonine" href="https://en.wikipedia.org/wiki/Threonine" title="Threonine">Thr</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Phenylalanine" href="https://en.wikipedia.org/wiki/Phenylalanine" title="Phenylalanine">Phe</a>–Thr–<a data-mce-href="https://en.wikipedia.org/wiki/Serine" href="https://en.wikipedia.org/wiki/Serine" title="Serine">Ser</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Aspartic_acid" href="https://en.wikipedia.org/wiki/Aspartic_acid" title="Aspartic acid">Asp</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Leucine" href="https://en.wikipedia.org/wiki/Leucine" title="Leucine">Leu</a>–Ser–<a data-mce-href="https://en.wikipedia.org/wiki/Lysine" href="https://en.wikipedia.org/wiki/Lysine" title="Lysine">Lys</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Glutamine" href="https://en.wikipedia.org/wiki/Glutamine" title="Glutamine">Gln</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Methionine" href="https://en.wikipedia.org/wiki/Methionine" title="Methionine">Met</a>–Glu–Glu–Glu–<a data-mce-href="https://en.wikipedia.org/wiki/Alanine" href="https://en.wikipedia.org/wiki/Alanine" title="Alanine">Ala</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Valine" href="https://en.wikipedia.org/wiki/Valine" title="Valine">Val</a>–<a data-mce-href="https://en.wikipedia.org/wiki/Arginine" href="https://en.wikipedia.org/wiki/Arginine" title="Arginine">Arg</a>–Leu–Phe–<a data-mce-href="https://en.wikipedia.org/wiki/Isoleucine" href="https://en.wikipedia.org/wiki/Isoleucine" title="Isoleucine">Ile</a>–Glu–<a data-mce-href="https://en.wikipedia.org/wiki/Tryptophan" href="https://en.wikipedia.org/wiki/Tryptophan" title="Tryptophan">Trp</a>–Leu–Lys–<a data-mce-href="https://en.wikipedia.org/wiki/Asparagine" href="https://en.wikipedia.org/wiki/Asparagine" title="Asparagine">Asn</a>–Gly–Gly–<a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">Pro</a>–Ser–Ser–Gly–Ala–Pro–Pro–Ser–Lys–Lys–Lys–Lys–Lys–Lys–NH<sub>2</sub></dd></dl>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
US 20110313131</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.co.in/patents/US20110313131" href="http://www.google.co.in/patents/US20110313131">http://www.google.co.in/patents/US20110313131</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">PATENT</span></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CN 105713082</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The title method comprises the steps of: (1) coupling Fmoc-Lys(Boc)-OH and resin to obtain Fmoc-Lys(Boc)-resin, (2) protecting amino acid with Fmoc, conducting solid-phase synthesis to obtain lixisenatide wholly protected 20-44-peptide resin, (3) conducting solid-phase synthesis to obtain wholly protected 15-19-peptide resin, (4) coupling the wholly protected 20-44-peptide resin and wholly protected 15-19-peptide resin, (5) coupling other amino acids till solid-phase synthesis finishes, (6) cracking lixisenatide peptide resin to obtain crude peptide, and (7) purifying through RP-HPLC. The method improves crude peptide purity and purifn. yield.</div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
PATENT</h1>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<a data-mce-href="http://www.google.com/patents/CN104211801A?cl=en" href="http://www.google.com/patents/CN104211801A?cl=en" target="_blank">CN104211801A</a></h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">利西拉, the English name: Lixisenatide, is a polypeptide containing 44 amino acids, the structural formula is as follows: peptide sequence as follows:</span></div>
<div class="patent-image small-patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://patentimages.storage.googleapis.com/CN104211801A/CN104211801AD00031.png" href="https://patentimages.storage.googleapis.com/CN104211801A/CN104211801AD00031.png"><img alt="Figure CN104211801AD00031" class="patent-full-image" data-mce-src="https://patentimages.storage.googleapis.com/CN104211801A/CN104211801AD00031.png" id="idf0001" src="https://patentimages.storage.googleapis.com/CN104211801A/CN104211801AD00031.png" style="height: auto; max-width: 100%;" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Al a-Val-Arg-Leu-Phe-IIe-Glu -Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pr O-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH 2 Li Xila to (Lixisenatide ) by Sanofi-Aventis developed once a day subcutaneously with glucagon-like peptide -I (GLP-I) receptor agonists, for the treatment of type II diabetes, on February 1, 2013 Sanofi Lee Division -Aventis of exenatide is approved EMEA, for the adjuvant treatment of poorly stable dose of basal insulin (or metformin) in the treatment of type II diabetes to improve HbAlc and postprandial blood glucose levels.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">CN201210030151. 2 used in a pure solid phase sequential coupling method synthetic peptides.</span> <span class="notranslate">The method amino resin as the carrier, using conventional coupling sequence, the final cut to give Li Xila.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate"> US6528486 patent for the compound, synthetic methods mentioned it to phase condensation method Fmoc / tBu strategy.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">The [0005] W02005058954 synthesis method including the gradual condensation process Fmoc / tBu strategy, Boc strategy of gradual condensation methods and genetic engineering.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">The W02001004156 synthesis method for the gradual condensation process Fmoc / tBu strategy.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate"> Since Li Xila abroad mostly used to synthesize Fmoc solid phase synthesis method, a gradual shrinking gradually synthesis step more, resulting in more types of product impurities, US 20130284912 Special Report polypeptide impurity: Di-Ser33- Leisy pull and Di-Ala35- Li Xila come, Di-Ser 33- Li Xila come and Di-Ala35- Li Xila to atmosphere amino acid sequence as follows: Di-Ser33- Li Xila to the amino acid sequence: H-His -Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Al a-Val-Arg-Leu-Phe-IIe-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Ser-Gly-Ala-Pr 〇-Pr〇-Ser-Lys_Lys_Lys_Lys_Lys_LyS-NH2 Di-Ala35- Li Xila to the amino acid sequence: H-His-Gly- Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Al a-Val-Arg-Leu-Phe-IIe-Glu-Trp-Leu-Lys -Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Ala-Pr 〇-Pr〇-Ser-Lys_Lys_Lys_Lys_Lys_LyS-NH2 toxicity of these impurities are impurities larger, and very difficult to separate from the main peak , the presence of the impurities seriously affect 利西拉 to content and the use of safety.</span> <span class="notranslate">Hence the need to find an effective way to remove it and to reach the high standard level of 0.1% or less.</span> <span class="notranslate">The present inventors have found that this impurity is difficult to remove by means of the prior art, although there are ways to remove part of, but removal is not ideal, it is difficult to achieve high quality standards is likely to cause 利西拉 level while reducing their yield.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">In summary, the existing Li Xila to the solid phase synthesis, low yield of the synthesis, impurities, in particular, are not well controlled impurity Di-Ser 33- Li Xila come and Di-Ala35 - Li Xila to, does not apply to industrial production</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Example i ^ a: Preparation 利西拉 to fine peptide acetate Weigh 利西拉 above 44. 70g to 45L crude peptide was dissolved in water, purified by C18 column, the first purification conditions: mobile phase: A phase: 0 I% TFA; B phase: acetonitrile; gradient program was: 15% B, 60 minutes to 60% B; detection wavelength 220 nm; peak fraction collection purposes.</span> <span class="notranslate">The second purification conditions: mobile phase was: A phase: 0 3% HAC; B phase: acetonitrile; gradient program was: 10% B, 60 minutes to 60% B; detection wavelength 220 nm; peak fraction collection purposes.</span> <span class="notranslate">Desalting conditions: Mobile phase: A phase: an aqueous solution of 20 mmol / L ammonium acetate: acetonitrile = 95: 5; B phase: water: acetonitrile = 95: 5; C phase: 0.03% aqueous solution of acetic acid: acetonitrile = 95 : 5; D phase: 0.03% aqueous solution of acetic acid: acetonitrile = 50: 50; gradient program: mobile phase A isocratic for 15 minutes, convert isocratic mobile phase B for 10 minutes, is converted into the flow Phase C isocratic 10 minutes, converted into a mobile phase D isocratic 25 minutes; detection wavelength 220 nm; peak fraction collection purposes; rotary evaporation concentrated and lyophilized to give Li Xila acetate fine peptide 22. 65g which HPLC spectrum shown in Figure 5, HPLC purity of 99.75% (area normalization method), Di-Ser33- Li Xila come to 0.03% (area normalization method), Di-Ala35- Li Xila to the content of 0.05% (area normalization method).</span> <span class="notranslate">Purification total yield of 51%, total yield 41%.</span> <span class="notranslate">Its mass spectrum as shown in Figure 6, [M + H] + = 4858. 691, 利西拉 precise molecular weight to the theoretical: 4857.53, the sample mass is consistent with the theoretical molecular weight.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/CN103709243A?cl=en" href="https://www.google.com/patents/CN103709243A?cl=en">CN 103709243</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Example 2: Preparation 利西拉 to crude peptide</span></div>
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<span class="notranslate">利西拉 [0116] Example 24 was prepared to be placed 125.4g peptide resin cleavage reaction to 10ml / g resin ratio added lysis reagent (TFA: thioanisole: EDT: TIS: water = 86: 5 : 5: 3: 1 (V / V)), stirred at room temperature 2.5h.</span> <span class="notranslate">The reaction was purified by frit funnel filtration, the filtrate was collected, the resin was washed 3 times and then a small amount of TFA, the combined filtrates concentrated under reduced pressure.</span> <span class="notranslate">Frozen precipitation in anhydrous ether was added, washed three times with anhydrous diethyl ether, and dried in vacuo to give a white solid powder, i.e. Li Xila to crude peptide 47.lg, by weight of the crude peptide yield 97.2%, HPLC purity 63.8% 0</span></div>
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<span class="notranslate">利西拉 to crude peptide preparation: 27 patients [0117] Example</span></div>
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<span class="notranslate">利西拉 [0118] The Example 25 was prepared to be placed 123.7g peptide resin cleavage reaction to 10ml / g resin ratio added lysis reagent (TFA: thioanisole: EDT: TIS: water = 86: 5 : 5: 3: 1 (V / V)), stirred at room temperature 2.5h.</span> <span class="notranslate">The reaction was purified by frit funnel filtration, the filtrate was collected, the resin was washed 3 times and then a small amount of TFA, the combined filtrates concentrated under reduced pressure.</span> <span class="notranslate">Frozen precipitation in anhydrous ether was added, washed three times with anhydrous diethyl ether, and dried in vacuo to give a white solid powder, i.e. Li Xila to crude peptide 46.9g, yield the crude peptide by weight 96.5%, HPLC purity 64.2% 0</span></div>
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<span class="notranslate">28 Example 2: Preparation 利西拉 to fine peptide acetate</span></div>
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<span class="notranslate"> Example weighed 26 to 27 after 利西拉 to any 30.0g crude peptide was dissolved in 3000ml of water using Waters2545RP-HPLC system, wavelength 230nm, 50 X 250mm column of reverse phase C18 column, 0.2% TFA conventional / acetonitrile mobile phase were fractionated peaks of fractions, refined peptide purity greater than 98.5%.</span> <span class="notranslate">The fine peptide solution using Waters2545RP-HPLC system, 50 X 250mm column was C18 reverse phase column, 0.1% acetic acid / acetonitrile mobile phase transfer salt, the purpose of peak fractions were collected, concentrated by rotary evaporation and lyophilized to give Li Xila acetate fine salt peptide> 9.0g, RP-HPLC purity ≥98.5%.</span> <span class="notranslate">Purification Yield ≥30%, total yield ≥29.0%.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
CN 102875663</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.at/patents/CN102875663B?cl=en" href="http://www.google.at/patents/CN102875663B?cl=en">http://www.google.at/patents/CN102875663B?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Example 9</span></div>
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<span class="notranslate">[0239] The crude peptide Li Xila to 4000g (including Li Xila to 1139g) was dissolved with purified water 100L, collected by filtration and the filtrate set aside.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0240] purification chromatographic conditions:</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0241] HPLC Model: Novasep LC450</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate"> Column: 450X250mm, built-phenyl silane bonded silica gel as stationary phase filler, the filler particle size of 10 μ m0</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate"> flow rate: 5000ml / min.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">The detection wavelength: 280nm.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate"> Mobile phase A phase: 10% 30mM D- 30mM sodium tartrate and disodium hydrogenphosphate in methanol / 90% aqueous (v / v), adjusted to pH 2.5 with phosphoric acid.</span></div>
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<span class="notranslate">[0246] Mobile phase A phase preparation process: Weigh 1280g 2070g D- sodium tartrate and disodium hydrogenphosphate, after an appropriate amount of purified water was dissolved through 0.45 μ m membrane filter, the filtrate collected all 300L tank, added 30L chromatographically pure After methanol was added to the 300L scale purification of water, adjusted to pH 2.5 with phosphoric acid.</span> <span class="notranslate">Repeat preparation run.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0247] The mobile phase B phase: HPLC grade acetonitrile.</span></div>
<div class="patent-image small-patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00132.png" href="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00132.png"><img alt="Figure CN102875663BD00132" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00132.png" src="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00132.png" id="idf0020" style="height: auto; max-width: 100%;" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0249] sample volume: 250.0g (6250ml).</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0250] Purification: column equilibration the sample so that after 5 minutes, run a gradient purification, monitoring and staging purposes peak fractions were collected.</span> <span class="notranslate">The collected fractions (chromatographic conditions purity testing to the same conditions as above 利西拉 determination to area normalization method measured) purity test, the purity of greater than or equal to 98% of the fractions after removing most of the acetonitrile in turn salt; purity of 70% or more less than 98% of the fraction recovered after removal of most of the acetonitrile and the purification procedure is repeated, again collected purity greater than or equal to 98% of the fraction after removal of most of the acetonitrile are also used to turn salt; purity of less than 70 % of fractions by waste disposal.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0251] points and 16 injections, repeat the above operation.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0252] turn salt chromatographic conditions:</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0253] HPLC Model: Novasep LC450</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0254] Column: 450 X 250mm, built-C8 reversed-phase chromatography packing, the particle size of the filler is 10 μ m.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0255] flow rate: 5000ml / min.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0256] The detection wavelength: 280nm.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0257] Mobile phase A phase: 0.2% acetic acid (v / v) solution.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0258] The mobile phase B phase: HPLC grade acetonitrile.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0259] gradient</span></div>
<div class="patent-image small-patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00141.png" href="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00141.png"><img alt="Figure CN102875663BD00141" class="patent-full-image" data-mce-src="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00141.png" src="http://patentimages.storage.googleapis.com/CN102875663B/CN102875663BD00141.png" id="idf0021" style="height: auto; max-width: 100%;" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0260] sample volume: 2500ml.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0261] Purification: The column equilibration the sample for 5 minutes, run a gradient purification, monitoring and collecting the target peak fractions.</span> <span class="notranslate">The purpose of the peak fractions were concentrated by rotary evaporation under reduced pressure to 9000ml after lyophilization.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0262] After the freeze-dried to give a white powder refined peptide 704g.</span> <span class="notranslate">Purity of 98.39%, the impurity content of less than 0.5%.</span> <span class="notranslate">Purification yield 61.8% (in crude Li Xila to content), total yield of 17.6%.</span></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
PATENT</h1>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://www.google.com/patents/CN102558338B?cl=en" href="https://www.google.com/patents/CN102558338B?cl=en">CN 102558338</a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<strong><em><span data-mce-style="color: #ff6600;" style="color: #ff6600;">MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR</span></em></strong></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">Preparation of Fmoc-Lys (Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -Rink Amide-MBHAResin:</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0096] To the resulting Fmoc-Lys (Boc) -Lys (Boc) -Lys (Boc) -RinkAmide-MBHAResin mouth of a 20% strength piperidine / DMF solution for 10 minutes, the reaction was drained, washed with DMF Resin 6 (50ml * 6).</span> <span class="notranslate">Weigh Fmoc-Lys (Boc) -〇H3.52g, H0Bt1.01g, HBTU2.84g, TMP1.98ml, DMF50ml added to dissolve slowly with stirring under ice-cooling for 3 minutes, at room temperature for 2 hours, the reaction Ninhydrin detection method completed, pumping off the reaction solution, DMF the resin was washed twice (50mlX2), DCM the resin was washed twice (50mlX2), to give Fmoc-Lys (B oc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -RinkAmide-MBHAResin.</span> <span class="notranslate">As used in the above operation Fmoc-Lys (Boc) -OH: HOBt: HBTU: TMP ratio is 1: 1: 1: 2, wherein Fmoc-Lys (Boc) -OH is the number of moles of Fmoc-RinkAmide-MBHAResin number of moles 3 times.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0097] Li Xila fully protected side chain was prepared to -Rink Amide-MBHA Resin:</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0098] To the resulting Fmoc-Lys (Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -RinkAmide-MBHA Resin added 20% piperidine / DMF solution for 10 minutes, drained reaction solution, washed 6 times with DMF.</span> <span class="notranslate">Weigh Jie 111〇 (3-1 ^ 8 billion (3) -0 13.528, 1 (»Shu 1.018,01 (:!! 1.391111 added 50,111,101 ^ dissolve slowly stirring for 3 minutes in an ice bath, poured into the solid phase resin is mixed with the reaction column, at room temperature for 2 hours, the reaction Ninhydrin detection method is completed, the reaction solution was deprived, DMF the resin was washed twice (50ml X 2), DCM the resin was washed twice (50ml X 2), to give Fmoc-Lys ( Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -Rink Amide-MBHAResin above operation used by the Fmoc-Lys (Boc) -〇H:. HOBt: DIC ratio is 1: 1: L2, which Fmoc-Lys (Boc) is three times the number of moles -〇H Fmoc-Rink Amide-MBHA Resin moles of repeat after the coupling step, followed by the completion of the 39 lysine to first. connecting protected amino acids histidine, followed by addition of 20% piperidine / DMF solution for 10 minutes, the reaction was drained, DMF the resin was washed six times (50ml X 6), DCM the resin was washed six times (50ml X 6 ), MeOH contraction of the resin three times with MeOH 50ml, each contraction 5min. After the resin was dried in vacuo to give a full side-chain protected peptide resin to the Li Xila 27. 5g, weight resin 17. 5g.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0099] Li Xila to crude peptide preparation:</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0100] Weigh side chains fully protected Li Xila to -Rink Amide-MBHA Resin 27. 5 grams, into a round bottom flask.</span><span class="notranslate">Configuration 275 ml lysis buffer, wherein trifluoroacetic acid: thioanisole: ethanedithiol: anisole, phenol = 93: 4: 1: 1.5: 2 (volume ratio).</span> <span class="notranslate">Lysate in the refrigerator after the pre-freeze 1 hour before Sheng Youli put to Silas to -Rink Amide-MBHA Resin round bottom flask, stirred at room temperature for 2 hours.</span> <span class="notranslate">The reaction mixture was filtered, the resin was washed with 20ml TFA and the combined filtrate.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0101] The volume of the filtrate was slowly poured into 2,750 ml of diethyl ether frozen (frozen advance ether), a white precipitate appears, at 3000 rpm / centrifuged 5 minutes, the resulting solid was washed twice with ether, then the solid was dried under vacuum to give Li Xila trifluoroacetate crude peptide to 15. 3g.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0102] Li Xila to large scale production of fine peptide:</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0103] Sample Preparation: The crude peptide was dissolved in water, the sample was completely dissolved by membrane filtration, the filtrate was collected for use.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0104] Purification conditions: Column: octadecyl silane bonded silica gel as stationary phase column, the column diameter and length: 300_X250mm.</span> <span class="notranslate">Mobile phase: A phase: 35mm〇l / L phosphoric acid solution adjusted with triethylamine to pH 6. 7; B phase: acetonitrile, flow rate: 2200ml / min, Gradient: B%: 12% ~32%, detection wavelength: 280nm .</span> <span class="notranslate">The injection volume was 75g.</span> <span class="notranslate">Purification process: the column with 50% acetonitrile rinse clean after balance sample, sample amount is 75g.</span> <span class="notranslate">Linear gradient 120min, the purpose of collecting peaks will be collected 利西拉 solution was concentrated by rotary evaporation under reduced pressure to about 80mg / ml and reserve the water temperature exceeds 40 ° C without conditions.</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="notranslate">[0105] turn salt: turn salt conditions: Column: octadecyl silane bonded silica gel as stationary phase column, the column diameter and length: 300mmX250mm.</span> <span class="notranslate">Mobile phase: A phase: mass concentration of 0.2% aqueous acetic acid; B phase: HPLC grade acetonitrile, flow rate: 2200ml / min, detection wavelength: 280nm.</span> <span class="notranslate">Gradient: B%: 6% ~36%.</span> <span class="notranslate">The injection volume was 48-60g.</span> <span class="notranslate">Salt transfer process: the column with 50% acetonitrile rinse clean after the sample, the sample volume is 1600ml sample solution.</span> <span class="notranslate">Linear gradient 90min, the purpose of collecting peaks collected Li Xila to solutions were concentrated by rotary evaporation to about 80ml / g after go to the appropriate size vials, then freeze-dried to obtain the purity of greater than 99.5% The Li Xila come.</span></div>
<h1 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
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lixisenatide</div>
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Sanofi Provides Update on Lixisenatide New Drug Application in U.S.</div>
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Paris, France – September 12, 2013 – Sanofi (EURONEXT: SAN and NYSE: SNY) announced today its decision to withdraw the lixisenatide New Drug Application (NDA) in the U.S., which included early interim results from the ongoing ELIXA cardiovascular (CV) outcomes study. The company plans to resubmit the NDA in 2015, after completion of the ELIXA CV study.</div>
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The decision to withdraw the lixisenatide application follows discussions with the U.S. Food and Drug Administration (FDA) regarding its proposed process for the review of interim data. Sanofi believes that potential public disclosure of early interim data, even with safeguards, could potentially compromise the integrity of the ongoing ELIXA study. Sanofi’s decision is not related to safety issues or deficiencies in the NDA………………………read all at</div>
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<a data-mce-href="http://www.pharmalive.com/sanofi-pulls-diabetes-drug-nda" href="http://www.pharmalive.com/sanofi-pulls-diabetes-drug-nda">http://www.pharmalive.com/sanofi-pulls-diabetes-drug-nda</a></div>
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EU</div>
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<img alt="" data-mce-src="https://i0.wp.com/diatribe.us/sites/default/files/images/Lyxumia%2020%20and%2010%20mcg%20and%20package%20v3.jpg" height="328" src="https://i0.wp.com/diatribe.us/sites/default/files/images/Lyxumia%2020%20and%2010%20mcg%20and%20package%20v3.jpg" style="height: auto; max-width: 100%;" width="492" /></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
</h2>
<div class="patent-section patent-tabular-section" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><tbody>
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<div class="patent-section patent-tabular-section" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187);"><thead class="patent-data-table-thead">
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</thead><tbody>
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<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><tbody>
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</tbody></table>
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<span class="mw-headline" id="References">References</span></h2>
<div class="reflist columns references-column-count references-column-count-2" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<ol class="references">
<li id="cite_note-1"> <span class="reference-text"><cite class="citation journal">Christensen, M; Knop, FK; Holst, JJ; Vilsboll, T (2009). "Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus". <i>IDrugs : the investigational drugs journal</i> <b>12</b> (8): 503–13. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/19629885" href="https://www.ncbi.nlm.nih.gov/pubmed/19629885" rel="nofollow">19629885</a>.</cite></span></li>
<li id="cite_note-2"> <span class="reference-text"><cite class="citation news"><a class="external text" data-mce-href="http://www.drugs.com/nda/lixisenatide_130219.html" href="http://www.drugs.com/nda/lixisenatide_130219.html" rel="nofollow">"Sanofi New Drug Application for Lixisenatide Accepted for Review by FDA"</a>. Drugs.com/PR Newsire. 19 February 2013.</cite></span></li>
<li id="cite_note-3"> <span class="reference-text"><cite class="citation journal"><a class="external text" data-mce-href="http://www.who.int/medicines/publications/druginformation/innlists/RL61final.pdf" href="http://www.who.int/medicines/publications/druginformation/innlists/RL61final.pdf" rel="nofollow">"International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 61"</a> (PDF). <i>WHO Drug Information</i> <b>23</b> (1): 66f. 2009.</cite></span></li>
</ol>
</div>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Lixisenatide">Lixisenatide</span></caption><tbody>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Lyxumia</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">License data</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small>EU</small> <a data-mce-href="https://en.wikipedia.org/wiki/European_Medicines_Agency" href="https://en.wikipedia.org/wiki/European_Medicines_Agency" title="European Medicines Agency">EMA</a>: <span title="www.ema.europa.eu"><a class="external text" data-mce-href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Lixisenatide" href="http://www.ema.europa.eu/ema/index.jsp?curl=%2Fpages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=&searchTab=searchByKey&alreadyLoaded=true&isNewQuery=true&status=Authorised&status=Withdrawn&status=Suspended&status=Refused&keywordSearch=Submit&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=generics&keyword=Lixisenatide" rel="nofollow">Lixisenatide</a></span></li>
</ul>
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</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Subcutaneous_injection" href="https://en.wikipedia.org/wiki/Subcutaneous_injection" title="Subcutaneous injection">Subcutaneous injection</a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United Kingdom">UK</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">POM</a> (Prescription only)</li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=827033-10-3" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=827033-10-3" rel="nofollow">827033-10-3</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_A10" href="https://en.wikipedia.org/wiki/ATC_code_A10" title="ATC code A10">A10BX10</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=A10BX10" href="http://www.whocc.no/atc_ddd_index/?code=A10BX10" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/PubChem" href="https://en.wikipedia.org/wiki/PubChem" title="PubChem">PubChem</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CID <span title="pubchem.ncbi.nlm.nih.gov"><a class="external text" data-mce-href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=16139342" href="https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=16139342" rel="nofollow">16139342</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/IUPHAR/BPS" href="https://en.wikipedia.org/wiki/IUPHAR/BPS" title="IUPHAR/BPS">IUPHAR/BPS</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.guidetopharmacology.org"><a class="external text" data-mce-href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7387" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7387" rel="nofollow">7387</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.chemspider.com"><a class="external text" data-mce-href="http://www.chemspider.com/Chemical-Structure.17295846.html" href="http://www.chemspider.com/Chemical-Structure.17295846.html" rel="nofollow">17295846</a></span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChEBI" href="https://en.wikipedia.org/wiki/ChEBI" title="ChEBI">ChEBI</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.ebi.ac.uk"><a class="external text" data-mce-href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:85662" href="https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:85662" rel="nofollow">CHEBI:85662</a></span></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>215</sub><span title="Hydrogen">H</span><sub>347</sub><span title="Nitrogen">N</span><sub>61</sub><span title="Oxygen">O</span><sub>65</sub><span title="Sulfur">S</span></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4858.49 g/mol</td></tr>
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///////FDA 2016, SANOFI, FDA, approves , Adlyxin, lixisenatide, type 2 diabetes, Sanofi-Aventis U.S. LLC, Bridgewater, New Jersey, <b>Lyxumia, 利西拉, PEPTIDE, </b></div>
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CCC(C)C(C(=O)NC(CCC(=O)O)C(=O)NC(Cc1c[nH]c2c1cccc2)C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(=O)N)C(=O)NCC(=O)NCC(=O)N3CCCC3C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N4CCCC4C(=O)N5CCCC5C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)N)NC(=O)C(Cc6ccccc6)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCSC)NC(=O)C(CCC(=O)N)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(Cc7ccccc7)NC(=O)C(C(C)O)NC(=O)CNC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(Cc8cnc[nH]8)N</div>
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AND</div>
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CCC(C)C(C(=O)NC(CCC(=O)O)C(=O)NC(CC1=CNC2=CC=CC=C21)C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(=O)N)C(=O)NCC(=O)NCC(=O)N3CCCC3C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N4CCCC4C(=O)N5CCCC5C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)N)NC(=O)C(CC6=CC=CC=C6)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCSC)NC(=O)C(CCC(=O)N)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(CC7=CC=CC=C7)NC(=O)C(C(C)O)NC(=O)CNC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(CC8=CN=CN8)N</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-569892385714118127.post-67120445067480568232016-07-17T12:58:00.001+05:302016-07-18T16:18:49.094+05:30Sreeni Labs Private Limited, Hyderabad, India ready to deliver New, Economical, Scalable Routes to your advanced intermediates & API's in early Clinical Drug Development Stages<div dir="ltr" style="text-align: left;" trbidi="on">
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<span data-mce-style="color: #ff0000;" style="color: red;"><em><strong>Sreeni Labs Private Limited, Hyderabad, India is ready to take up challenging synthesis projects from your preclinical and clinical development and supply from few grams to multi-kilo quantities. Sreeni Labs has proven route scouting ability to design and develop innovative, cost effective, scalable routes by using readily available and inexpensive starting materials. The selected route will be further developed into a robust process and demonstrate on kilo gram scale and produce 100's of kilos of in a relatively short time.</strong></em></span></div>
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<span data-mce-style="color: #800080;" style="color: purple;">Accelerate your early development at competitive price by taking your route selection, process development and material supply challenges (gram scale to kilogram scale) to Sreeni Labs…………</span></div>
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<span data-mce-style="color: #0000ff;" style="color: blue;">INTRODUCTION</span></h2>
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Sreeni Labs based in Hyderabad, India is working with various global customers and solving variety of challenging synthesis problems. Their customer base ranges from USA, Canada, India and Europe. Sreeni labs Managing Director, Dr. Sreenivasa Reddy Mundla has worked at Procter & Gamble Pharmaceuticals and Eli Lilly based in USA.</div>
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The main strength of Sreeni Labs is in the design, development of innovative and highly economical synthetic routes and development of a selected route into a robust process followed by production of quality product from 100 grams to 100s of kg scale. Sreeni Labs main motto is adding value in everything they do.</div>
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They have helped number of customers from virtual biotech, big pharma, specialty chemicals, catalog companies, and academic researchers and drug developers, solar energy researchers at universities and institutions by successfully developing highly economical and simple chemistry routes to number of products that were made either by very lengthy synthetic routes or by using highly dangerous reagents and Suzuki coupling steps. They are able to supply materials from gram scale to multi kilo scale in a relatively short time by developing very short and efficient synthetic routes to a number of advanced intermediates, specialty chemicals, APIs and reference compounds. They also helped customers by drastically reducing number of steps, telescoping few steps into a single pot. For some projects, Sreeni Labs was able to develop simple chemistry and avoided use of palladium & expensive ligands. They always begin the project with end in the mind and design simple chemistry and also use readily available or easy to prepare starting materials in their design of synthetic routes</div>
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Over the years, Sreeni labs has successfully made a variety of products ranging from few mg to several kilogram scale. Sreeni labs has plenty of experience in making small select libraries of compounds, carbocyclic compounds like complex terpenoids, retinal derivatives, alkaloids, and heterocyclic compounds like multi substituted beta carbolines, pyridines, quinolines, quinolones, imidazoles, aminoimidazoles, quinoxalines, indoles, benzimidazoles, thiazoles, oxazoles, isoxazoles, carbazoles, benzothiazoles, azapines, benzazpines, natural and unnatural aminoacids, tetrapeptides, substituted oligomers of thiophenes and fused thiophenes, RAFT reagents, isocyanates, variety of ligands, heteroaryl, biaryl, triaryl compounds, process impurities and metabolites.</div>
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Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They can also take up custom synthesis and scale up of medchem analogues and building blocks. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving couple of PO based (fee for service) projects.<br />
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Some of the compounds prepared by Sreeni labs;</div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-3.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-3.jpg" rel="attachment wp-att-7653"><img alt="str1" class="alignnone wp-image-7653" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-3.jpg" height="422" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-3.jpg" style="height: auto; max-width: 100%;" width="640" /></a><a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-4.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-4.jpg" rel="attachment wp-att-7654"><img alt="str1" class="alignnone wp-image-7654" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-4.jpg" height="404" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-4.jpg" style="height: auto; max-width: 100%;" width="640" /></a></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-9.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-9.jpg" rel="attachment wp-att-7659"><img alt="str1" class="alignnone wp-image-7659" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-9.jpg" height="335" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-9.jpg" style="height: auto; max-width: 100%;" width="444" /></a><a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-10.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-10.jpg" rel="attachment wp-att-7660"><img alt="str1" class="alignnone wp-image-7660" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-10.jpg" height="304" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-10.jpg" style="height: auto; max-width: 100%;" width="461" /></a></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-11.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-11.jpg" rel="attachment wp-att-7661"><img alt="str1" class="alignnone wp-image-7661" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-11.jpg" height="292" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-11.jpg" style="height: auto; max-width: 100%;" width="463" /></a><a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-12.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-12.jpg" rel="attachment wp-att-7662"><img alt="str1" class="alignnone wp-image-7662" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-12.jpg" height="451" src="http://www.allfordrugs.com/wp-content/uploads/2016/07/str1-12.jpg" style="height: auto; max-width: 100%;" width="482" /></a></div>
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<span data-mce-style="font-size: xx-large;" style="font-size: x-large;"><span data-mce-style="color: #ff0000;" style="color: red;"><br /></span></span>
<span data-mce-style="font-size: xx-large;" style="font-size: x-large;"><span data-mce-style="color: #ff0000;" style="color: red;">See presentation below</span></span><br />
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LINK ON SLIDESHARE<br />
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<iframe allowfullscreen="allowfullscreen" frameborder="0" height="485" marginheight="0" marginwidth="0" scrolling="no" src="//www.slideshare.net/slideshow/embed_code/key/267dDoOaaShicc" style="border-width: 1px; border: 1px solid #ccc; margin-bottom: 5px; max-width: 100%;" width="595"> </iframe>
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<strong> <a href="https://www.slideshare.net/SreenivasaReddy23/sreeni-labs-profile" target="_blank" title="Sreeni Labs Profile">Sreeni Labs Profile</a> </strong> from <strong><a href="https://www.slideshare.net/SreenivasaReddy23" target="_blank">Sreenivasa Reddy</a></strong></div>
<small class="lighter-color-text">Managing Director at Sreeni Labs Private Limited</small></div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">Few Case Studies : Source SEEENI LABS</span></em></strong></h1>
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<span data-mce-style="color: #800000;" style="color: maroon;">QUOTE.............</span></div>
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<span data-mce-style="color: #000080;" style="color: navy;">One virtual biotech company customer from USA, through a common friend approached Sreeni Labs and told that they are buying a tetrapeptide from Bachem on mg scale at a very high price and requested us to see if we can make 5g. We accepted the challenge and developed solution phase chemistry and delivered 6g and also the process procedures in 10 weeks time. The customer told that they are using same procedures with very minor modifications and produced the tetrapeptide ip to 100kg scale as the molecule is in Phase III.</span><br />
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<span data-mce-style="color: #800000;" style="color: maroon;">One East coast customer in our first meeting told that they are working with 4 CROs of which two are in India and two are in China and politely asked why they should work with Sreeni Labs. We told that give us a project where your CROs failed to deliver and we will give a quote and work on it. You pay us only if we deliver and you satisfy with the data. They immediately gave us a project to make 1.5g and we delivered 2g product in 9 weeks. After receiving product and the data, the customer was extremely happy as their previous CRO couldn't deliver even a milligram in four months with 3 FTEs.</span><br />
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<span data-mce-style="color: #800080;" style="color: purple;">One Midwest biotech company was struggling to remove palladium from final API as they were doing a Suzuki coupling with a very expensive aryl pinacol borane and bromo pyridine derivative with an expensive ligand and relatively large amount of palldium acetate. The cost of final step catalyst, ligand and the palladium scavenging resin were making the project not viable even though the product is generating excellent data in the clinic. At this point we signed an FTE agreement with them and in four months time, we were able to design and develop a non suzuki route based on acid base chemistry and made 15g of API and compared the analytical data and purity with the Suzuki route API. This solved all three problems and the customer was very pleased with the outcome.</span><br />
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<span data-mce-style="color: #003300;" style="color: #003300;">One big pharma customer from east coast, wrote a structure of chemical intermediate on a paper napkin in our first meeting and asked us to see if we can make it. We told that we can make it and in less than 3 weeks time we made a gram sample and shared the analytical data. The customer was very pleased and asked us to make 500g. We delivered in 4 weeks and in the next three months we supplied 25kg of the same product.</span><br />
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<span data-mce-style="color: #800000;" style="color: maroon;">Through a common friend reference, a European customer from a an academic institute, sent us an email requesting us to quote for 20mg of a compound with compound number mentioned in J. med. chem. paper. It is a polycyclic compound with four contiguous stereogenic centers. We gave a quote and delivered 35 mg of product with full analytical data which was more pure than the published in literature. Later on we made 8g and 6g of the same product.</span><br />
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<span data-mce-style="color: #993300;" style="color: #993300;">One West coast customer approached us through a common friend's reference and told that they need to improve the chemistry of an advanced intermediate for their next campaign. At that time they are planning to make 15kg of that intermediate and purchased 50kg of starting raw material for $250,000. They also put five FTEs at a CRO for 5 months to optimize the remaining 5 steps wherein they are using LAH, Sodium azide, palladium catalyst and a column chromatography. We requested the customer not to purchase the 50kg raw material, and offered that we will make the 15kg for the price of raw material through a new route in less than three months time. You pay us only after we deliver 15 kg material. The customer didn't want to take a chance with their timeline as they didn't work with us before but requested us to develop the chemistry. In 7 weeks time, we developed a very simple four step route for their advanced intermediate and made 50g. We used very inexpensive and readily available starting material. Our route gave three solid intermediates and completely eliminated chromatographic purifications.</span><br />
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<span data-mce-style="color: #ff0000;" style="color: red;">One of my former colleague introduced an academic group in midwest and brought us a medchem project requiring synthesis of 65 challenging polyene compounds on 100mg scale. We designed synthetic routes and successfully prepared 60 compounds in a 15 month time. </span></div>
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UNQUOTE............</div>
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<strong><em><span data-mce-style="color: #ff0000;" style="color: red;">The man behind Seeni labs is Dr. </span></em></strong><span data-mce-style="color: #ff0000;" style="color: red;">Sreenivasa Reddy </span><span style="color: red;">Mundla</span><span style="color: red;"> </span></div>
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<img alt="Sreenivasa Reddy" data-mce-src="https://media.licdn.com/mpr/mpr/shrinknp_400_400/AAEAAQAAAAAAAAi0AAAAJGY4YjEyMjBlLWI4NGItNDM4YS05MmYxLWY2YWE5YTA3ZWU1MQ.jpg" height="400" src="https://media.licdn.com/mpr/mpr/shrinknp_400_400/AAEAAQAAAAAAAAi0AAAAJGY4YjEyMjBlLWI4NGItNDM4YS05MmYxLWY2YWE5YTA3ZWU1MQ.jpg" style="height: auto; max-width: 100%;" width="400" /></div>
<h2 style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">Dr. Sreenivasa Reddy Mundla</span></h2>
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Managing Director at Sreeni Labs Private Limited</div>
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Sreeni Labs Private Limited</div>
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Road No:12, Plot No:24,25,26</div>
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<li>IDA, Nacharam<br />Hyderabad, 500076<br />Telangana State, India</li>
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Links</div>
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LINKEDIN <a class="view-public-profile" data-mce-href="https://in.linkedin.com/in/sreenivasa-reddy-10b5876" href="https://in.linkedin.com/in/sreenivasa-reddy-10b5876">https://in.linkedin.com/in/sreenivasa-reddy-10b5876</a></div>
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FACEBOOK <a data-mce-href="https://www.facebook.com/sreenivasa.mundla" href="https://www.facebook.com/sreenivasa.mundla">https://www.facebook.com/sreenivasa.mundla</a></div>
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RESEARCHGATE <a data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla/info" href="https://www.researchgate.net/profile/Sreenivasa_Mundla/info">https://www.researchgate.net/profile/Sreenivasa_Mundla/info</a></div>
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<a href="https://www.blogger.com/null">EMAIL mundlasr@hotmail.com, </a><a href="https://www.blogger.com/null">Info@sreenilabs.com, </a><a href="https://www.blogger.com/null">Sreeni@sreenilabs.com</a></div>
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<a href="https://www.blogger.com/null">Phone :+91-9866092626, India</a><br />
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<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Dr. Sreenivasa Mundla Reddy</div>
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<a data-mce-href="https://newdrugapprovals.files.wordpress.com/2016/07/65a3c-sm.jpg" href="https://newdrugapprovals.files.wordpress.com/2016/07/65a3c-sm.jpg"><img alt="" border="0" class="" data-mce-src="https://newdrugapprovals.files.wordpress.com/2016/07/65a3c-sm.jpg?w=227" height="520" src="https://newdrugapprovals.files.wordpress.com/2016/07/65a3c-sm.jpg?w=227" style="height: auto; max-width: 100%;" width="393" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span data-mce-style="font-size: medium;" style="font-size: small;"><span data-mce-style="font-family: arial, tahoma, helvetica, freesans, sans-serif;" style="font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;">Dr. M. Sreenivasa Reddy obtained Ph.D from University of Hyderabad under the direction Prof Professor Goverdhan Mehta in 1992. From 1992-1994, he was a post doctoral fellow at University of Wisconsin in Professor Jame Cook's lab. From 1994 to 2000, worked at Chemical process R&D at Procter & Gamble Pharmaceuticals (P&G). From 2001 to 2007 worked at Global Chemical Process R&D at Eli Lilly and Company in Indianapolis. </span></span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span data-mce-style="font-size: medium;" style="font-size: small;"><span data-mce-style="font-family: arial, tahoma, helvetica, freesans, sans-serif;" style="font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;">In 2007 resigned to his job and founded Sreeni Labs based in Hyderabad, Telangana, India and started working with various global customers and solving various challenging synthesis problems.</span></span><span data-mce-style="font-size: medium;" style="font-size: small;"><span data-mce-style="font-family: arial, tahoma, helvetica, freesans, sans-serif;" style="font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"> </span><br /><span data-mce-style="font-family: arial, tahoma, helvetica, freesans, sans-serif;" style="font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;">The main strength of Sreeni Labs is in the design, development of a novel chemical route and its development into a robust process followed by production of quality product from 100 grams to 100's of kg scale.</span></span><span data-mce-style="font-size: medium;" style="font-size: small;"><span data-mce-style="font-family: arial, tahoma, helvetica, freesans, sans-serif;" style="font-family: "arial" , "tahoma" , "helvetica" , "freesans" , sans-serif;"> </span></span></div>
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<span data-mce-style="font-size: medium;" style="font-size: small;">They have helped number of customers by successfully developing highly economical simple chemistry routes to number of products that were made by Suzuki coupling. they are able to shorten the route by drastically reducing number of steps, avoiding use of palladium & expensive ligands. they always use readily available or easy to prepare starting materials in their design of synthetic routes.</span></div>
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<span data-mce-style="font-size: medium;" style="font-size: small;">Sreeni Labs is Looking for any potential opportunities where people need development of cost effective scalable routes followed by quick scale up to produce quality products in the pharmaceutical & specialty chemicals area. They have flexible business model that will be in sink with customers. One can test their abilities & capabilities by giving PO based projects</span></div>
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Experience</h3>
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<a data-mce-href="https://www.linkedin.com/title/founder-%26-managing-director?trk=mprofile_title" href="https://www.linkedin.com/title/founder-%26-managing-director?trk=mprofile_title" title="Learn more about this title">Founder & Managing Director</a></h4>
<h5>
<a data-mce-href="https://www.linkedin.com/vsearch/p?company=Sreeni+Labs+Private+Limited&trk=prof-exp-company-name" href="https://www.linkedin.com/vsearch/p?company=Sreeni+Labs+Private+Limited&trk=prof-exp-company-name" name="company" title="Find others who have worked at this company">Sreeni Labs Private Limited</a></h5>
</header><span class="experience-date-locale">August 2007 – Present (8 years 11 months)</span></div>
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Sreeni Labs Profile</div>
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<a data-mce-href="https://www.linkedin.com/company/1663?trk=prof-exp-company-name" href="https://www.linkedin.com/company/1663?trk=prof-exp-company-name"><span class="new-miniprofile-container /biz/miniprofile/1663?pathWildcard=1663"><img alt="" class="lazy-load" data-mce-src="https://media.licdn.com/media/AAEAAQAAAAAAAAbPAAAAJDE5MDVjNTYwLTc3OWEtNGU5NC04ZmFmLWZkMjdjYzQwYWUyNw.png" height="238" src="https://media.licdn.com/media/AAEAAQAAAAAAAAbPAAAAJDE5MDVjNTYwLTc3OWEtNGU5NC04ZmFmLWZkMjdjYzQwYWUyNw.png" style="height: auto; max-width: 100%;" width="238" /></span></a></h5>
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<a data-mce-href="https://www.linkedin.com/title/principal-research-scientist?trk=mprofile_title" href="https://www.linkedin.com/title/principal-research-scientist?trk=mprofile_title" title="Learn more about this title">Principal Research Scientist</a></h4>
<h5>
<span class="new-miniprofile-container /biz/miniprofile/1663?pathWildcard=1663"><b><a data-mce-href="https://www.linkedin.com/company/1663?trk=prof-exp-company-name" href="https://www.linkedin.com/company/1663?trk=prof-exp-company-name">Eli Lilly and Company</a></b></span></h5>
</header><span class="experience-date-locale">March 2001 – August 2007 (6 years 6 months)</span></div>
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<a data-mce-href="https://www.linkedin.com/company/1116?trk=prof-exp-company-name" href="https://www.linkedin.com/company/1116?trk=prof-exp-company-name"><span class="new-miniprofile-container /biz/miniprofile/1116?pathWildcard=1116"><img alt="" class="lazy-load" data-mce-src="https://media.licdn.com/media/p/4/005/073/13e/3525bc5.png" height="206" src="https://media.licdn.com/media/p/4/005/073/13e/3525bc5.png" style="height: auto; max-width: 100%;" width="209" /></span></a></h5>
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<a data-mce-href="https://www.linkedin.com/title/senior-research-scientist?trk=mprofile_title" href="https://www.linkedin.com/title/senior-research-scientist?trk=mprofile_title" title="Learn more about this title">Senior Research Scientist</a></h4>
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<span class="new-miniprofile-container /biz/miniprofile/1116?pathWildcard=1116"><b><a data-mce-href="https://www.linkedin.com/company/1116?trk=prof-exp-company-name" href="https://www.linkedin.com/company/1116?trk=prof-exp-company-name">Procter & Gamble</a></b></span></h5>
</header><span class="experience-date-locale">July 1994 – February 2001 (6 years 8 months)</span></div>
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Education</h3>
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<a data-mce-href="https://www.linkedin.com/edu/school?id=19691&trk=prof-edu-school-logo" href="https://www.linkedin.com/edu/school?id=19691&trk=prof-edu-school-logo" title="More details for this school"><span class="new-miniprofile-container /edu/school-rich-mini-profile?id=19691&entityId=19691&entityType=SCHOOL"><img alt="University of Wisconsin-Milwaukee" class="lazy-load" data-mce-src="https://media.licdn.com/mpr/mpr/shrink_100_100/p/7/005/019/23e/32a9f30.png" height="176" src="https://media.licdn.com/mpr/mpr/shrink_100_100/p/7/005/019/23e/32a9f30.png" style="height: auto; max-width: 100%;" width="176" /></span></a></h5>
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<a data-mce-href="https://www.linkedin.com/edu/school?id=19691&trk=prof-edu-school-name" href="https://www.linkedin.com/edu/school?id=19691&trk=prof-edu-school-name" title="More details for this school">University of Wisconsin-Milwaukee</a></h4>
<h5>
<span class="degree">PDF, </span><span class="major"><a data-mce-href="https://www.linkedin.com/edu/fos?id=100877&trk=prof-edu-field_of_study" href="https://www.linkedin.com/edu/fos?id=100877&trk=prof-edu-field_of_study" title="Explore this field of study">Synthetic Organic Chemistry</a></span></h5>
</header><span class="education-date">1992 – 1994</span></div>
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<a data-mce-href="https://www.linkedin.com/edu/school?id=13656&trk=prof-edu-school-logo" href="https://www.linkedin.com/edu/school?id=13656&trk=prof-edu-school-logo" title="More details for this school"><span class="new-miniprofile-container /edu/school-rich-mini-profile?id=13656&entityId=13656&entityType=SCHOOL"><img alt="University of Hyderabad" class="lazy-load" data-mce-src="https://media.licdn.com/mpr/mpr/shrink_100_100/AAEAAQAAAAAAAAQmAAAAJGI0ZjQxNWQ2LTMxMTktNDA2MS05YmNmLWQwMmYxYmE1ZDQxNQ.png" height="172" src="https://media.licdn.com/mpr/mpr/shrink_100_100/AAEAAQAAAAAAAAQmAAAAJGI0ZjQxNWQ2LTMxMTktNDA2MS05YmNmLWQwMmYxYmE1ZDQxNQ.png" style="height: auto; max-width: 100%;" width="172" /></span></a></h5>
<br />
<a data-mce-href="https://www.linkedin.com/edu/school?id=13656&trk=prof-edu-school-name" href="https://www.linkedin.com/edu/school?id=13656&trk=prof-edu-school-name" title="More details for this school">University of Hyderabad</a><br />
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<span class="degree">Doctor of Philosophy (Ph.D.), </span></h5>
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1986 – 1992</h5>
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<a class="taggee _hli" data-mce-href="https://www.facebook.com/hari.santhapuram" href="https://www.facebook.com/hari.santhapuram" id="js_qc">Hari Krishna Santhapuram</a></div>
<span class="fbPhotoTagList" id="fbPhotoSnowliftTagList">With <span class="fbPhotoTagListTag tagItem"><a class="taggee" data-mce-href="https://www.facebook.com/sreenivasa.mundla" href="https://www.facebook.com/sreenivasa.mundla">Sreenivasa Mundla</a></span>, <span class="fbPhotoTagListTag tagItem"><a class="textTagHovercardLink taggee" data-mce-href="https://www.blogger.com/null" href="https://www.blogger.com/null">Narahara sastry</a></span>, <span class="fbPhotoTagListTag tagItem"><a class="taggee" data-mce-href="https://www.facebook.com/ram.kishanrao.75" href="https://www.facebook.com/ram.kishanrao.75">Ram Kishan Rao</a></span>, <span class="fbPhotoTagListTag tagItem"><a class="taggee" data-mce-href="https://www.facebook.com/jagadeesh.bharatam" href="https://www.facebook.com/jagadeesh.bharatam">Jagadeesh Bharatam</a></span>, <span class="fbPhotoTagListTag tagItem"><a class="taggee" data-mce-href="https://www.facebook.com/gunjur" href="https://www.facebook.com/gunjur">Jagadish Gunjur</a></span> and <span class="fbPhotoTagListTag tagItem"><a class="textTagHovercardLink taggee" data-mce-href="https://www.blogger.com/null" href="https://www.blogger.com/null">Jagadish Bharatham</a></span>.</span></div>
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PUBLICATIONS</div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/270004059_Expansion_of_First-in-Class_Drug_Candidates_That_Sequester_Toxic_All-Trans-Retinal_and_Prevent_Light-Induced_Retinal_Degeneration?ev=prf_pub" href="https://www.researchgate.net/publication/270004059_Expansion_of_First-in-Class_Drug_Candidates_That_Sequester_Toxic_All-Trans-Retinal_and_Prevent_Light-Induced_Retinal_Degeneration?ev=prf_pub">Expansion of First-in-Class Drug Candidates That Sequester Toxic All-Trans-Retinal and Prevent Light-Induced Retinal Degeneration</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Jianye_Zhang2" href="https://www.researchgate.net/profile/Jianye_Zhang2">Jianye Zhang</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Zhiqian_Dong" href="https://www.researchgate.net/profile/Zhiqian_Dong">Zhiqian Dong</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa Reddy Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2061492629_X_Eric_Hu" href="https://www.researchgate.net/researcher/2061492629_X_Eric_Hu">X Eric Hu</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/William_Seibel" href="https://www.researchgate.net/profile/William_Seibel">William Seibel</a> ·<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/49643409_Ruben_Papoian" href="https://www.researchgate.net/researcher/49643409_Ruben_Papoian">Ruben Papoian</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/39698086_Krzysztof_Palczewski" href="https://www.researchgate.net/researcher/39698086_Krzysztof_Palczewski">Krzysztof Palczewski</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Marcin_Golczak" href="https://www.researchgate.net/profile/Marcin_Golczak">Marcin Golczak</a></div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/250500843_ChemInform_Abstract_Regioselective_Synthesis_of_4Halo_ortho-Dinitrobenzene_Derivatives?ev=prf_pub" href="https://www.researchgate.net/publication/250500843_ChemInform_Abstract_Regioselective_Synthesis_of_4Halo_ortho-Dinitrobenzene_Derivatives?ev=prf_pub">ChemInform Abstract: Regioselective Synthesis of 4Halo ortho-Dinitrobenzene Derivative</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa Mundla</a></div>
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Aug 2010 · ChemInform</div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/244450953_Optimization_of_a_Dihydropyrrolopyrazole_Series_of_Transforming_Growth_Factor-b_Type_I_Receptor_Kinase_Domain_Inhibitors_Discovery_of_an_Orally_Bioavailable_Transforming_Growth_Factor-b_Receptor_Type_?ev=prf_pub" href="https://www.researchgate.net/publication/244450953_Optimization_of_a_Dihydropyrrolopyrazole_Series_of_Transforming_Growth_Factor-b_Type_I_Receptor_Kinase_Domain_Inhibitors_Discovery_of_an_Orally_Bioavailable_Transforming_Growth_Factor-b_Receptor_Type_?ev=prf_pub">Optimization of a Dihydropyrrolopyrazole Series of Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: Discovery of an Orally Bioavailable Transforming Growth Factor-β Receptor Type I Inhibitor as Antitumor Agent</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li" href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li">Hong-yu Li</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38649449_William_T_McMillen" href="https://www.researchgate.net/researcher/38649449_William_T_McMillen">William T. McMillen</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Charles_Heap" href="https://www.researchgate.net/profile/Charles_Heap">Charles R. Heap</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/39132262_Denis_J_McCann" href="https://www.researchgate.net/researcher/39132262_Denis_J_McCann">Denis J. McCann</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Lei_Yan2" href="https://www.researchgate.net/profile/Lei_Yan2">Lei Yan</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Robert_Campbell13" href="https://www.researchgate.net/profile/Robert_Campbell13">Robert M. Campbell</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R. Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2037595721_Chi-Hsin_R_King" href="https://www.researchgate.net/researcher/2037595721_Chi-Hsin_R_King">Chi-Hsin R. King</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/29376557_Elizabeth_A_Dierks" href="https://www.researchgate.net/researcher/29376557_Elizabeth_A_Dierks">Elizabeth A. Dierks</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Bryan_Anderson2" href="https://www.researchgate.net/profile/Bryan_Anderson2">Bryan D. Anderson</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/34592617_Karen_S_Britt" href="https://www.researchgate.net/researcher/34592617_Karen_S_Britt">Karen S. Britt</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Karen_Huss" href="https://www.researchgate.net/profile/Karen_Huss">Karen L. Huss</a></div>
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Apr 2008 · Journal of Medicinal Chemistry</div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/250480602_ChemInform_Abstract_A_Concise_Synthesis_of_Quinazolinone_TGF-b_RI_Inhibitor_Through_One-Pot_Three-Component_Suzuki-MiyauraEtherification_and_Imidate-Amide_Rearrangement_Reactions?ev=prf_pub" href="https://www.researchgate.net/publication/250480602_ChemInform_Abstract_A_Concise_Synthesis_of_Quinazolinone_TGF-b_RI_Inhibitor_Through_One-Pot_Three-Component_Suzuki-MiyauraEtherification_and_Imidate-Amide_Rearrangement_Reactions?ev=prf_pub">ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li" href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li">Hong-yu Li</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Yan_Wang127" href="https://www.researchgate.net/profile/Yan_Wang127">Yan Wang</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38649449_William_T_McMillen" href="https://www.researchgate.net/researcher/38649449_William_T_McMillen">William T. McMillen</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Arindam_Chatterjee5" href="https://www.researchgate.net/profile/Arindam_Chatterjee5">Arindam Chatterjee</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38218802_John_E_Toth" href="https://www.researchgate.net/researcher/38218802_John_E_Toth">John E. Toth</a> ·<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R. Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/31497595_Matthew_Voss" href="https://www.researchgate.net/researcher/31497595_Matthew_Voss">Matthew Voss</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2017044757_Robert_D_Boyer" href="https://www.researchgate.net/researcher/2017044757_Robert_D_Boyer">Robert D. Boyer</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/6056871_J_Scott_Sawyer" href="https://www.researchgate.net/researcher/6056871_J_Scott_Sawyer">J. Scott Sawyer</a></div>
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Feb 2008 · ChemInform</div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/244188204_ChemInform_Abstract_A_Concise_Synthesis_of_Quinazolinone_TGF-b_RI_Inhibitor_Through_One-Pot_Three-Component_Suzuki-MiyauraEtherification_and_Imidate-Amide_Rearrangement_Reactions?ev=prf_pub" href="https://www.researchgate.net/publication/244188204_ChemInform_Abstract_A_Concise_Synthesis_of_Quinazolinone_TGF-b_RI_Inhibitor_Through_One-Pot_Three-Component_Suzuki-MiyauraEtherification_and_Imidate-Amide_Rearrangement_Reactions?ev=prf_pub">ChemInform Abstract: A Concise Synthesis of Quinazolinone TGF-β RI Inhibitor Through One-Pot Three-Component Suzuki—Miyaura/Etherification and Imidate—Amide Rearrangement Reactions</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li" href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li">Hong-yu Li</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/69147300_Yan_Wang" href="https://www.researchgate.net/researcher/69147300_Yan_Wang">Yan Wang</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38649449_William_T_McMillen" href="https://www.researchgate.net/researcher/38649449_William_T_McMillen">William T. McMillen</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Arindam_Chatterjee5" href="https://www.researchgate.net/profile/Arindam_Chatterjee5">Arindam Chatterjee</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38218802_John_E_Toth" href="https://www.researchgate.net/researcher/38218802_John_E_Toth">John E. Toth</a> ·<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R. Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/31497595_Matthew_Voss" href="https://www.researchgate.net/researcher/31497595_Matthew_Voss">Matthew Voss</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2017044757_Robert_D_Boyer" href="https://www.researchgate.net/researcher/2017044757_Robert_D_Boyer">Robert D. Boyer</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/6056871_J_Scott_Sawyer" href="https://www.researchgate.net/researcher/6056871_J_Scott_Sawyer">J. Scott Sawyer</a></div>
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Nov 2007 · Tetrahedron</div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/7240039_Dihydropyrrolopyrazole_Transforming_Growth_Factor-b_Type_I_Receptor_Kinase_Domain_Inhibitors_A_Novel_Benzimidazole_Series_with_Selectivity_versus_Transforming_Growth_Factor-b_Type_II_Receptor_Kinase_a?ev=prf_pub" href="https://www.researchgate.net/publication/7240039_Dihydropyrrolopyrazole_Transforming_Growth_Factor-b_Type_I_Receptor_Kinase_Domain_Inhibitors_A_Novel_Benzimidazole_Series_with_Selectivity_versus_Transforming_Growth_Factor-b_Type_II_Receptor_Kinase_a?ev=prf_pub">Dihydropyrrolopyrazole Transforming Growth Factor-β Type I Receptor Kinase Domain Inhibitors: A Novel Benzimidazole Series with Selectivity versus Transforming Growth Factor-β Type II Receptor Kinase and Mixed Lineage Kinase-7</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li" href="https://www.researchgate.net/researcher/63147512_Hong-yu_Li">Hong-yu Li</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/69147300_Yan_Wang" href="https://www.researchgate.net/researcher/69147300_Yan_Wang">Yan Wang</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Charles_Heap" href="https://www.researchgate.net/profile/Charles_Heap">Charles R Heap</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2037595721_Chi-Hsin_R_King" href="https://www.researchgate.net/researcher/2037595721_Chi-Hsin_R_King">Chi-Hsin R King</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/31497595_Matthew_Voss" href="https://www.researchgate.net/researcher/31497595_Matthew_Voss">Matthew Voss</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2029782961_David_K_Clawson" href="https://www.researchgate.net/researcher/2029782961_David_K_Clawson">David K Clawson</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2001497573_Lei_Yan" href="https://www.researchgate.net/researcher/2001497573_Lei_Yan">Lei Yan</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Robert_Campbell13" href="https://www.researchgate.net/profile/Robert_Campbell13">Robert M Campbell</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Bryan_Anderson2" href="https://www.researchgate.net/profile/Bryan_Anderson2">Bryan D Anderson</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/34467186_Jill_R_Wagner" href="https://www.researchgate.net/researcher/34467186_Jill_R_Wagner">Jill R Wagner</a> ·<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/34592617_Karen_Britt" href="https://www.researchgate.net/researcher/34592617_Karen_Britt">Karen Britt</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/30824907_Ku_X_Lu" href="https://www.researchgate.net/researcher/30824907_Ku_X_Lu">Ku X Lu</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38649449_William_T_McMillen" href="https://www.researchgate.net/researcher/38649449_William_T_McMillen">William T McMillen</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/39224884_Jonathan_M_Yingling" href="https://www.researchgate.net/researcher/39224884_Jonathan_M_Yingling">Jonathan M Yingling</a></div>
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Apr 2006 · Journal of Medicinal Chemistry</div>
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<a class="publication-preview ga-publication-viewer open-viewer js-open-viewer js-publication-item-fulltext-content" data-mce-href="https://www.researchgate.net/publication/244230702_Studies_on_the_Rh_and_Ir_mediated_tandem_Pauson-Khand_reaction_A_new_entry_into_the_dicyclopenta_a_dcyclooctene_ring_system" href="https://www.researchgate.net/publication/244230702_Studies_on_the_Rh_and_Ir_mediated_tandem_Pauson-Khand_reaction_A_new_entry_into_the_dicyclopenta_a_dcyclooctene_ring_system"><img alt="" class="image-responsive lazyloaded" data-mce-src="https://i1.rgstatic.net/publication/244230702_Studies_on_the_Rh_and_Ir_mediated_tandem_Pauson-Khand_reaction_A_new_entry_into_the_dicyclopenta_a_dcyclooctene_ring_system/links/54bcf96c0cf24e50e940da6b/smallpreview.png" src="https://i1.rgstatic.net/publication/244230702_Studies_on_the_Rh_and_Ir_mediated_tandem_Pauson-Khand_reaction_A_new_entry_into_the_dicyclopenta_a_dcyclooctene_ring_system/links/54bcf96c0cf24e50e940da6b/smallpreview.png" style="height: auto; max-width: 100%;" /></a></div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/244230702_Studies_on_the_Rh_and_Ir_mediated_tandem_Pauson-Khand_reaction_A_new_entry_into_the_dicyclopenta_a_dcyclooctene_ring_system?ev=prf_pub" href="https://www.researchgate.net/publication/244230702_Studies_on_the_Rh_and_Ir_mediated_tandem_Pauson-Khand_reaction_A_new_entry_into_the_dicyclopenta_a_dcyclooctene_ring_system?ev=prf_pub">Studies on the Rh and Ir mediated tandem Pauson–Khand reaction. A new entry into the dicyclopenta[ a, d]cyclooctene ring system</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38295100_Hui_Cao" href="https://www.researchgate.net/researcher/38295100_Hui_Cao">Hui Cao</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R. Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/James_Cook30" href="https://www.researchgate.net/profile/James_Cook30">James M. Cook</a></div>
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Aug 2003 · Tetrahedron Letters</div>
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<span class="publication-type">Article:</span> <span class="publication-title js-publication-title"><a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/250447820_ChemInform_Abstract_A_New_Method_for_the_Synthesis_of_26-Dinitro_and_2Halo6-nitrostyrenes?ev=prf_pub" href="https://www.researchgate.net/publication/250447820_ChemInform_Abstract_A_New_Method_for_the_Synthesis_of_26-Dinitro_and_2Halo6-nitrostyrenes?ev=prf_pub">ChemInform Abstract: A New Method for the Synthesis of 2,6-Dinitro and 2Halo6-nitrostyrenes</a></span></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R. Mundla</a></div>
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Nov 2000 · ChemInform</div>
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<span class="publication-type">Article:</span> <a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/250447186_ChemInform_Abstract_A_Novel_Method_for_the_Efficient_Synthesis_of_2-Arylamino-2-imidazolines?ev=prf_pub" href="https://www.researchgate.net/publication/250447186_ChemInform_Abstract_A_Novel_Method_for_the_Efficient_Synthesis_of_2-Arylamino-2-imidazolines?ev=prf_pub"><span class="publication-title js-publication-title">ChemInform Abstract: A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines</span></a></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R. Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/82677917_Larry_J_Wilson" href="https://www.researchgate.net/researcher/82677917_Larry_J_Wilson">Larry J. Wilson</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sean_Klopfenstein" href="https://www.researchgate.net/profile/Sean_Klopfenstein">Sean R. Klopfenstein</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/William_Seibel" href="https://www.researchgate.net/profile/William_Seibel">William L. Seibel</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/82763815_Nick_N_Nikolaides" href="https://www.researchgate.net/researcher/82763815_Nick_N_Nikolaides">Nick N. Nikolaides</a></div>
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Nov 2000 · ChemInform</div>
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<span class="publication-type">Article:</span> <a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/256871054_A_new_method_for_the_synthesis_of_26-dinitro_and_2-halo-6-nitrostyrenes?ev=prf_pub" href="https://www.researchgate.net/publication/256871054_A_new_method_for_the_synthesis_of_26-dinitro_and_2-halo-6-nitrostyrenes?ev=prf_pub"><span class="publication-title js-publication-title">A new method for the synthesis of 2,6-dinitro and 2-halo-6-nitrostyrenes</span></a></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R Mundla</a></div>
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Aug 2000 · Tetrahedron Letters</div>
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<span class="publication-type">Article:</span> <a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/229353012_A_Novel_Method_for_the_Efficient_Synthesis_of_2-Arylamino-2-imidazolines?ev=prf_pub" href="https://www.researchgate.net/publication/229353012_A_Novel_Method_for_the_Efficient_Synthesis_of_2-Arylamino-2-imidazolines?ev=prf_pub"><span class="publication-title js-publication-title">A Novel Method for the Efficient Synthesis of 2-Arylamino-2-imidazolines</span></a></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R Mundla</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/82677917_Larry_J_Wilson" href="https://www.researchgate.net/researcher/82677917_Larry_J_Wilson">Larry J Wilson</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sean_Klopfenstein" href="https://www.researchgate.net/profile/Sean_Klopfenstein">Sean R Klopfenstein</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/William_Seibel" href="https://www.researchgate.net/profile/William_Seibel">William L. Seibel</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/82763815_Nick_N_Nikolaides" href="https://www.researchgate.net/researcher/82763815_Nick_N_Nikolaides">Nick N Nikolaides</a></div>
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Aug 2000 · Tetrahedron Letters</div>
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<span class="publication-type">Article:</span> <a class="js-publication-title-link ga-publication-item" data-mce-href="https://www.researchgate.net/publication/244228127_Regioselective_Synthesis_of_4-Halo_ortho-Dinitrobenzene_Derivatives?ev=prf_pub" href="https://www.researchgate.net/publication/244228127_Regioselective_Synthesis_of_4-Halo_ortho-Dinitrobenzene_Derivatives?ev=prf_pub"><span class="publication-title js-publication-title">Regioselective Synthesis of 4-Halo ortho-Dinitrobenzene Derivatives</span></a></div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Sreenivasa R Mundla</a></div>
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Jun 2000 · Tetrahedron Letters</div>
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<a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2023235886_Eric_D_Cox" href="https://www.researchgate.net/researcher/2023235886_Eric_D_Cox">Eric D. Cox</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/34155588_Hernando_Diaz-Arauzo" href="https://www.researchgate.net/researcher/34155588_Hernando_Diaz-Arauzo">Hernando Diaz-Arauzo</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2040577365_Qi_Huang" href="https://www.researchgate.net/researcher/2040577365_Qi_Huang">Qi Huang</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Sreenivasa_Mundla" href="https://www.researchgate.net/profile/Sreenivasa_Mundla">Mundla S. Reddy</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/33707069_Chunrong_Ma" href="https://www.researchgate.net/researcher/33707069_Chunrong_Ma">Chunrong Ma</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/2062793162_Brad_Harris" href="https://www.researchgate.net/researcher/2062793162_Brad_Harris">Brad Harris</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/researcher/38880890_Ruth_McKernan" href="https://www.researchgate.net/researcher/38880890_Ruth_McKernan">Ruth McKernan</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/Phil_Skolnick" href="https://www.researchgate.net/profile/Phil_Skolnick">Phil Skolnick</a> · <a class="authors js-author-name ga-publications-authors" data-mce-href="https://www.researchgate.net/profile/James_Cook30" href="https://www.researchgate.net/profile/James_Cook30">James M. Cook</a></div>
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Aug 1998 · Journal of Medicinal Chemistry</div>
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<span data-mce-style="font-size: xx-large;" style="font-size: x-large;"><span data-mce-style="color: #ff0000;" style="color: red;">Patents by Inventor Dr. Sreenivasa Reddy Mundla</span></span></div>
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<h6 class="heading-6 has-no-margin">
<a data-mce-href="http://patents.justia.com/patent/7872020" href="http://patents.justia.com/patent/7872020">TGF-? inhibitors</a></h6>
</div>
<div class="meta">
<div class="number">
<b>Patent number: </b>7872020</div>
<div class="abstract">
<b>Abstract: </b>The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro -4H-pyrrolo[1,2-b]pyrazole monohydrate.</div>
<div class="type">
<b>Type: </b>Grant</div>
<div class="date-filed">
<b>Filed: </b>June 29, 2006</div>
<div class="date-issued">
<b>Date of Patent: </b>January 18, 2011</div>
<div class="assignees">
<b>Assignee: </b>Eli Lilly and Company</div>
<div class="inventors">
<b>Inventor: </b>Sreenivasa Reddy Mundla</div>
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<li class="has-padding-content-block-30 -zb"><div class="head">
<h6 class="heading-6 has-no-margin">
<a data-mce-href="http://patents.justia.com/patent/20100120854" href="http://patents.justia.com/patent/20100120854">TGF-BETA INHIBITORS</a></h6>
</div>
<div class="meta">
<div class="number">
<b>Publication number: </b>20100120854</div>
<div class="abstract">
<b>Abstract: </b>The present invention provides crystalline 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate.</div>
<div class="type">
<b>Type: </b>Application</div>
<div class="date-filed">
<b>Filed: </b>June 29, 2006</div>
<div class="date-issued">
<b>Publication date: </b>May 13, 2010</div>
<div class="assignees">
<b>Applicant: </b>ELI LILLY AND COMPANY</div>
<div class="inventors">
<b>Inventor: </b>Sreenivasa Reddy Mundla</div>
</div>
</li>
<li class="has-padding-content-block-30 -zb"><div class="head">
<h6 class="heading-6 has-no-margin">
<a data-mce-href="http://patents.justia.com/patent/6066740" href="http://patents.justia.com/patent/6066740">Process for making 2-amino-2-imidazoline, guanidine and 2-amino-3,4,5,6-tetrahydropyrimidine derivatives</a></h6>
</div>
<div class="meta">
<div class="number">
<b>Patent number: </b>6066740</div>
<div class="abstract">
<b>Abstract: </b>The present invention provides a process for making 2-amino-2-imidazoline, guanidine, and 2-amino-3,4,5,6-tetrahydroyrimidine derivatives by preparing the corresponding activated 2-thio-subsituted-2-derivative in a two-step, one-pot procedure and by further reacting yields this isolated derivative with the appropriate amine or its salts in the presence of a proton source. The present process allows for the preparation of 2-amino-2-imidazolines, quanidines, and 2-amino-3,4,5,6-tetrahydropyrimidines under reaction conditions that eliminate the need for lengthy, costly, or multiple low yielding steps, and highly toxic reactants. This process allows for improved yields and product purity and provides additional synthetic flexibility.</div>
<div class="type">
<b>Type: </b>Grant</div>
<div class="date-filed">
<b>Filed: </b>November 25, 1997</div>
<div class="date-issued">
<b>Date of Patent: </b>May 23, 2000</div>
<div class="assignees">
<b>Assignee: </b>The Procter & Gamble Company</div>
<div class="inventors">
<b>Inventors: </b>Michael Selden Godlewski, Sean Rees Klopfenstein, Sreenivasa Reddy Mundla, William Lee Seibel, Randy Stuart Muth</div>
</div>
</li>
</ul>
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<div class="number-and-title" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="patent-title">TGF-β inhibitors</span><br />
<a data-mce-href="http://www.google.co.in/patents/US7872020" href="http://www.google.co.in/patents/US7872020"><span class="patent-number">US 7872020 B2</span></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="patent-bibdata-value-list"><span class="patent-bibdata-value"><a data-mce-href="http://www.google.co.in/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Sreenivasa+Reddy+Mundla%22" href="http://www.google.co.in/search?tbo=p&tbm=pts&hl=en&q=ininventor:%22Sreenivasa+Reddy+Mundla%22">Sreenivasa Reddy Mundla</a></span></span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
The present invention provides 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl) -5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole monohydrate, i.e., Formula I.</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://patentimages.storage.googleapis.com/US7872020B2/US07872020-20110118-C00002.png" href="http://patentimages.storage.googleapis.com/US7872020B2/US07872020-20110118-C00002.png"><img alt="Figure US07872020-20110118-C00002" class="patent-full-image" data-mce-src="https://blogger.googleusercontent.com/img/proxy/AVvXsEiXxtLeB12GUuVMJTS8fYG7GzPZqtNWGlYg6uWOoNoa0Azjp1J4AmcogO_AU-KyrJN3bYDhSsHKoxMGzmO11EonLCHovcO9KsFX4p96f9FsU4VcQT3WgefVe0EQmeHlmOCO-OS0UQ4IpcNrJ17RX4_3nyNIpbz1ti8fbIRVAPGtWxTPlB3xvIzNBMf36PxehgTBddl7pg=" height="131" id="EMI-C00002" src="https://blogger.googleusercontent.com/img/proxy/AVvXsEiXxtLeB12GUuVMJTS8fYG7GzPZqtNWGlYg6uWOoNoa0Azjp1J4AmcogO_AU-KyrJN3bYDhSsHKoxMGzmO11EonLCHovcO9KsFX4p96f9FsU4VcQT3WgefVe0EQmeHlmOCO-OS0UQ4IpcNrJ17RX4_3nyNIpbz1ti8fbIRVAPGtWxTPlB3xvIzNBMf36PxehgTBddl7pg=" style="height: auto; max-width: 100%;" width="280" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
EXAMPLE 1 Preparation of 2-(6-methyl-pyridin-2-yl)-3-[6-amido-quinolin-4-yl-5,6-dihydro-4H -pyrrolo[1,2-b]pyrazole monohydrate</div>
<div class="patent-image" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://patentimages.storage.googleapis.com/US7872020B2/US07872020-20110118-C00008.png" href="http://patentimages.storage.googleapis.com/US7872020B2/US07872020-20110118-C00008.png"><img alt="Figure US07872020-20110118-C00008" class="patent-full-image" data-mce-src="https://blogger.googleusercontent.com/img/proxy/AVvXsEhEkbYwyZXWX1hhlAzkDNGFTq0dtfinKuY_rmTVPTQf4TXB6kbmunz6lJch9PYkFrRJ4Qgcs-zLn4bbZBFJ5irjPCbxQ7uTASMMmBWtqvtqay4cURq035bnRmY4UyHUEnIizWRhcdMa4ZNQNp4i3jLiAW-Ia1225yXsxb5IpIJRGpgFVsQMf-2K77W9TgylLKCfH2AnrQ=" height="447" id="EMI-C00008" src="https://blogger.googleusercontent.com/img/proxy/AVvXsEhEkbYwyZXWX1hhlAzkDNGFTq0dtfinKuY_rmTVPTQf4TXB6kbmunz6lJch9PYkFrRJ4Qgcs-zLn4bbZBFJ5irjPCbxQ7uTASMMmBWtqvtqay4cURq035bnRmY4UyHUEnIizWRhcdMa4ZNQNp4i3jLiAW-Ia1225yXsxb5IpIJRGpgFVsQMf-2K77W9TgylLKCfH2AnrQ=" style="height: auto; max-width: 100%;" width="804" /></a></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Galunisertib</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<sup>1</sup>H NMR (CDCl<sub>3</sub>): δ=9.0 ppm (d, 4.4 Hz, 1H); 8.23-8.19 ppm (m, 2H); 8.315 ppm (dd, 1.9 Hz, 8.9 Hz, 1H); 7.455 ppm (d, 4.4 Hz, 1H); 7.364 ppm (t, 7.7 Hz, 1H); 7.086 ppm (d, 8.0 Hz, 1H); 6.969 ppm (d, 7.7 Hz, 1H); 6.022 ppm (m, 1H); 5.497 ppm (m, 1H); 4.419 ppm (t, 7.3 Hz, 2H); 2.999 ppm (m, 2H); 2.770 ppm (p, 7.2 Hz, 7.4 Hz, 2H); 2.306 ppm (s, 3H); 1.817 ppm (m, 2H). MS ES+: 370.2; Exact: 369.16</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://blogger.googleusercontent.com/img/proxy/AVvXsEhgnOEJKGPOPputxswausiQH3z8ef0IJCZ6Lp20sB2QLnmn1CUIvDAPS-XDQeFA4wd4mnbxAxQO8lkZOWx7zlEQpXOoTSMTEgfTNFRUZd-RhYIkzc6k5t42aSsqFMvPl1DJNUU8-SJ1pLjoOOqn4cRORTDVUXQmdG10EFWN111pLVr73Q=" height="409" src="https://blogger.googleusercontent.com/img/proxy/AVvXsEhgnOEJKGPOPputxswausiQH3z8ef0IJCZ6Lp20sB2QLnmn1CUIvDAPS-XDQeFA4wd4mnbxAxQO8lkZOWx7zlEQpXOoTSMTEgfTNFRUZd-RhYIkzc6k5t42aSsqFMvPl1DJNUU8-SJ1pLjoOOqn4cRORTDVUXQmdG10EFWN111pLVr73Q=" style="height: auto; max-width: 100%;" width="409" /></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
ABOVE MOLECULE IS</div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://newdrugapprovals.org/2016/05/04/galunisertib/" href="https://newdrugapprovals.org/2016/05/04/galunisertib/">https://newdrugapprovals.org/2016/05/04/galunisertib/</a></div>
<div class="good-title" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
Galunisertib</div>
<div class="clearfix" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<i class="pull-left icon-bq icon-blackRed icon-Red">Phase III</i></div>
<div class="pic-logo" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
A TGF-beta receptor type-1 inhibitor potentially for the treatment of myelodysplastic syndrome (MDS) and solid tumours.</div>
<div class="addr yfdm" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="f-red f_n">LY-2157299</span></div>
<div class="addr" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
<span class="f-red">CAS No.</span><span class="f-red f-cas">700874-72-2</span></div>
<div style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
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<br /></div>
<div class="addr" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px;">
READ MY PRESENTATION ON<br />
<span class="j-title-breadcrumb">Accelerating Generic Approvals, see how you can accelerate your drug development programme</span></div>
<h1 class="notranslate slideshow-title-text" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif;">
<span class="j-title-breadcrumb">Accelerating Generic Approvals by Dr Anthony Crasto</span></h1>
<div>
<span class="j-title-breadcrumb"><iframe allowfullscreen="" frameborder="0" height="485" marginheight="0" marginwidth="0" scrolling="no" src="//www.slideshare.net/slideshow/embed_code/key/puknCbVxZH2Dn9" style="border-width: 1px; border: 1px solid #ccc; margin-bottom: 5px; max-width: 100%;" width="595"> </iframe> </span><br />
<div style="margin-bottom: 5px;">
<span class="j-title-breadcrumb"><strong> <a href="https://www.slideshare.net/anthonycrasto64/accelerating-generic-approvals-by-dr-anthony-crasto" target="_blank" title="Accelerating Generic Approvals by Dr Anthony Crasto">Accelerating Generic Approvals by Dr Anthony Crasto</a> </strong> from <strong><a href="https://www.slideshare.net/anthonycrasto64" target="_blank">Anthony Melvin Crasto Ph.D</a></strong> </span></div>
<br /></div>
<div>
<br /></div>
<div data-mce-style="margin-bottom: 5px;" style="color: #333333; font-family: Georgia, "Times New Roman", "Bitstream Charter", Times, serif; font-size: 16px; line-height: 24px; margin-bottom: 5px;">
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KEYWORDS Sreenivasa Mundla Reddy, Managing Director, Sreeni Labs Private Limited, Hyderabad, Telangana, India, new, economical, scalable routes, early clinical drug development stages, Custom synthesis, custom manufacturing, drug discovery, PHASE 1, PHASE 2, PHASE 3, API, drugs, medicines</div>
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<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<img alt="H3D" class="" data-mce-src="http://h3d.co.za/wp-content/uploads/2015/09/H3DLogo.png" height="158" src="http://h3d.co.za/wp-content/uploads/2015/09/H3DLogo.png" style="height: auto; max-width: 100%;" width="640" /></div>
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<br /></div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
UCT’s H3D is a center of excellence for research and innovation with an already strong track record in malaria drug discovery. The vision of H3D is to be the leading organization for integrated drug discovery and development on the African continent.</div>
<h1 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<img alt="" data-mce-src="http://www.vukuzenzele.gov.za/sites/www.vukuzenzele.gov.za/files/images-2015-decjan/p4-malaria.gif" height="638" src="http://www.vukuzenzele.gov.za/sites/www.vukuzenzele.gov.za/files/images-2015-decjan/p4-malaria.gif" style="height: auto; max-width: 100%;" width="640" /></h1>
<h1 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
ABOUT H3D</h1>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<strong>H3D is Africa’s first integrated drug discovery and development centre. The Centre was founded at the University of Cape Town in April 2011 and pioneers world-class drug discovery in Africa.</strong></div>
<h3 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Our Vision</h3>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
To be the leading organisation for integrated drug discovery and development from Africa, addressing global unmet medical needs.</div>
<h3 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Our Mission</h3>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
To discover and develop innovative medicines for unmet medical needs on the African continent and beyond, by performing state-of-the-art research and development and bridging the gap between basic science and clinical studies.</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
We embrace partnerships with local and international governments, pharmaceutical companies, academia, and the private sector, as well as not-for-profit and philanthropic organisations, while training scientists to be world experts in the field.</div>
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The H3D collaboration with the Medicines for Malaria Venture (MMV) focuses on delivering potential agents against malaria that will be affordable and safe to use. In line with the global aim to eradicate malaria, projects are pursued that not only eliminates blood-stage Plasmodium falciparum and Plasmodium vivax infection, but also acts against liver stages and blocks transmission of the infection. The projects embrace multidisciplinary activities to optimise hit compounds from screening libraries through the drug discovery pipeline and deliver clinical candidates.</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<em><span data-mce-style="color: #800000;" style="color: maroon;">Merck Serono Announces Recipients of the Second Annual €1 Million Grant for Multiple Sclerosis Innovation</span></em></div>
<div class="txt_standard" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<em><span data-mce-style="color: #800000;" style="color: maroon;">Darmstadt, Germany, September 12, 2014 – Merck Serono, the biopharmaceutical division of Merck, today announced the recipients of the second annual Grant for Multiple Sclerosis Innovation (GMSI) at MS Boston 2014, the joint meeting of the Americas Committee for Treatment and Research in MS (ACTRIMS) and European Committee for Treatment and Research in MS (ECTRIMS), taking place September 10-13 in Boston, U.S.A.</span></em></div>
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<em><span data-mce-style="color: #800000;" style="color: maroon;"><a class="lnk_intxt" data-mce-href="http://biopharma.merckgroup.com/corp.merckserono_2011/en/images/GMSI_Press_Release_9.10.14_tcm1494_128975.pdf?Version=" data-mce-style="color: #800000;" href="http://biopharma.merckgroup.com/corp.merckserono_2011/en/images/GMSI_Press_Release_9.10.14_tcm1494_128975.pdf?Version=" style="color: maroon;" target="_blank">Read Press Release</a></span></em></div>
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<img alt="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/7/7e/Anopheles_stephensi.jpeg" height="423" src="https://upload.wikimedia.org/wikipedia/commons/7/7e/Anopheles_stephensi.jpeg" style="height: auto; max-width: 100%;" width="640" /></div>
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<strong>Merck signed a research agreement with the University of Cape Town (UCT)</strong>, South Africa, to co-develop a new R&D platform. It aims at identifying new lead programs for potential treatments against malaria, with the potential to expand it to other tropical diseases. It combines Merck’s R&D expertise and the drug discovery capabilities of the UCT Drug Discovery and Development Centre, H3D.<br />UCT’s H3D is a center of excellence for research and innovation with an already strong track record in malaria drug discovery. The vision of H3D is to be the leading organization for integrated drug discovery and development on the African continent. They say that working with partners like Merck is critical to build up a comprehensive pipeline to tackle malaria and related infectious diseases.</div>
<h3 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Journal Publications:</h3>
<ol style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li>Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization C. Soares de Melo, T-S. Feng, R. van der Westhuyzen, R.K. Gessner, L. Street, G. Morgans, D. Warner, A. Moosa, K. Naran, N. Lawrence, H. Boshoff, C. Barry, C. Harris, R. Gordon, K. Chibale. Biorg. Med. Chem. 2015, 23, 7240-7250.</li>
<li>A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum- Infected Mouse Models from Structure−Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines. C. Le Manach, T. Paquet, C. Brunschwig, M. Njoroge, Z. Han, D. Gonzàlez Cabrera, S. Bashyam, R. Dhinakaran, D. Taylor, J. Reader, M. Botha, A. Churchyard, S. Lauterbach, T. Coetzer, L-M. Birkholtz, S. Meister, E. Winzeler, D. Waterson, M. Witty, S. Wittlin, M-B. Jiménez-Díaz, M. Santos Martínez, S. Ferrer, I. Angulo-Barturen, L. Street, and K. Chibale, J. Med. Chem. 2015, XX, XXXX</li>
<li>Structure−Activity Relationship Studies of Orally Active Antimalarial 2,4-Diamino-thienopyrimidines. D. Gonzàlez Cabrera, F. Douelle, C. Le Manach, Z. Han, T. Paquet, D. Taylor, M. Njoroge, N. Lawrence, L. Wiesner, D. Waterson, M. Witty, S. Wittlin, L. Street and K. Chibale. J Med Chem. 2015, 58, 7572-7579.</li>
<li>Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2. Le Manach, T. Paquet, D. Gonzalez Cabrera, Y. Younis, D. Taylor, L. Wiesner, N. Lawrence, S. Schwager, D. Waterson, M.J. Witty, S. Wittlin, L. Street, and K. Chibale. <em>J. Med. Chem</em>. 2014, <em>57</em>, 8839−8848.</li>
<li>Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 1. Le Manach, D. González Cabrera, F. Douelle, A.T. Nchinda, Y. Younis, D. Taylor, L. Wiesner, K. White, E. Ryan, C. March, S. Duffy, V. Avery, D. Waterson, M. J. Witty, S. Wittlin; S. Charman, L. Street, and K. Chibale. <em>J. Med. Chem.</em> 2014, <em>57</em>, 2789-2798.</li>
<li>2,4-Diamino-thienopyrimidines as Orally Active Antimalarial Agents. D. González Cabrera, C. Le Manach, F. Douelle, Y. Younis, T.-S. Feng, T. Paquet, A.T. Nchinda, L.J. Street, D. Taylor, C. de Kock, L. Wiesner, S. Duffy, K.L. White, K.M. Zabiulla, Y. Sambandan, S. Bashyam, D. Waterson, M.J. Witty, A. Charman, V.M. Avery, S. Wittlin, and K. Chibale. <em>J. Med. Chem.</em> 2014,<em>57</em>, 1014-1022.</li>
<li>Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension. Burger, T.L. Reudelhuber, A. Mahajan, K. Chibale,E.D. Sturrock, R.M. Touyz. <em>Clin. Sci. (Lond). </em>2014,<em> 127</em><em>(1)</em>, 57-63.</li>
<li>Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor. Denti, S.K. Sharp, W.L. Kröger, S.L. Schwager, A. Mahajan, M. Njoroge, L. Gibhard, I. Smit, K. Chibale, L. Wiesner, E.D. Sturrock, N.H. Davies. <em>Eur. J. Pharm. Sci.</em>2014, <em>56, </em>113-119.</li>
<li>Fragment-based design for the development of N-domain-selective angiotensin-1-converting enzyme inhibitors. R.G. Douglas, R.K. Sharma, G. Masuyer, L. Lubbe, I. Zamora, K.R. Acharya, K. Chibale, E.D. Sturrock. <em>Sci. (Lond). </em>2014,<em> 126(4),</em>305-313.</li>
<li>Fast in vitro methods to determine the speed of action and the stage-specificity of anti-malarials in Plasmodium falciparum. Le Manach, C. Scheurer, S. Sax, S. Schleiferböck, D. González Cabrera, Y. Younis, T. Paquet, L. Street, P.J. Smith, X. Ding, D. Waterson, M.J. Witty, D. Leroy, K. Chibale and S. Wittlin*. <em>Malaria Journal,</em> 2013, <em>12</em>, 424.</li>
<li>Structure-Activity-Relationship Studies Around the 2-Amino Group and Pyridine Core of Antimalarial 3,5-Diarylaminopyridines Lead to a Novel Series of Pyrazine Analogues with Oral in vivo Activity. Y. Younis, F. Douelle, González Cabrera, C. Le Manach, A.T. Nchinda, T. Paquet, L.J. Street, K.L. White, K. M. Zabiulla, J.T. Joseph, S. Bashyam, D. Waterson, M.J. Witty, S. Wittlin, S.A. Charman, and K. Chibale*<sup> </sup><em> J. Med. Chem.</em> 2013, <em>56</em>, 8860−8871.</li>
<li>Cell-based Medicinal Chemistry Optimization of High Throughput Screening (HTS) Hits for Orally Active Antimalarials-Part 2: Hits from SoftFocus Kinase and other Libraries. Y. Younis, L. J. Street, D. Waterson, M.J. Witty, and K. Chibale. <i>J. Med. Chem. </i>2013, <em>56</em>, 7750−7754.</li>
<li>Structure-Activity Relationship Studies of Orally active Antimalarial 3,5-Substituted 2-Aminopyridines. D. González Cabrera, F. Douelle, Y. Younis, T.-S. Feng, C. Le Manach, A.T. Nchinda, L.J. Street, C. Scheurer, J. Kamber, K. White, O. Montagnat, E. Ryan, K. Katneni, K.M. Zabiulla, J. Joseph, S. Bashyam, D. Waterson, M.J. Witty, S. Charman, S. Wittlin, and K. Chibale* <span class="s1"><i>J. Med. Chem. </i></span>2012, <em>55</em>, 11022– 11030.</li>
<li>3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential. Y. Younis, F. Douelle, T.-S. Feng, D. González Cabrera, C. Le Manach, A.T. Nchinda, S. Duffy, K.L. White, M. Shackleford, J. Morizzi, J. Mannila, K. Katneni, R. Bhamidipati, K. M. Zabiulla, J.T. Joseph, S. Bashyam, D. Waterson, M.J. Witty, D. Hardick, S. Wittlin, V. Avery, S.A. Charman, and K. Chibale*. <sup> </sup><em>J. Med. Chem. </em> 2012, <em>55</em>, 3479−3487.</li>
<li>Novel Orally Active Antimalarial Thiazoles. D. González Cabrera, F. Douelle, T.-S Feng, A.T. Nchinda, Y. Younis, K.L. White, Wu,E. Ryan, J.N. Burrows,D. Waterson, M.J. Witty,S. Wittlin,S.A. Charman and K. Chibale. <em>J. Med. Chem. </em>2011, <em>54</em>, 7713–7719.</li>
<li>Synthesis and molecular modeling of a lisinopril-tryptophan analogue inhibitor of angiotensin I-converting enzyme. A.T. Nchinda, K. Chibale, P. Redelinghuys and E.D. Sturrock. <em>Med. Chem. Lett. </em>2006, <em>16(17)</em>, 4616-4619.</li>
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<h3 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Patents</h3>
<ol style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li>Anti-Malarial Agents. Y. Younis, K. Chibale, M.J. Witty, D. Waterson. (2016) US9266842 B2.</li>
<li>New Anti-Malarial Agents. D. Waterson, M.J. Witty, K. Chibale, L. Street, D. González Cabrera, T. Paquet. EP patent application (2015), No. 15 176 514.6.</li>
<li>Preparation of aminopyrazine compounds as antimalarial agents for treatment of malaria. Y. Younis, K. Chibale, M.J. Witty, D. Waterson. PCT Int Appl. (2013), WO 2013121387 A1 20130822.</li>
<li>Preparation of peptides as angiotensin I-converting enzyme (ACE) inhibitors. E.D. Sturrock, A.T. Nchinda, K. Chibale. PCT Int. ppl. (2006), WO 2006126087 A2 20061130.</li>
<li>Preparation of peptides as angiotensin I-converting enzyme (ACE) inhibitors, E.D. Sturrock, A.T. Nchinda, K. Chibale. PCT Int. ppl. (2006), WO 2006126086 A2 20061130.</li>
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<h3>
Head Office, Medicinal Chemistry Unit</h3>
<strong>Physical Address:</strong><br />Department of Chemistry<br />7.32 H3D Lab Suite, PD Hahn Building, Level 7<br />North Lane off Ring Road<br />Upper Campus, University of Cape Town<br />Rondebosch, 7700, South Africa<br />
<h4>
T | 021 650 5495<br />F | 021 650 5195</h4>
<strong>Postal Address:</strong><br />University of Cape Town<br />Private Bag X3<br />Rondebosch 7701<br />South Africa</div>
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P. D. Hahn Bldg, Rondebosch, Cape Town, 7700, South Africa</div>
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//////<strong>H3D, Africa, integrated drug discovery and development centre, University of Cape Town </strong></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-36745109282804314152016-06-20T12:10:00.001+05:302016-06-20T12:10:36.089+05:30Metal Synergy in a Potential Anti-Cancer Drug<div dir="ltr" style="text-align: left;" trbidi="on">
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<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Metal Synergy in a Potential Anti-Cancer Drug</h2>
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Ruthenium teams up with platinum in a promising anticancer drug</div>
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<a data-mce-href="http://app.news.wiley.com/e/er?elq_mid=10181&elq_cid=1558306&s=1133198723&lid=47584&elqTrackId=bc0b1e276506437aa1288ab76cc244d4&elq=5e1e6fd40c3c4aafab8a8d6cb5df1e6f&elqaid=10181&elqat=1" href="http://app.news.wiley.com/e/er?elq_mid=10181&elq_cid=1558306&s=1133198723&lid=47584&elqTrackId=bc0b1e276506437aa1288ab76cc244d4&elq=5e1e6fd40c3c4aafab8a8d6cb5df1e6f&elqaid=10181&elqat=1">Read more</a></div>
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/////////Ruthenium, anticancer drug, platinum</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-61219624320713034852016-06-20T12:06:00.001+05:302016-06-20T12:06:45.991+05:30(±)-Integrifolin, Compound from plants keeps human cancer cells from multipying<div dir="ltr" style="text-align: left;" trbidi="on">
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-34.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-34.jpg" rel="attachment wp-att-7008"><img alt="STR1" class="alignnone wp-image-7008" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-34.jpg" height="577" src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-34.jpg" style="height: auto; max-width: 100%;" width="646" /></a></div>
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CAS 89647-87-0</div>
<div class="molecularFormula" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
C<sub>15</sub> H<sub>18</sub> O<sub>4, 262.30</sub></div>
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Azuleno[4,5-<em>b</em>]furan-2(3<em>H</em>)-one, decahydro-4,8-dihydroxy-3,6,9-tris(methylene)-, (3a<em>R</em>,4<em>R</em>,6a<em>R</em>,8<em>S</em>,9a<em>R</em>,9b<em>R</em>)-</div>
<dl class="keyProperties detailList" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<dt class="keyProperty delegateToggle delegateTab" data-event-source="detail" data-selected-item="Molecular Weight" data-tab-id="PREDICTED_PROPERTIES_89647-87-0_CHEMICAL_tab" data-tab-panel-id="PREDICTED_PROPERTIES_89647-87-0_CHEMICAL" data-tab-set-id="PREDICTED_PROPERTIES_89647-87-0" data-toggle-ids="PREDICTED_PROPERTIES_89647-87-0_content" data-toggle-to="on"><ul>
<li>Azuleno[4,5-b]furan-2(3H)-one, decahydro-4,8-dihydroxy-3,6,9-tris(methylene)-, [3aR-(3aα,4β,6aα,8β,9aα,9bβ)]-</li>
<li class="alt">(3aR,4R,6aR,8S,9aR,9bR)-Decahydro-4,8-dihydroxy-3,6,9-tris(methylene)azuleno[4,5-b]furan-2(3H)-one</li>
<li>8-epi-Deacylcynaropicrin</li>
<li class="alt">8β-Hydroxyzaluzanin C</li>
<li>Integrifolin</li>
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<li class="alt">Integrifolin (guaianolide)</li>
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Paper</div>
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<img alt="thumbnail image: Total Synthesis of (±)-Integrifolin" class="" data-mce-src="http://www.chemistryviews.org/common/images/thumbnails/source/1552b44844b.jpg" height="195" src="http://www.chemistryviews.org/common/images/thumbnails/source/1552b44844b.jpg" style="height: auto; max-width: 100%;" width="260" /></div>
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(±)-Integrifolin</h2>
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Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim</div>
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Total Synthesis of (±)-Integrifolin</h2>
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Compound from plants keeps human cancer cells from multipying</div>
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<a data-mce-href="http://app.news.wiley.com/e/er?elq_mid=10181&elq_cid=1558306&s=1133198723&lid=47589&elqTrackId=a217a4f7149844529d93e378054d9768&elq=5e1e6fd40c3c4aafab8a8d6cb5df1e6f&elqaid=10181&elqat=1" href="http://app.news.wiley.com/e/er?elq_mid=10181&elq_cid=1558306&s=1133198723&lid=47589&elqTrackId=a217a4f7149844529d93e378054d9768&elq=5e1e6fd40c3c4aafab8a8d6cb5df1e6f&elqaid=10181&elqat=1">Read more</a> at Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim</div>
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<a data-mce-href="http://www.chemistryviews.org/details/ezine/9412451/Total_Synthesis_of_-Integrifolin.html?elq_mid=10181&elq_cid=1558306" href="http://www.chemistryviews.org/details/ezine/9412451/Total_Synthesis_of_-Integrifolin.html?elq_mid=10181&elq_cid=1558306">http://www.chemistryviews.org/details/ezine/9412451/Total_Synthesis_of_-Integrifolin.html?elq_mid=10181&elq_cid=1558306</a></div>
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(±)-Integrifolin</div>
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<img alt="" data-mce-src="http://www.friendsoflanecovenationalpark.org.au/Images/Flowering/Flowers/Banksia/Banksia_integrifolia_043.jpg" src="http://www.friendsoflanecovenationalpark.org.au/Images/Flowering/Flowers/Banksia/Banksia_integrifolia_043.jpg" style="height: auto; max-width: 100%;" /></div>
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<span data-mce-style="color: #000000;" style="color: black;"><i><span data-mce-style="font-family: Arial, Helvetica, sans-serif; font-size: xx-small;" style="font-family: Arial, Helvetica, sans-serif; font-size: xx-small;"><strong>Banksia integrifolia</strong></span></i></span></div>
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<span data-mce-style="color: #000000;" style="color: black;"><strong><span data-mce-style="font-family: Arial, Helvetica, sans-serif;" style="font-family: Arial, Helvetica, sans-serif;">Coast Banksia</span></strong></span></div>
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<span data-mce-style="color: #000000;" style="color: black;"><strong><span data-mce-style="font-family: Arial, Helvetica, sans-serif;" style="font-family: Arial, Helvetica, sans-serif;">Family: Proteaceae</span></strong></span></div>
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<span data-mce-style="color: #000000; font-family: Arial, Helvetica, sans-serif;" style="color: black; font-family: Arial, Helvetica, sans-serif;"><i><span data-mce-style="font-family: Arial, Helvetica, sans-serif; font-size: xx-small;" style="font-size: xx-small;">Banksia integrifolia</span></i> is a tall shrub or small tree 6 - 16m tall. It is common in sandy coastal areas, but also grows in the forests of tablelands. The light grey bark is hard and rough.</span></div>
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<span data-mce-style="color: #000000; font-family: Arial, Helvetica, sans-serif;" style="color: black; font-family: Arial, Helvetica, sans-serif;">Mature leaves 5 -10 cm long, are stiff, entire (untoothed), dull dark green above and hairy-white underneath. They are generally lanceolate. Younger leaves are irregularly toothed and shorter than the mature leaves. The species name 'integrifolia' means whole-leaved.</span></div>
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<span data-mce-style="color: #000000; font-family: Arial, Helvetica, sans-serif;" style="color: black; font-family: Arial, Helvetica, sans-serif;">The pale yellow flower spikes of <i><span data-mce-style="font-family: Arial, Helvetica, sans-serif; font-size: xx-small;" style="font-size: xx-small;">Banksia integrifolia</span></i> range from 7-14cm long and 7cm wide. The bent styles emerge from individual flowers on the spike, straightening and spreading.</span></div>
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<span data-mce-style="color: #000000; font-family: Arial, Helvetica, sans-serif;" style="color: black; font-family: Arial, Helvetica, sans-serif;">A short time after flowering, the seed pods protrude cleanly from the woody cone and open to shed black, papery, winged seeds.</span></div>
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<span data-mce-style="color: #000000; font-family: Arial, Helvetica, sans-serif;" style="color: black; font-family: Arial, Helvetica, sans-serif;"><i><span data-mce-style="font-family: Arial, Helvetica, sans-serif; font-size: xx-small;" style="font-size: xx-small;">Banksia integrifolia</span></i> flowers from January to June.</span></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-32.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-32.jpg" rel="attachment wp-att-7005"><img alt="STR1" class="alignnone size-full wp-image-7005" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-32.jpg" height="163" src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-32.jpg" style="height: auto; max-width: 100%;" width="526" /></a></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-33.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-33.jpg" rel="attachment wp-att-7006"><img alt="STR1" class="alignnone size-full wp-image-7006" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-33.jpg" height="451" src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-33.jpg" style="height: auto; max-width: 100%;" width="679" /></a></div>
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<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb1958/33/8/33_8_3361/_pdf" href="https://www.jstage.jst.go.jp/article/cpb1958/33/8/33_8_3361/_pdf">https://www.jstage.jst.go.jp/article/cpb1958/33/8/33_8_3361/_pdf</a></div>
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<a data-mce-href="http://onlinelibrary.wiley.com/store/10.1002/chem.201601275/asset/supinfo/chem201601275-sup-0001-misc_information.pdf?v=1&s=4f61b6fb79f80891032817c35a8f12c1a20177d0" href="http://onlinelibrary.wiley.com/store/10.1002/chem.201601275/asset/supinfo/chem201601275-sup-0001-misc_information.pdf?v=1&s=4f61b6fb79f80891032817c35a8f12c1a20177d0">////</a>///(±)-Integrifolin, human cancer cells, multipying</div>
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C=C1C(=O)O[C@@H]2[C@H]3C(=C)[C@@H](O)C[C@H]3C(=C)C[C@@H](O)[C@@H]12</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-46536054086146772432016-06-07T09:58:00.002+05:302016-06-07T09:58:37.738+05:30Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder<div dir="ltr" style="text-align: left;" trbidi="on">
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A larger SI indicates a greater likelihood that sticking will occur.</div>
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Defining SI for Assessing Adhesion of Powder to the Punch</h2>
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One cause of sticking is that when a powder is being compacted, the adhesive force between powder particles of the tablet and the punch surface exceeds the adhesive forces of powder particles within the tablet. Φ<sub>p</sub> represents the frictional force acting between particles in the powder bed, and Φ<sub>w</sub> represents the frictional force between the powder and the punch surface. The larger these values, the higher the friction and adhesion of the powder. We defined SI, which represents the degree of adhesion of a powder to the punch surface, as the value obtained by dividing Φ<sub>w</sub> by Φ<sub>p</sub> according to the following formula.</div>
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Sticking is a failure of pharmaceutical production that occurs when a powder containing a large amount of adhesive is being tableted. This is most frequently observed when long-term tableting is carried out, making it extremely difficult to predict its occurrence during the tablet formula design stage. The efficiency of the pharmaceutical production process could be improved if it were possible to predict whether a particular formulation was likely to stick during tableting. To address this issue, in the present study we prepared tablets composed of blended ibuprofen (Ibu), a highly adhesive drug, and measured the degree of adherence of powder particles to the surface of the tablet punch. We also measured the shear stress of the powder to determine the practical angle of internal friction (Φ<sub>p</sub>) of the powder bed as well as the angle of wall friction (Φ<sub>w</sub>) relative to the punch surface. These values were used to define a sticking index (SI), which showed a high correlation with the amount of Ibu that adhered to the punch during tableting; sticking occurred at SI >0.3. When the amount of lubricant added to the formulation was changed to yield tablets exhibiting different SI values without changing the compounding ratio, sticking did not occur at SI ≤0.3. These results suggest that determining the SI of a pharmaceutical powder before tableting allows prediction of the likelihood of sticking during tableting.</div>
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<h2 class="mod-article-heading inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Predicting the Occurrence of Sticking during Tablet Production by Shear Testing of a Pharmaceutical Powder</h2>
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<a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Shohei+Nakamura" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Shohei+Nakamura">Shohei Nakamura<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Natsuki+Otsuka" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Natsuki+Otsuka">Natsuki Otsuka<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yukari+Yoshino" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yukari+Yoshino">Yukari Yoshino<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Takatoshi+Sakamoto" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Takatoshi+Sakamoto">Takatoshi Sakamoto<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Hiroshi+Yuasa" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Hiroshi+Yuasa">Hiroshi Yuasa<sup>1)</sup></a></div>
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1) Department of Pharmaceutical Technology, School of Clinical Pharmacy, College of Pharmaceutical Sciences, Matsuyama University</div>
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Released on J-STAGE 20160501</div>
<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb/64/5/64_c15-00992/_html" href="https://www.jstage.jst.go.jp/article/cpb/64/5/64_c15-00992/_html">https://www.jstage.jst.go.jp/article/cpb/64/5/64_c15-00992/_html</a></div>
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///////////sticking, shear stress, internal friction angle, wall friction angle, sticking index, ibuprofen, Tablet Production, Shear Testing, Pharmaceutical Powder</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-54056860668840122882016-06-07T09:57:00.000+05:302016-06-07T09:57:50.446+05:303,5-Dibromo-N-(4,6-difluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide having potent anti-norovirus activity<div dir="ltr" style="text-align: left;" trbidi="on">
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-15.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-15.jpg" rel="attachment wp-att-6703"><img alt="STR1" class="alignnone size-full wp-image-6703" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-15.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1-15.jpg" height="433" style="height: auto; max-width: 100%;" width="442" /></a></div>
<h2 id="sec04.51" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
3,5-Dibromo-<i>N</i>-(4,6-difluorobenzo[<i>d</i>]thiazol-2-yl)thiophene-2-carboxamide</h2>
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New and novel anti-norovirus agents</div>
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There is an urgent need for structurally novel anti-norovirus agents. In this study, we describe the synthesis, anti-norovirus activity, and structure–activity relationship (SAR) of a series of heterocyclic carboxamide derivatives. Heterocyclic carboxamide <b>1</b> (50% effective concentration (EC<sub>50</sub>)=37 µM) was identified by our screening campaign using the cytopathic effect reduction assay. Initial SAR studies suggested the importance of halogen substituents on the heterocyclic scaffold and identified 3,5-<i>di</i>-boromo-thiophene derivative <b>2j</b> (EC<sub>50</sub>=24 µM) and 4,6-<i>di</i>-fluoro-benzothiazole derivative <b>3j</b> (EC<sub>50</sub>=5.6 µM) as more potent inhibitors than <b>1</b>. Moreover, their hybrid compound, 3,5-<i>di</i>-bromo-thiophen-4,6-<i>di</i>-fluoro-benzothiazole <b>4b</b>, showed the most potent anti-norovirus activity with a EC<sub>50</sub> value of 0.53 µM (70-fold more potent than <b>1</b>). Further investigation suggested that <b>4b</b> might inhibit intracellular viral replication or the late stage of viral infection.</div>
<h2 id="sec04.51" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
3,5-Dibromo-<i>N</i>-(4,6-difluorobenzo[<i>d</i>]thiazol-2-yl)thiophene-2-carboxamide (4b)</h2>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1.png" href="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1.png" rel="attachment wp-att-6702"><img alt="STR1" class="alignnone wp-image-6702" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1.png" src="http://www.allfordrugs.com/wp-content/uploads/2016/06/STR1.png" height="384" style="height: auto; max-width: 100%;" width="787" /></a></div>
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According to the same procedure used for <b>2f</b>, starting from 3,5-dibromothiophene-2-carboxylic acid (286 mg, 1.00 mmol) and 4,6-difluorobenzo[<i>d</i>]thiazol-2-amine (204 mg, 1.10 mmol), <b>4b</b> (270 mg, 60%) was obtained as white powder. mp: 245–246°C. <sup>1</sup>H-NMR (DMSO-<i>d</i><sub>6</sub>) δ: 7.43 (1H, dt, <i>J</i>=10.2, 2.0 Hz), 7.56 (1H, s), 7.83 (1H, dd, <i>J</i>=8.4, 2.0 Hz). <sup>13</sup>C-NMR (DMSO-<i>d</i><sub>6</sub>) δ: 102.2 (dd, <i>J</i>=28.0, 23.1 Hz), 104.7 (dd, <i>J</i>=26.4, 3.3 Hz), 114.3, 118.4, 131.4 (d, <i>J</i>=7.4 Hz), 134.3 (d, <i>J</i>=10.7 Hz), 134.9, 135.2, 152.7 (d, <i>J</i>=241.2, 20.7 Hz), 158.3 (dd, <i>J</i>=242.2, 10.7 Hz), 159.0, 159.7. HPLC purity: >99%, ESI-MS <i>m</i>/<i>z</i> 453 [M+H]<sup>+</sup>.</div>
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Antiviral Activity and Cytotoxicity of Tetra-halogenated Hybrid Compounds</div>
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<tr><th colspan="6" rowspan="1" style="font-family: inherit; font-size: inherit;"><img align="middle" alt="" data-mce-src="https://www.jstage.jst.go.jp/article/cpb/64/5/64_c16-00001/Graphics/figureT03.png" src="https://www.jstage.jst.go.jp/article/cpb/64/5/64_c16-00001/Graphics/figureT03.png" style="height: auto; max-width: 100%;" /></th></tr>
<tr><th colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Compound</th><th colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">R<sub>6</sub></th><th colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">R<sub>7</sub></th><th colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">R<sub>8</sub></th><th colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">EC<sub>50</sub> (µM)<i><sup>a</sup></i><sup>)</sup></th><th colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">CC<sub>50</sub> (µM)<i><sup>b</sup></i><sup>)</sup></th></tr>
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<tr><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;"><b>4a</b></td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Cl</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">H</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">H</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">2.1</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">>100</td></tr>
<tr><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;"><b>4b</b></td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Br</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">H</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Br</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">0.53</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">>100</td></tr>
<tr><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;"><b>4c</b></td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Cl</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">H</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Cl</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">1.1</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">>100</td></tr>
<tr><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;"><b>4d</b></td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Cl</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">Cl</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">H</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">1.4</td><td colspan="1" rowspan="1" style="font-family: inherit; font-size: inherit;">31</td></tr>
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<i>a</i>) EC<sub>50</sub> was evaluated by the CPE reduction assay. 280 TCID<sub>50</sub>/50 µL of MNV and a dilution series of each compound were incubated for 30 min. The mixture was exposed to RAW264.7 cells for 1 h (in duplicate). <i>b</i>) Cytotoxicity was evaluated by the WST-8 assay. RAW264.7 cells were treated with dilution series of each compound (in triplicate) for 72 h.</div>
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<h2 class="mod-article-heading inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Discovery and Synthesis of Heterocyclic Carboxamide Derivatives as Potent Anti-norovirus Agents</h2>
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<a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Mai+Ohba" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Mai+Ohba">Mai Ohba<sup>1) 2)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Tomoichiro+Oka" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Tomoichiro+Oka">Tomoichiro Oka<sup>3)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Takayuki+Ando" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Takayuki+Ando">Takayuki Ando<sup>1) 2)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Saori+Arahata" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Saori+Arahata">Saori Arahata<sup>4)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Asaka+Ikegaya" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Asaka+Ikegaya">Asaka Ikegaya<sup>4)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Hirotaka+Takagi" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Hirotaka+Takagi">Hirotaka Takagi<sup>5)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Naohisa+Ogo" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Naohisa+Ogo">Naohisa Ogo<sup>1) 2)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Kazuhiro+Owada" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Kazuhiro+Owada">Kazuhiro Owada<sup>2)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Fumihiko+Kawamori" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Fumihiko+Kawamori">Fumihiko Kawamori<sup>4)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Qiuhong+Wang" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Qiuhong+Wang">Qiuhong Wang<sup>6)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Linda+J.+Saif" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Linda+J.+Saif">Linda J. Saif<sup>6)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Akira+Asai" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Akira+Asai">Akira Asai<sup>1)</sup></a></div>
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1) Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka 2) Department of Pharmaceutical and Food Science, Shizuoka Institute of Environment and Hygiene 3) Department of Virology II, National Institute of Infectious Diseases 4) Department of Microbiology, Shizuoka Institute of Environment and Hygiene 5) Division of Biological Safety Control and Research, National Institute of Infectious Diseases 6) Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University</div>
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<img alt="" data-mce-src="http://www.cdc.gov/norovirus/images/how-get-norovirus-lg.jpg" src="http://www.cdc.gov/norovirus/images/how-get-norovirus-lg.jpg" style="height: auto; max-width: 100%;" /></div>
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<div class="section sticky " id="intro">
<h1 class="firstHeading">
<a data-mce-href="http://www.wikihow.com/Kill-Norovirus" href="http://www.wikihow.com/Kill-Norovirus">How to Kill Norovirus</a></h1>
<img alt="" data-mce-src="http://phenomena.nationalgeographic.com/files/2013/01/purple-norovirus.001-660x228.jpg" src="http://phenomena.nationalgeographic.com/files/2013/01/purple-norovirus.001-660x228.jpg" style="height: auto; max-width: 100%;" /><br />
<div class="sp_method_toc" id="method_toc">
Three Methods:<a class="" data-mce-href="http://www.wikihow.com/Kill-Norovirus#Killing_Norovirus_with_Good_Hygiene_sub" href="http://www.wikihow.com/Kill-Norovirus#Killing_Norovirus_with_Good_Hygiene_sub">Killing Norovirus with Good Hygiene</a><a class="" data-mce-href="http://www.wikihow.com/Kill-Norovirus#Killing_Norovirus_in_Your_Home_sub" href="http://www.wikihow.com/Kill-Norovirus#Killing_Norovirus_in_Your_Home_sub">Killing Norovirus in Your Home</a><a class="" data-mce-href="http://www.wikihow.com/Kill-Norovirus#Treating_Norovirus_sub" href="http://www.wikihow.com/Kill-Norovirus#Treating_Norovirus_sub">Treating Norovirus</a><a data-mce-href="http://www.wikihow.com/Kill-Norovirus#Questions_and_Answers_sub" href="http://www.wikihow.com/Kill-Norovirus#Questions_and_Answers_sub" id="qa_toc">Community Q&A</a></div>
Norovirus is a contagious virus that affects many people each year. You can get norovirus through interaction with an infected person, by eating contaminated food, touching contaminated surfaces, or drinking contaminated water. However, there are ways to kill norovirus before it infects you. To do this, you will have to maintain personal hygiene and keep your home contamination-free.<br />
<div class="clearall">
Method1</div>
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<div class="section steps sticky ">
<h3 class="">
<span class="mw-headline" id="Killing_Norovirus_with_Good_Hygiene">Killing Norovirus with Good Hygiene</span></h3>
<div class="section_text" id="steps_1">
<ol class="steps_list_2">
<li class="hasad"><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-1-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-1-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-1-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 1" class="whcdn" data-mce-src="http://pad1.whstatic.com/images/thumb/1/12/Kill-Norovirus-Step-1-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-1-Version-2.jpg.webp" src="http://pad1.whstatic.com/images/thumb/1/12/Kill-Norovirus-Step-1-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-1-Version-2.jpg.webp" data-src="http://pad1.whstatic.com/images/thumb/1/12/Kill-Norovirus-Step-1-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-1-Version-2.jpg" height="546" id="img_5755915622e25" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
1</div>
<div class="step">
<b class="whb">Wash your hands thoroughly.</b> If you think you may have come into contact with the virus, you must wash your hands thoroughly to avoid the spread of infection. To wash your hands to avoid contamination, use soap and hot water. Alcohol hand sanitizer is generally considered ineffective against this particular kind of virus. You should wash your hands if<sup class="reference" id="_ref-1"><a data-mce-href="http://www.wikihow.com/Kill-Norovirus#_note-1" href="http://www.wikihow.com/Kill-Norovirus#_note-1">[1]</a></sup>:<br />
<ul>
<li>You have come into contact with someone who has norovirus.</li>
<li>Before and after you interact with someone with norovirus.</li>
<li>If you visit a hospital, even if you don’t think you interacted with anyone with norovirus.</li>
<li>After going to the bathroom.</li>
<li>Before and after eating.</li>
<li>If you are a nurse or doctor, wash your hands before and after coming into contact with an infected patient, even if you wear gloves.</li>
</ul>
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</li>
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<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-2-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-2-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-2-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 2" class="whcdn" data-mce-src="http://pad3.whstatic.com/images/thumb/2/2c/Kill-Norovirus-Step-2-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-2-Version-2.jpg.webp" src="http://pad3.whstatic.com/images/thumb/2/2c/Kill-Norovirus-Step-2-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-2-Version-2.jpg.webp" data-src="http://pad3.whstatic.com/images/thumb/2/2c/Kill-Norovirus-Step-2-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-2-Version-2.jpg" height="546" id="img_5755915622f44" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
2</div>
<div class="step">
<b class="whb">Avoid cooking for others if you are sick.</b> If you have been infected and are sick, do not handle any food or cook for others in your family. If you do, they are almost certain to get the infection too.<br />
<ul>
<li>If a family member is contaminated, do not let them cook for anyone else. Try to limit the amount of time healthy family members spend with the sick family member.</li>
</ul>
</div>
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</li>
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-3-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-3-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-3-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 3" class="whcdn" data-mce-src="http://pad1.whstatic.com/images/thumb/4/44/Kill-Norovirus-Step-3-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-3-Version-2.jpg.webp" src="http://pad1.whstatic.com/images/thumb/4/44/Kill-Norovirus-Step-3-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-3-Version-2.jpg.webp" data-src="http://pad1.whstatic.com/images/thumb/4/44/Kill-Norovirus-Step-3-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-3-Version-2.jpg" height="546" id="img_5755915623056" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
3</div>
<div class="step">
<b class="whb">Wash your food before eating or cooking it.</b> Wash all food items such as meats, fruits and vegetables thoroughly before consumption or for use in cooking. This is important as norovirus has the tendency to survive even at temperatures well above 140 degrees Fahrenheit (60 degrees Celsius).<sup class="reference" id="_ref-2"><a data-mce-href="http://www.wikihow.com/Kill-Norovirus#_note-2" href="http://www.wikihow.com/Kill-Norovirus#_note-2">[2]</a></sup><br />
<ul>
<li>Remember to carefully wash any vegetables or fruit, before consuming them, whether you prefer them fresh or cooked.</li>
</ul>
</div>
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</div>
</li>
<li class="hasad"><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-4-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-4-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-4-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 4" class="whcdn" data-mce-src="http://pad1.whstatic.com/images/thumb/3/3b/Kill-Norovirus-Step-4-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-4-Version-2.jpg.webp" src="http://pad1.whstatic.com/images/thumb/3/3b/Kill-Norovirus-Step-4-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-4-Version-2.jpg.webp" data-src="http://pad1.whstatic.com/images/thumb/3/3b/Kill-Norovirus-Step-4-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-4-Version-2.jpg" height="546" id="img_5755915623162" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
4</div>
<div class="step">
<b class="whb">Cook your food thoroughly before eating it.</b> Seafood should be cooked thoroughly before eating it. Quick steaming your food will generally not kill the virus, as it can survive the steaming process. Instead, bake or boil your food at temperatures higher than 140F (60C) if you are concerned about it’s origins.<sup class="reference" id="_ref-3"><a data-mce-href="http://www.wikihow.com/Kill-Norovirus#_note-3" href="http://www.wikihow.com/Kill-Norovirus#_note-3">[3]</a></sup><br />
<ul>
<li>If you suspect any kind of food of being contaminated, you should dispose of it immediately. For instance, if a contaminated family member handled the food, you should either throw the food out or isolate it and make sure that only the person who already has the virus eats it.</li>
</ul>
</div>
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</div>
<div class="adunit2 dfpad">
</div>
</li>
</ol>
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</div>
</div>
</div>
<a class="anchor mce-item-anchor" href="https://www.blogger.com/null" name="Killing_Norovirus_in_Your_Home_sub" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url(http://www.allfordrugs.com/wp-includes/js/tinymce/skins/lightgray/img/anchor.gif) 50% 50% no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;"></a><br />
<div class="section steps sticky ">
<div class="altblock">
Method2</div>
<h3 class="">
<span class="mw-headline" id="Killing_Norovirus_in_Your_Home">Killing Norovirus in Your Home</span></h3>
<div class="section_text" id="steps_2">
<ol class="steps_list_2">
<li class="hasad"><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-5-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-5-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-5-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 5" class="whcdn" data-mce-src="http://pad2.whstatic.com/images/thumb/4/47/Kill-Norovirus-Step-5-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-5-Version-2.jpg.webp" src="http://pad2.whstatic.com/images/thumb/4/47/Kill-Norovirus-Step-5-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-5-Version-2.jpg.webp" data-src="http://pad2.whstatic.com/images/thumb/4/47/Kill-Norovirus-Step-5-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-5-Version-2.jpg" height="546" id="img_575591562326a" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
1</div>
<div class="step">
<b class="whb">Use bleach to clean surfaces.</b> Chlorine bleach is an effective cleaning agent that kills norovirus. Increase the concentration or buy a new bottle of chlorine bleach if the bleach you have has been open for more than a month. Bleach becomes less effective the longer it remains open. Before applying bleach to a visible surface, test it somewhere that is not easily seen to make sure that it won’t damage the surface. If the surface is damaged by bleach, you can also use phenolic solutions, such as Pine-Sol, to clean the surface. There are certain concentrations of chlorine bleach you can use for different surfaces.<sup class="reference" id="_ref-4"><a data-mce-href="http://www.wikihow.com/Kill-Norovirus#_note-4" href="http://www.wikihow.com/Kill-Norovirus#_note-4">[4]</a></sup><br />
<ul>
<li>For stainless steel surfaces and items used for food consumption: Dissolve one tablespoon of bleach in a gallon of water and clean the stainless steel.</li>
<li>For non-porous surfaces like countertops, sinks, or tile floors: Dissolve one third of a cup of bleach in a gallon of water.</li>
<li>For porous surfaces, like wooden floors: Dissolve one and two thirds of a cup of bleach in a gallon of water.</li>
</ul>
</div>
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</div>
<div class="dfpad">
</div>
</li>
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-6-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-6-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-6-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 6" class="whcdn" data-mce-src="http://pad2.whstatic.com/images/thumb/3/37/Kill-Norovirus-Step-6-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-6-Version-2.jpg.webp" src="http://pad2.whstatic.com/images/thumb/3/37/Kill-Norovirus-Step-6-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-6-Version-2.jpg.webp" data-src="http://pad2.whstatic.com/images/thumb/3/37/Kill-Norovirus-Step-6-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-6-Version-2.jpg" height="546" id="img_575591562336f" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
2</div>
<div class="step">
<b class="whb">Rinse surfaces with clean water after using bleach.</b> After cleaning the surfaces, leave the solution to work for 10 to 20 minutes. After the time period elapses, rinse the surface with clean water. After these two steps, close off the area, and leave it like that for one hour.<br />
<ul>
<li>Leave the windows open, if possible, as breathing in bleach can be hazardous to your health.</li>
</ul>
</div>
<div class="clearall">
</div>
</li>
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-7-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-7-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-7-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 7" class="whcdn" data-mce-src="http://pad1.whstatic.com/images/thumb/8/83/Kill-Norovirus-Step-7-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-7-Version-2.jpg.webp" src="http://pad1.whstatic.com/images/thumb/8/83/Kill-Norovirus-Step-7-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-7-Version-2.jpg.webp" data-src="http://pad1.whstatic.com/images/thumb/8/83/Kill-Norovirus-Step-7-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-7-Version-2.jpg" height="546" id="img_5755915623471" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
3</div>
<div class="step">
<b class="whb">Clean areas exposed to feces or vomit.</b> For areas exposed to feces or vomit contamination there are special cleaning procedures that you should try to follow. This is because the vomit or feces of a person contaminated with norovirus can easily cause you to become infected. To clean the vomit or feces:<br />
<ul>
<li>Put disposable gloves on. Consider wearing a facemask that covers your mouth and nose as well.</li>
<li>Using paper towels, gently clean the vomit and feces. Be careful not to splash or drip while cleaning.</li>
<li>Use disposable cloths to clean and disinfect the entire area with chlorine bleach.</li>
<li>Use sealed plastic bags to dispose of all the waste materials.</li>
</ul>
</div>
<div class="clearall">
</div>
</li>
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-8-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-8-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-8-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 8" class="whcdn" data-mce-src="http://pad2.whstatic.com/images/thumb/9/90/Kill-Norovirus-Step-8-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-8-Version-2.jpg.webp" src="http://pad2.whstatic.com/images/thumb/9/90/Kill-Norovirus-Step-8-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-8-Version-2.jpg.webp" data-src="http://pad2.whstatic.com/images/thumb/9/90/Kill-Norovirus-Step-8-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-8-Version-2.jpg" height="546" id="img_5755915623571" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
4</div>
<div class="step">
<b class="whb">Clean your carpets.</b> If the feces or vomit gets on a carpeted area, there are other steps you can take to make sure that the area is clean and disinfected. To clean the carpeted area:<br />
<ul>
<li>Wear disposable gloves if you can while cleaning the carpets. You should also consider wearing a facemask that covers your mouth and nose.</li>
<li>Use any absorbent material to clean all the visible feces or vomit. Place all contaminated materials in a plastic bag to prevent aerosols from forming. The bag should be sealed and put into the garbage can.</li>
<li>The carpet should then be cleaned with steam at 170 degrees Fahrenheit (76 degrees Celsius) for about five minutes, or, if you want to save time, clean the carpet for one minute with 212 degrees Fahrenheit (100 degrees Celsius) steam.</li>
</ul>
</div>
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</li>
<li class="hasad"><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-9-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-9-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-9-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 9" class="whcdn" data-mce-src="http://pad1.whstatic.com/images/thumb/f/fa/Kill-Norovirus-Step-9-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-9-Version-2.jpg.webp" src="http://pad1.whstatic.com/images/thumb/f/fa/Kill-Norovirus-Step-9-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-9-Version-2.jpg.webp" data-src="http://pad1.whstatic.com/images/thumb/f/fa/Kill-Norovirus-Step-9-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-9-Version-2.jpg" height="546" id="img_5755915623672" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
5</div>
<div class="step">
<b class="whb">Disinfect clothing.</b> If any of your clothing or a family member’s clothing has become contaminated, or is suspected of having been contaminated, you should take care when washing the fabric. To clean clothing and linens:<br />
<ul>
<li>Remove any traces of vomit or feces by wiping it away with paper towels or a disposable absorbent material.</li>
<li>Put the contaminated clothing into the washing machine in a pre-wash cycle. After this stage is complete, wash the clothes using a regular washing cycle and detergent. The clothes should be dried separately from the uncontaminated clothes. A drying temperature exceeding 170 degrees Fahrenheit is recommended.</li>
<li>Do not wash contaminated clothing with uncontaminated cleaning.</li>
</ul>
</div>
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</div>
<div class="adunit3 dfpad">
</div>
</li>
</ol>
<div class="clearall">
</div>
</div>
</div>
<a class="anchor mce-item-anchor" href="https://www.blogger.com/null" name="Treating_Norovirus_sub" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url(http://www.allfordrugs.com/wp-includes/js/tinymce/skins/lightgray/img/anchor.gif) 50% 50% no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;"></a><br />
<div class="section steps sticky ">
<div class="altblock">
Method3</div>
<h3 class="">
<span class="mw-headline" id="Treating_Norovirus">Treating Norovirus</span></h3>
<div class="section_text" id="steps_3">
<ol class="steps_list_2">
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-10-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-10-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-10-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 10" class="whcdn" data-mce-src="http://pad2.whstatic.com/images/thumb/8/8e/Kill-Norovirus-Step-10-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-10-Version-2.jpg.webp" src="http://pad2.whstatic.com/images/thumb/8/8e/Kill-Norovirus-Step-10-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-10-Version-2.jpg.webp" data-src="http://pad2.whstatic.com/images/thumb/8/8e/Kill-Norovirus-Step-10-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-10-Version-2.jpg" height="546" id="img_575591562377d" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
1</div>
<div class="step">
<b class="whb">Recognize symptoms.</b> If you think you may have been infected with norovirus, it is helpful to know what symptoms to look for. If you do have the virus, the following steps will help you to deal with the illness while it lasts. Symptoms include<sup class="reference" id="_ref-5"><a data-mce-href="http://www.wikihow.com/Kill-Norovirus#_note-5" href="http://www.wikihow.com/Kill-Norovirus#_note-5">[5]</a></sup>:<br />
<ul>
<li>Fever. Just like in any other infection, the norovirus infection will cause fever. Fever is a way in which the body fights infection. The body temperature will rise, making the virus more vulnerable to the immune system. Your body temperature will most likely rise above 100.4 degrees Fahrenheit (38 degrees Celsius) when suffering from a Norovirus infection.</li>
<li>Headaches. High body temperatures will cause blood vessels to dilate in your entire body, including your head. The high amount of blood inside your head will cause pressure to build up, and the protective membranes covering your brain will suffer inflammation and become painful.</li>
<li>Stomach cramps. Norovirus infections usually settle in the stomach. Your stomach may become inflamed, causing pain.</li>
<li>Diarrhea. Diarrhea is a common symptom of Norovirus contamination. It occurs as a defense mechanism, through which the body is trying to flush out the virus.</li>
<li>Vomiting. Vomiting is another common symptom of an infection with Norovirus. Like in the case of diarrhea, the body is trying to eliminate the virus from the system by vomiting.</li>
</ul>
</div>
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</div>
</li>
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-11-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-11-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-11-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 11" class="whcdn" data-mce-src="http://pad3.whstatic.com/images/thumb/d/db/Kill-Norovirus-Step-11-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-11-Version-2.jpg.webp" src="http://pad3.whstatic.com/images/thumb/d/db/Kill-Norovirus-Step-11-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-11-Version-2.jpg.webp" data-src="http://pad3.whstatic.com/images/thumb/d/db/Kill-Norovirus-Step-11-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-11-Version-2.jpg" height="546" id="img_575591562387b" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
2</div>
<div class="step">
<b class="whb">Understand that while there is no treatment, there are ways to manage symptoms.</b> Unfortunately, there is no specific drug that acts against the virus. However, you can combat the symptoms that the norovirus causes. Remember that the virus is self-limiting, which means that it generally goes away on its own.<br />
<ul>
<li>The virus generally lasts for a few days to a week.</li>
</ul>
</div>
<div class="clearall">
</div>
</li>
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-12-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-12-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-12-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 12" class="whcdn" data-mce-src="http://pad2.whstatic.com/images/thumb/0/0c/Kill-Norovirus-Step-12-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-12-Version-2.jpg.webp" src="http://pad2.whstatic.com/images/thumb/0/0c/Kill-Norovirus-Step-12-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-12-Version-2.jpg.webp" data-src="http://pad2.whstatic.com/images/thumb/0/0c/Kill-Norovirus-Step-12-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-12-Version-2.jpg" height="546" id="img_5755915623977" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
3</div>
<div class="step">
<b class="whb">Drink lots of fluids.</b> Consuming a lot of water and other fluids will help to keep you hydrated. This can help to keep your fever low and your headaches to a minimum. It is also important to drink water if you have been vomiting or have had diarrhea. When these too symptoms occur, it is very likely that you will become dehydrated.<br />
<ul>
<li>If you get bored with water, you can drink ginger tea, which may help to manage your stomach pains while also hydrating you.</li>
</ul>
</div>
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</div>
</li>
<li><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-13-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-13-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-13-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 13" class="whcdn" data-mce-src="http://pad3.whstatic.com/images/thumb/8/81/Kill-Norovirus-Step-13-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-13-Version-2.jpg.webp" src="http://pad3.whstatic.com/images/thumb/8/81/Kill-Norovirus-Step-13-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-13-Version-2.jpg.webp" data-src="http://pad3.whstatic.com/images/thumb/8/81/Kill-Norovirus-Step-13-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-13-Version-2.jpg" height="546" id="img_5755915623a72" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
4</div>
<div class="step">
<b class="whb">Consider taking anti-vomiting drugs.</b> Anti-emetic (vomit-preventing) drugs such as ondansetron and domperidone can be given to provide symptomatic relief if you are vomiting frequently.<sup class="reference" id="_ref-6"><a data-mce-href="http://www.wikihow.com/Kill-Norovirus#_note-6" href="http://www.wikihow.com/Kill-Norovirus#_note-6">[6]</a></sup><br />
<ul>
<li>However, keep in mind that these drugs can only be obtained with a prescription from your doctor.</li>
</ul>
</div>
<div class="clearall">
</div>
</li>
<li class="final_li hasad"><div class="mwimg largeimage floatcenter ">
<a class="image lightbox" data-href="/Image:Kill-Norovirus-Step-14-Version-2.jpg?ajax=true&aid=4935630" data-mce-href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-14-Version-2.jpg" href="http://www.wikihow.com/Kill-Norovirus#/Image:Kill-Norovirus-Step-14-Version-2.jpg"><img alt="Image titled Kill Norovirus Step 14" class="whcdn" data-mce-src="http://pad3.whstatic.com/images/thumb/3/38/Kill-Norovirus-Step-14-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-14-Version-2.jpg.webp" src="http://pad3.whstatic.com/images/thumb/3/38/Kill-Norovirus-Step-14-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-14-Version-2.jpg.webp" data-src="http://pad3.whstatic.com/images/thumb/3/38/Kill-Norovirus-Step-14-Version-2.jpg/aid4935630-728px-Kill-Norovirus-Step-14-Version-2.jpg" height="546" id="img_5755915623b6c" style="height: auto; max-width: 100%;" width="728" /></a></div>
<div class="step_num">
5</div>
<div class="step">
<b class="whb">Seek medical help if the infection is severe.</b> As mentioned above, most infections subside after a few days. If the virus persists for longer than a week, you should consider seeking medical help. This is particularly important if the person who is sick is a child or elderly person, or a person with lowered immunity</div>
</li>
</ol>
</div>
</div>
</div>
<div class="mod-article-meta" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div class="keywords normal ">
////////////norovirus, heterocyclic carboxamide, antiviral activity, murine norovirus</div>
<div class="keywords normal ">
Brc1cc(Br)sc1C(=O)Nc2nc3c(F)cc(F)cc3s2</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-569892385714118127.post-84363632839195492152016-06-07T09:55:00.002+05:302016-06-07T09:55:31.853+05:30Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate<div dir="ltr" style="text-align: left;" trbidi="on">
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<img alt="" class="" data-mce-src="https://www.jstage.jst.go.jp/pub/cpb/64/4/64_c15-00838/figure/64_c15-00838.png" height="377" src="https://www.jstage.jst.go.jp/pub/cpb/64/4/64_c15-00838/figure/64_c15-00838.png" style="height: auto; max-width: 100%;" width="908" /></div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<br /></div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
The aim of this study was to prepare and evaluate solid dispersion tablets containing a poorly water-soluble drug using porous calcium silicate (PCS) by a wet granulation method. Nifedipine (NIF) was used as the model poorly water-soluble drug. Solid dispersion tablets were prepared with the wet granulation method using ethanol and water by a high-speed mixer granulator. The binder and disintegrant were selected from 7 and 4 candidates, respectively. The dissolution test was conducted using the JP 16 paddle method. The oral absorption of NIF was studied in fasted rats. Xylitol and crospovidone were selected as the binder and disintegrant, respectively. The dissolution rates of NIF from solid dispersion formulations were markedly enhanced compared with NIF powder and physical mixtures. Powder X-ray diffraction (PXRD) confirmed the reduced crystallinity of NIF in the solid dispersion formulations. Fourier transform infrared (FT-IR) showed the physical interaction between NIF and PCS in the solid dispersion formulations. NIF is present in an amorphous state in granules prepared by the wet granulation method using water. The area under the plasma concentration–time curve (<i>AUC</i>) and peak concentration (<i>C</i><sub>max</sub>) values of NIF after dosing rats with the solid dispersion granules were significantly greater than those after dosing with NIF powder. The solid dispersion formulations of NIF prepared with PCS using the wet granulation method exhibited accelerated dissolution rates and superior oral bioavailability. This method is very simple, and may be applicable to the development of other poorly water-soluble drugs.</div>
<div class="mod-article-meta" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div class="date normal inner-left">
<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article" href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article">https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article</a></div>
<div class="date normal inner-left">
</div>
</div>
<div class="date normal inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media.......... <a data-mce-href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article" href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article">read</a> all</div>
<div class="date normal inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<h1 id="sec04">
Conclusion</h1>
<div class="fj-sec-p">
Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.</div>
</div>
<h2 class="mod-article-heading inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Preparation and Evaluation of Solid Dispersion Tablets by a Simple and Manufacturable Wet Granulation Method Using Porous Calcium Silicate</h2>
<div class="mod-article-meta" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div class="author normal inner-left">
<a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yumi+Fujimoto" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yumi+Fujimoto">Yumi Fujimoto<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Nobuaki+Hirai" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Nobuaki+Hirai">Nobuaki Hirai<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Tomoka+Takatani-Nakase" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Tomoka+Takatani-Nakase">Tomoka Takatani-Nakase<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Koichi+Takahashi" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Koichi+Takahashi">Koichi Takahashi<sup>1)</sup></a></div>
<div class="affiliation normal inner-left">
1) Department of Pharmaceutics, School of Pharmaceutical Sciences, Mukogawa Women’s University</div>
<div class="date normal inner-left">
<input alt="" data-mce-src="https://www.jstage.jst.go.jp/pub/images/icon_toggle_plus.png" height="10" src="https://www.jstage.jst.go.jp/pub/images/icon_toggle_plus.png" type="image" width="10" /> Released on J-STAGE 20160401</div>
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<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article" href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article">https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article</a></div>
<div class="date normal inner-left">
</div>
</div>
<div class="date normal inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
The ‘Biopharmaceutics Classification System’ (BCS) is a very important key word in the research and development of oral formulations. The BCS classifies drugs into four classes depending on the solubility and membrane permeability of the drug. Most oral formulations show drug efficacy by first dissolving in the digestive tract then being absorbed through the membrane of the small intestine, thus entering the circulation. Oral formulations have been developed using various strategies depending on the drug’s BCS class, solubility, and membrane permeability. It was recently estimated that between 40 and 70% of all new chemical entities identified in drug discovery programs are insufficiently soluble in aqueous media.......... <a data-mce-href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article" href="https://www.jstage.jst.go.jp/article/cpb/64/4/64_c15-00838/_article">read</a> all</div>
<div class="date normal inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<h1 id="sec04">
Conclusion</h1>
<div class="fj-sec-p">
Solid dispersion formulations of NIF with PCS using the wet granulation method were prepared and evaluated. These formulations exhibited much higher dissolution rates than NIF powder, comparable to ASD. Furthermore, these formulations provided superior bioavailability in rats compared with NIF powder. NIF was present in the amorphous state in the granules after preparation by a wet granulation method using water. The wet granulation method proposed here is very simple, and may be applicable to other poorly water-soluble drugs.</div>
</div>
<div class="mod-article-meta" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div class="keywords normal ">
//////////////// poorly water-soluble drug, porous calcium silicate (PCS), wet granulation method, dissolution, surface solid dispersion, high-speed mixer granulator,</div>
</div>
</div>
DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-60405907487761424012016-06-07T09:54:00.002+05:302016-06-07T09:54:36.635+05:30A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters<div dir="ltr" style="text-align: left;" trbidi="on">
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<a href="https://www.jstage.jst.go.jp/A_PRedirectJournalInit?sryCd=cpb&noVol=64&noIssue=3&kijiCd=64_c15-00644&fromScreenID=AF06S010&norec=1&screenID=AF90S010&languagekind=en" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" target="_blank"><img alt="" src="https://www.jstage.jst.go.jp/pub/cpb/64/3/64_c15-00644/figure/64_c15-00644.png" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></a></div>
<div style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
In the pharmaceutical tablet film coating process, we clarified that a difference in exhaust air relative humidity can be used to detect differences in process parameters values, the relative humidity of exhaust air was different under different atmospheric air humidity conditions even though all setting values of the manufacturing process parameters were the same, and the water content of tablets was correlated with the exhaust air relative humidity. Based on this experimental data, the exhaust air relative humidity index (EHI), which is an empirical equation that includes as functional parameters the pan coater type, heated air flow rate, spray rate of coating suspension, saturated water vapor pressure at heated air temperature, and partial water vapor pressure at atmospheric air pressure, was developed. The predictive values of exhaust relative humidity using EHI were in good correlation with the experimental data (correlation coefficient of 0.966) in all datasets. EHI was verified using the date of seven different drug products of different manufacturing scales. The EHI model will support formulation researchers by enabling them to set film coating process parameters when the batch size or pan coater type changes, and without the time and expense of further extensive testing.</div>
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EHI is defined as the following equation:</div>
<div id="equation1" style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin: 0px; outline: 0px; padding: 0px;">
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In general, pharmaceutical film coatings are applied in order to protect core tablets from light or for masking the taste of the active pharmaceutical ingredients. Therefore, the surface state of the coating layer is important to maintain the expected performance. During the coating process, however, the coating layer surface state is affected by the water content of the tablets. In a conventional approach, the water content of drug products is maintained at the validated level by monitoring the product’s temperature and/or the exhaust air temperature during the coating process. In a scale up study, the batch scale and manufacturing equipment are changed according to the progress of the process development stage. At each stage, the water content of drug products is constantly monitored and well-controlled to secure the consistency of the drug product’s quality. In this approach, numerous experiments are necessary to optimize the process parameters in each batch scale. As a result, the costs of materials, human resources, and time for development will become considerable.</div>
<h2 class="mod-article-heading inner-left" style="background-color: white; border: 0px; color: #333333; font-family: Arial, Helvetica, sans-serif; font-size: 25.4736003875732px; font-weight: normal; line-height: 1.1em; margin: 0.5em 0px; outline: 0px; padding: 0px;">
A Novel Scale Up Model for Prediction of Pharmaceutical Film Coating Process Parameters</h2>
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<a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yasuhiro+Suzuki" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Yasuhiro Suzuki<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">1)</span></a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Tatsuya+Suzuki" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Tatsuya Suzuki<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">1)</span></a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Hidemi+Minami" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Hidemi Minami<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">1)</span></a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Katsuhide+Terada" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Katsuhide Terada<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">2)</span></a></div>
<div class="affiliation normal inner-left" style="border: 0px; font-size: 13.9200000762939px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
1) Formulation Technology Research Laboratories, Daiichi Sankyo Co., Ltd. 2) Faculty of Pharmaceutical Science, Toho University</div>
<div class="date normal inner-left" style="background: url(http://www.allfordrugs.com/wp-content/themes/suffusion/images/caldark.png) no-repeat; border: 0px; color: white; float: left; font-size: 20.8799991607666px; font-stretch: normal; height: 48px; line-height: 20.8799991607666px; margin: 0px 0px 0px -893px; outline: 0px; padding: 0px; position: relative; right: 58px; text-align: center; width: 48px;">
<a href="https://www.blogger.com/null" id="main_toggleC1" style="border: 0px; color: #227ad1; margin: 0px; outline: 0px; padding: 0px;"></a><input alt="" height="10" src="https://www.jstage.jst.go.jp/pub/images/icon_toggle_plus.png" style="border-color: rgb(204, 204, 204) rgb(170, 170, 170) rgb(170, 170, 170) rgb(204, 204, 204); border-style: solid; border-width: 1px; line-height: 1.5em; padding: 5px 3px 3px 5px;" type="image" width="10" />Released on J-STAGE 20160301</div>
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<a href="https://www.jstage.jst.go.jp/article/cpb/64/3/64_c15-00644/_article" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">https://www.jstage.jst.go.jp/article/cpb/64/3/64_c15-00644/_article</a></div>
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<h1 class="mod-page-heading" style="background-color: white; border: 0px; color: #333333; font-family: Arial, Helvetica, sans-serif; font-size: 27.8400001525879px; font-weight: normal; line-height: 1.1em; margin: 0.5em 0px; outline: 0px; padding: 0px;">
Chemical and Pharmaceutical Bulletin<br /><a href="https://www.jstage.jst.go.jp/AF06S010SryTopHyj?sryCd=cpb&noVol=64&noIssue=" style="border: 0px; color: #227ad1; font-size: 27.8400001525879px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Vol. 64</a> (2016) <a href="https://www.jstage.jst.go.jp/AF06S010SryTopHyj?sryCd=cpb&noVol=64&noIssue=3" style="border: 0px; color: #227ad1; font-size: 27.8400001525879px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">No. 3</a> p. 215-221</h1>
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http://doi.org/10.1248/cpb.c15-00644</div>
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Conclusion</h1>
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In this study, the relationship between film coating process parameters and EARH was clarified. In addition, it was confirmed that the EARH affected the water content of tablets. These results indicated that the water content of tablets can be regulated by controlling the EARH. From these results, we proposed the EHI for quantification of the pharmaceutical film coating process. The fitting parameters in the EHI equation were set using the experimental data of 10 drug products and 7 kinds of pan coaters. These fitting parameters of EHI were validated by evaluating the correlation coefficient determined by comparing the calculated values of EARH and the measured experimental values of EARH from various drug products, pan coater scales and coating parameters. The main advantage of the EHI method is that commercial scale coating conditions can be predicted using only one film coating experimental result from a lab-scale pan coater.</div>
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/////////<a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=pan+coater" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">pan coater</a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=exhaust+air+relative+humidity+index+%28EHI%29" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">exhaust air relative humidity index (EHI)</a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=scale+up" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">scale up</a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=drying+ability" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">drying ability</a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=atmospheric+air" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">atmospheric air</a>, <a href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=tablet+water+content" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">tablet water content</a></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-23573593484903971152016-06-06T12:47:00.001+05:302016-06-06T12:47:58.267+05:30Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism<div dir="ltr" style="text-align: left;" trbidi="on">
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<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/Graphics/figure1.png" href="https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/Graphics/figure1.png" target="_blank"><img alt="" class="" data-mce-src="https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/Graphics/figure1.png" height="956" src="https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/Graphics/figure1.png" style="height: auto; max-width: 100%;" width="724" /></a><br />Fig. 1. Schematic Representation of a Complex Fluidized-Bed Granulator</div>
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1: Exhaust air, 2: bag filter, 3: partition tube, 4: impeller, 5: rotor disc, 6: inlet air, 7: screen, 8: spray nozzle.</div>
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<h2 class="mod-article-heading inner-left" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Preparation of Fine Particles with Improved Solubility Using a Complex Fluidized-Bed Granulator Equipped with a Particle-Sizing Mechanism</h2>
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<div class="author normal inner-left">
<a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Shouichi+Hosaka" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Shouichi+Hosaka">Shouichi Hosaka<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yasufumi+Okamura" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yasufumi+Okamura">Yasufumi Okamura<sup>1)</sup></a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yuji+Tokunaga" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?chshnmHkwtsh=Yuji+Tokunaga">Yuji Tokunaga<sup>1)</sup></a></div>
<div class="affiliation normal inner-left">
1) Research and Development Division, Sawai Pharmaceutical Co., Ltd.</div>
<div class="affiliation normal inner-left">
Released on J-STAGE 20160601</div>
<h1 class="mod-page-heading">
Chemical and Pharmaceutical Bulletin<br /><a data-mce-href="https://www.jstage.jst.go.jp/AF06S010SryTopHyj?sryCd=cpb&noVol=64&noIssue=" href="https://www.jstage.jst.go.jp/AF06S010SryTopHyj?sryCd=cpb&noVol=64&noIssue=">Vol. 64</a> (2016) <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010SryTopHyj?sryCd=cpb&noVol=64&noIssue=6" href="https://www.jstage.jst.go.jp/AF06S010SryTopHyj?sryCd=cpb&noVol=64&noIssue=6">No. 6</a> p. 644-649</h1>
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http://doi.org/10.1248/cpb.c15-00640</div>
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<a data-mce-href="https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/_html" href="https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/_html">https://www.jstage.jst.go.jp/article/cpb/64/6/64_c15-00640/_html</a></div>
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<h1 id="abstract" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Abstract</h1>
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A new type of fluidized-bed granulator equipped with a particle-sizing mechanism was used for the preparation of fine particles that improved the solubility of a poorly water-soluble drug substance. Cefteram pivoxyl (CEF) was selected as a model drug substance, and its solution with a hydrophilic polymer, hydroxypropyl cellulose (HPC-L), was sprayed on granulation grade lactose monohydrate (Lac). Three types of treated particles were prepared under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable. By processing CEF with HPC-L using a complex fluidized-bed granulator equipped with a particle-sizing mechanism, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed CEF. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile. This technique may represent a method with which to design fine particles of approximately 100 µm in size with a narrow distribution, which can improve the solubility of a drug substance with low solubility.</div>
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<h1 id="sec04" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Conclusion</h1>
<div class="fj-sec-p" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
Three types of treated particles were prepared using a complex fluidized-bed granulator equipped with a particle-sizing mechanism under different conditions focused on the spraying air pressure and the amount of HPC-L. When the amount of HPC-L was changed, the size of the obtained particles was similar. However, particle size distribution was dependent on the amount of HPC-L. Its distribution became more homogenous with greater amounts of HPC-L, but the particle size distribution obtained by decreasing the spraying air pressure was not acceptable.</div>
<div class="fj-sec-p" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
By processing CEF with HPC-L using this device, the dissolution ratio was elevated by approximately 40% compared to that of unprocessed one. Moreover, in the dissolution profile of treated CEF, the initial burst was suppressed, and nearly zero order release was observed up to approximately 60% in the dissolution profile.</div>
<div class="fj-sec-p" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
The present method is applicable to the design of fine particles of approximately 100 µm in size with a narrow distribution, which improved the solubility of drug substance.</div>
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////////<a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=fine+particle" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=fine+particle">fine particle</a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=particle+size+distribution" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=particle+size+distribution">particle size distribution</a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=dissolution" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=dissolution">dissolution</a>, <a data-mce-href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=complex+fluidized-bed+granulator" href="https://www.jstage.jst.go.jp/AF06S010ShsiKskGmnHyj?keywdHkwtsh=complex+fluidized-bed+granulator">complex fluidized-bed granulator</a></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com1tag:blogger.com,1999:blog-569892385714118127.post-35611255078190158932016-06-06T12:11:00.000+05:302016-06-06T12:11:09.414+05:30Nanomedicine<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="" src="http://www.rccorp.us/img/blue.png" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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<b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nanomedicine</b> is the medical application of <a href="https://en.wikipedia.org/wiki/Nanotechnology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanotechnology">nanotechnology</a>.<span class="reference" id="cite_ref-Nanomed1_1-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Nanomed1-1" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[1]</a></span> Nanomedicine ranges from the medical applications of <a href="https://en.wikipedia.org/wiki/Nanomaterials" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanomaterials">nanomaterials</a>and<a href="https://en.wikipedia.org/wiki/BioBrick" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="BioBrick">biological devices</a>, to <a href="https://en.wikipedia.org/wiki/Nanoelectronics" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoelectronics">nanoelectronic</a> biosensors, and even possible future applications of <a href="https://en.wikipedia.org/wiki/Molecular_nanotechnology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Molecular nanotechnology">molecular nanotechnology</a> such as<a href="https://en.wikipedia.org/wiki/Molecular_machine#Biological" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Molecular machine">biological machines</a>. Current problems for nanomedicine involve understanding the issues related to <a href="https://en.wikipedia.org/wiki/Nanotoxicology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanotoxicology">toxicity</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Implications_of_nanotechnology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Implications of nanotechnology">environmental impact</a> of <a href="https://en.wikipedia.org/wiki/Nanomaterials" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanomaterials">nanoscale materials</a> (materials whose structure is on the scale of nanometers, i.e. billionths of a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Meter" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Meter">meter</a>).</div>
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Functionalities can be added to nanomaterials by interfacing them with biological molecules or structures. The size of nanomaterials is similar to that of most biological molecules and structures; therefore, nanomaterials can be useful for both in vivo and in vitro biomedical research and applications. Thus far, the integration of nanomaterials with biology has led to the development of diagnostic devices, contrast agents, analytical tools, physical therapy applications, and drug delivery vehicles.</div>
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Nanomedicine seeks to deliver a valuable set of research tools and clinically useful devices in the near future.<span class="reference" id="cite_ref-2" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-2" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[2]</a></span><span class="reference" id="cite_ref-3" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-3" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[3]</a></span> The <a href="https://en.wikipedia.org/wiki/National_Nanotechnology_Initiative" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="National Nanotechnology Initiative">National Nanotechnology Initiative</a> expects new commercial applications in the <a href="https://en.wikipedia.org/wiki/Pharmaceutical_industry" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Pharmaceutical industry">pharmaceutical industry</a> that may include advanced drug delivery systems, new therapies, and <a href="https://en.wikipedia.org/wiki/In_vivo" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="In vivo">in vivo</a>imaging.<span class="reference" id="cite_ref-4" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-4" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[4]</a></span> Nanomedicine research is receiving funding from the US <a href="https://en.wikipedia.org/wiki/National_Institutes_of_Health" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="National Institutes of Health">National Institutes of Health</a>, including the funding in 2005 of a five-year plan to set up four nanomedicine centers.</div>
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Nanomedicine is a large industry, with nanomedicine sales reaching $6.8 billion in 2004, and with over 200 companies and 38 products worldwide, a minimum of $3.8 billion in nanotechnology R&D is being invested every year.<span class="reference" id="cite_ref-5" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-5" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[5]</a></span> In April 2006, the journal <a href="https://en.wikipedia.org/wiki/Nature_Materials" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nature Materials">Nature Materials</a>estimated that 130 nanotech-based drugs and delivery systems were being developed worldwide.<span class="reference" id="cite_ref-6" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-6" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[6]</a></span> As the nanomedicine industry continues to grow, it is expected to have a significant impact on the economy.</div>
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<span class="mw-headline" id="Drug_delivery" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">Drug delivery</span></h2>
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<a href="https://en.wikipedia.org/wiki/Nanoparticle" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoparticle">Nanoparticles</a> <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">(top)</i>, <a href="https://en.wikipedia.org/wiki/Liposome" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Liposome">liposomes</a><i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">(middle)</i>, and <a href="https://en.wikipedia.org/wiki/Dendrimer" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Dendrimer">dendrimers</a> <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">(bottom)</i>are some <a href="https://en.wikipedia.org/wiki/Nanomaterials" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanomaterials">nanomaterials</a> being investigated for use in nanomedicine.</div>
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Nanotechnology has provided the possibility of delivering drugs to specific cells using nanoparticles.</div>
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The overall drug consumption and side-effects may be lowered significantly by depositing the active agent in the morbid region only and in no higher dose than needed. Targeted drug delivery is intended to reduce the side effects of drugs with concomitant decreases in consumption and treatment expenses. <a href="https://en.wikipedia.org/wiki/Drug_delivery" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Drug delivery">Drug delivery</a> focuses on maximizing <a href="https://en.wikipedia.org/wiki/Bioavailability" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Bioavailability">bioavailability</a> both at specific places in the body and over a period of time. This can potentially be achieved by molecular targeting by nanoengineered devices.<span class="reference" id="cite_ref-7" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-7" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[7]</a></span><span class="reference" id="cite_ref-8" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-8" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[8]</a></span> More than $65 billion are wasted each year due to poor bioavailability. A benefit of using nanoscale for medical technologies is that smaller devices are less invasive and can possibly be implanted inside the body, plus biochemical reaction times are much shorter. These devices are faster and more sensitive than typical drug delivery.<span class="reference" id="cite_ref-9" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-9" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[9]</a></span> The efficacy of drug delivery through nanomedicine is largely based upon: a) efficient encapsulation of the drugs, b) successful delivery of drug to the targeted region of the body, and c) successful release of the drug.</div>
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Drug delivery systems, lipid- <span class="reference" id="cite_ref-10" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-10" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[10]</a></span> or polymer-based nanoparticles,<span class="reference" id="cite_ref-youtube.com_11-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-youtube.com-11" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[11]</a></span> can be designed to improve the <a href="https://en.wikipedia.org/wiki/Pharmacokinetics" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Pharmacokinetics">pharmacokinetics</a> and <a href="https://en.wikipedia.org/wiki/Biodistribution" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Biodistribution">biodistribution</a> of the drug.<span class="reference" id="cite_ref-12" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-12" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[12]</a></span><span class="reference" id="cite_ref-13" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-13" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[13]</a></span><span class="reference" id="cite_ref-14" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-14" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[14]</a></span> However, the pharmacokinetics and pharmacodynamics of nanomedicine is highly variable among different patients.<span class="reference" id="cite_ref-15" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-15" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[15]</a></span>When designed to avoid the body’s defence mechanisms,<span class="reference" id="cite_ref-:0_16-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-:0-16" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[16]</a></span> nanoparticles have beneficial properties that can be used to improve drug delivery. Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranes and into cell<a href="https://en.wikipedia.org/wiki/Cytoplasm" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Cytoplasm">cytoplasm</a>. Triggered response is one way for drug molecules to be used more efficiently. Drugs are placed in the body and only activate on encountering a particular signal. For example, a drug with poor solubility will be replaced by a drug delivery system where both hydrophilic and hydrophobic environments exist, improving the solubility.<span class="reference" id="cite_ref-17" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-17" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[17]</a></span> Drug delivery systems may also be able to prevent tissue damage through regulated drug release; reduce drug clearance rates; or lower the volume of distribution and reduce the effect on non-target tissue. However, the biodistribution of these nanoparticles is still imperfect due to the complex host’s reactions to nano- and microsized materials<span class="reference" id="cite_ref-:0_16-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-:0-16" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[16]</a></span> and the difficulty in targeting specific organs in the body. Nevertheless, a lot of work is still ongoing to optimize and better understand the potential and limitations of nanoparticulate systems. While advancement of research proves that targeting and distribution can be augmented by nanoparticles, the dangers of nanotoxicity become an important next step in further understanding of their medical uses.<span class="reference" id="cite_ref-18" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-18" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[18]</a></span></div>
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Nanoparticles can be used in combination therapy for decreasing <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibiotic_resistance" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Antibiotic resistance">antibiotic resistance</a> or for their antimicrobial properties.<span class="reference" id="cite_ref-19" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-19" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[19]</a></span><span class="reference" id="cite_ref-20" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-20" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[20]</a></span><span class="reference" id="cite_ref-21" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-21" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[21]</a></span>Nanoparticles might also used to circumvent <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Multidrug_resistance" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Multidrug resistance">multidrug resistance</a> (MDR) mechanisms.<span class="reference" id="cite_ref-22" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-22" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[22]</a></span></div>
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<span class="mw-headline" id="Types_of_systems_used" style="border: 0px; font-size: 23.1072006225586px; margin: 0px; outline: 0px; padding: 0px;">Types of systems used</span></h3>
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Two forms of nanomedicine that have already been tested in mice and are awaiting human trials that will be using gold <a href="https://en.wikipedia.org/wiki/Nanoshell" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoshell">nanoshells</a> to help diagnose and treat cancer,<span class="reference" id="cite_ref-23" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-23" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[23]</a></span> and using <a href="https://en.wikipedia.org/wiki/Liposome" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Liposome">liposomes</a> as <a href="https://en.wikipedia.org/wiki/Vaccine" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Vaccine">vaccine</a> adjuvants and as vehicles for drug transport.<span class="reference" id="cite_ref-24" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-24" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[24]</a></span><span class="reference" id="cite_ref-25" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-25" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[25]</a></span> Similarly, drug detoxification is also another application for nanomedicine which has shown promising results in rats.<span class="reference" id="cite_ref-26" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-26" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[26]</a></span> Advances in Lipid nanotechnology was also instrumental in engineering medical nanodevices and novel drug delivery systems as well as in developing sensing applications.<span class="reference" id="cite_ref-27" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-27" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[27]</a></span> Another example can be found in <a href="https://en.wikipedia.org/wiki/Dendrimer" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Dendrimer">dendrimers</a> and nanoporous materials. Another example is to use block co-polymers, which form <a href="https://en.wikipedia.org/wiki/Micelle" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Micelle">micelles</a>for drug encapsulation.<span class="reference" id="cite_ref-youtube.com_11-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-youtube.com-11" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[11]</a></span></div>
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Polymeric nano-particles are a competing technology to lipidic (based mainly on <a href="https://en.wikipedia.org/wiki/Phospholipid" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Phospholipid">Phospholipids</a>) nano-particles. There is an additional risk of toxicity associated with polymers not widely studied or understood. The major advantages of polymers is stability, lower cost and predictable characterisation. However, in the patient’s body this very stability (slow degradation) is a negative factor. Phospholipids on the other hand are membrane lipids (already present in the body and surrounding each cell), have a GRAS (Generally Recognised As Safe) status from FDA and are derived from natural sources without any complex chemistry involved. They are not metabolised but rather absorbed by the body and the degradation products are themselves nutrients (fats or micronutrients).</div>
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Protein and peptides exert multiple biological actions in the human body and they have been identified as showing great promise for treatment of various diseases and disorders. These macromolecules are called <a href="https://en.wikipedia.org/wiki/Biopharmaceutical" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Biopharmaceutical">biopharmaceuticals</a>. Targeted and/or controlled delivery of these biopharmaceuticals using <a href="https://en.wikipedia.org/wiki/Nanomaterials" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanomaterials">nanomaterials</a> like <a href="https://en.wikipedia.org/wiki/Nanoparticle" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoparticle">nanoparticles</a> and <a href="https://en.wikipedia.org/wiki/Dendrimer" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Dendrimer">Dendrimers</a> is an emerging field called nanobiopharmaceutics, and these products are called nanobiopharmaceuticals.</div>
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Another highly efficient system for <a href="https://en.wikipedia.org/wiki/MicroRNA" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="MicroRNA">microRNA</a> delivery for example are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nanoparticles" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoparticles">nanoparticles</a> formed by the self-assembly of two different microRNAs deregulated in cancer.<span class="reference" id="cite_ref-28" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-28" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[28]</a></span></div>
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Another vision is based on small electromechanical systems; <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nanoelectromechanical_system" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoelectromechanical system">nanoelectromechanical systems</a> are being investigated for the active release of drugs. Some potentially important applications include cancer treatment with iron nanoparticles or gold shells.Nanotechnology is also opening up new opportunities in implantable delivery systems, which are often preferable to the use of injectable drugs, because the latter frequently display first-order kinetics (the blood concentration goes up rapidly, but drops exponentially over time). This rapid rise may cause difficulties with toxicity, and drug efficacy can diminish as the drug concentration falls below the targeted range.</div>
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<span class="mw-headline" id="Applications" style="border: 0px; font-size: 23.1072006225586px; margin: 0px; outline: 0px; padding: 0px;">Applications</span></h3>
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Some nanotechnology-based drugs that are commercially available or in human clinical trials include:</div>
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<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Abraxane" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Abraxane">Abraxane</a>, approved by the U.S. <a href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Food and Drug Administration">Food and Drug Administration</a> (FDA) to treat <a href="https://en.wikipedia.org/wiki/Breast_cancer" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Breast cancer">breast cancer</a>,<span class="reference" id="cite_ref-29" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-29" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[29]</a></span> <a href="https://en.wikipedia.org/wiki/Non-small-cell_lung_carcinoma" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Non-small-cell lung carcinoma">non-small- cell lung cancer</a> (NSCLC)<span class="reference" id="cite_ref-30" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-30" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[30]</a></span>and <a href="https://en.wikipedia.org/wiki/Pancreatic_cancer" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Pancreatic cancer">pancreatic cancer</a>,<span class="reference" id="cite_ref-31" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-31" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[31]</a></span> is the nanoparticle albumin bound paclitaxel.</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Doxil" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Doxil">Doxil</a> was originally approved by the FDA for the use on HIV-related <a href="https://en.wikipedia.org/wiki/Kaposi%27s_sarcoma" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Kaposi's sarcoma">Kaposi’s sarcoma</a>. It is now being used to also treat ovarian cancer and multiple myeloma. The drug is encased in <a href="https://en.wikipedia.org/wiki/Liposome" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Liposome">liposomes</a>, which helps to extend the life of the drug that is being distributed. Liposomes are self-assembling, spherical, closed colloidal structures that are composed of lipid bilayers that surround an aqueous space. The liposomes also help to increase the functionality and it helps to decrease the damage that the drug does to the heart muscles specifically.<span class="reference" id="cite_ref-32" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-32" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[32]</a></span></li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Onivyde, liposome encapsulated <a href="https://en.wikipedia.org/wiki/Irinotecan" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Irinotecan">irinotecan</a> to treat metastatic pancreatic cancer, was approved by FDA in October 2015.<span class="reference" id="cite_ref-33" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-33" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[33]</a></span></li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">C-dots (Cornell dots) are the smallest silica-based nanoparticles with the size <10 nm. The particles are infused with organic dye which will light up with <a href="https://en.wikipedia.org/wiki/Fluorescence" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Fluorescence">fluorescence</a>. Clinical trial is underway since 2011 to use the C-dots as diagnostic tool to assist surgeons to identify the location of tumor cells.<span class="reference" id="cite_ref-34" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-34" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[34]</a></span></li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">An early phase clinical trial using the platform of ‘Minicell’ nanoparticle for drug delivery have been tested on patients with advanced and untreatable cancer. Built from the membranes of mutant bacteria, the minicells were loaded with <a href="https://en.wikipedia.org/wiki/Paclitaxel" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Paclitaxel">paclitaxel</a> and coated with<a href="https://en.wikipedia.org/wiki/Cetuximab" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Cetuximab">cetuximab</a>, antibodies that bind the <a href="https://en.wikipedia.org/wiki/Epidermal_growth_factor_receptor" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Epidermal growth factor receptor">epidermal growth factor receptor</a> (EGFR) which is often overexpressed in a number of cancers, as a ‘homing’ device to the tumor cells. The tumor cells recognize the bacteria from which the minicells have been derived, regard it as invading <a href="https://en.wikipedia.org/wiki/Microorganism" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Microorganism">microorganism</a> and engulf it. Once inside, the payload of anti-cancer drug kills the tumor cells. Measured at 400 <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nanometers" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanometers">nanometers</a>, the minicell is bigger than synthetic particles developed for drug delivery. The researchers indicated that this larger size gives the minicells a better profile in side-effects because the minicells will preferentially leak out of the porous blood vessels around the tumor cells and do not reach the liver, digestive system and skin. This Phase 1 clinical trial demonstrated that this treatment is well tolerated by the patients. As a platform technology, the minicell drug delivery system can be used to treat a number of different cancers with different anti-cancer drugs with the benefit of lower dose and less side-effects.<span class="reference" id="cite_ref-35" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-35" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[35]</a></span><span class="reference" id="cite_ref-36" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-36" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[36]</a></span></li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">In 2014, a Phase 3 clinical trial for treating inflammation and pain after <a href="https://en.wikipedia.org/wiki/Cataract" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Cataract">cataract</a> surgery, and a Phase 2 trial for treating <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Dry_eye_disease" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Dry eye disease">dry eye disease</a> were initiated using nanoparticle<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Loteprednol_etabonate" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Loteprednol etabonate">loteprednol etabonate</a>.<span class="reference" id="cite_ref-37" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-37" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[37]</a></span> In 2015, the product, KPI-121 was found to produce statistically significant positive results for the post-surgery treatment.<span class="reference" id="cite_ref-38" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-38" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[38]</a></span></li>
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<span class="mw-headline" id="Cancer" style="border: 0px; margin: 0px; outline: 0px; padding: 0px;">Cancer</span></h4>
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Existing and potential drug nanocarriers have been reviewed.<span class="reference" id="cite_ref-39" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-39" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[39]</a></span><span class="reference" id="cite_ref-40" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-40" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[40]</a></span><span class="reference" id="cite_ref-41" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-41" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[41]</a></span><span class="reference" id="cite_ref-42" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-42" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[42]</a></span></div>
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Nanoparticles have high surface area to volume ratio. This allows for many functional groups to be attached to a nanoparticle, which can seek out and bind to certain <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tumor_cell" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Tumor cell">tumor cells</a>. Additionally, the small size of nanoparticles (10 to 100 nanometers), allows them to preferentially accumulate at tumor sites (because tumors lack an effective lymphatic drainage system).<span class="reference" id="cite_ref-43" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-43" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[43]</a></span> Limitations to conventional cancer chemotherapy include drug resistance, lack of selectivity, and lack of solubility. Nanoparticles have the potential to overcome these problems.<span class="reference" id="cite_ref-Chidambaram_44-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Chidambaram-44" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[44]</a></span></div>
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<img alt="" src="http://spie.org/Images/Graphics/Newsroom/Imported-2013/004967/004967_10_fig1.jpg" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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In <a href="https://en.wikipedia.org/wiki/Photodynamic_therapy" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Photodynamic therapy">photodynamic therapy</a>, a particle is placed within the body and is illuminated with light from the outside. The light gets absorbed by the particle and if the particle is metal, energy from the light will heat the particle and surrounding tissue. Light may also be used to produce high energy oxygen molecules which will chemically react with and destroy most organic molecules that are next to them (like tumors). This therapy is appealing for many reasons. It does not leave a “toxic trail” of reactive molecules throughout the body (chemotherapy) because it is directed where only the light is shined and the particles exist. Photodynamic therapy has potential for a noninvasive procedure for dealing with diseases, growth and tumors. <a href="https://en.wikipedia.org/wiki/John_Kanzius" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="John Kanzius">Kanzius RF</a> therapy is one example of such therapy (nanoparticle hyperthermia) . Also, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Gold_nanoparticles" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Gold nanoparticles">gold nanoparticles</a>have the potential to join numerous therapeutic functions into a single platform, by targeting specific tumor cells, tissues and organs.<span class="reference" id="cite_ref-45" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-45" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[45]</a></span><span class="reference" id="cite_ref-46" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-46" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[46]</a></span></div>
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<a class="image" href="https://en.wikipedia.org/wiki/File:Algorithm_cancer_magnetic_nanotherapy.jpg" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Algorithm Cancer Magnetic Nanotherapy"><img alt="Algorithm Cancer Magnetic Nanotherapy" data-file-height="2306" data-file-width="3353" src="https://upload.wikimedia.org/wikipedia/commons/thumb/9/94/Algorithm_cancer_magnetic_nanotherapy.jpg/220px-Algorithm_cancer_magnetic_nanotherapy.jpg" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/9/94/Algorithm_cancer_magnetic_nanotherapy.jpg/330px-Algorithm_cancer_magnetic_nanotherapy.jpg 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/9/94/Algorithm_cancer_magnetic_nanotherapy.jpg/440px-Algorithm_cancer_magnetic_nanotherapy.jpg 2x" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="220" /></a></div>
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<span class="mw-headline" id="Visualization" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">Visualization</span></h2>
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<i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">In vivo</i> imaging is another area where tools and devices are being developed. Using nanoparticle<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Contrast_agents" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Contrast agents">contrast agents</a>, images such as ultrasound and MRI have a favorable distribution and improved contrast. This might be accomplished by self assembled biocompatible nanodevices that will detect, evaluate, treat and report to the clinical doctor automatically.<span class="noprint Inline-Template Template-Fact" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">[<i style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;"><a href="https://en.wikipedia.org/wiki/Wikipedia:Citation_needed" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Wikipedia:Citation needed"><span style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;" title="This claim needs references to reliable sources. (February 2016)">citation needed</span></a></i>]</span></div>
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The small size of nanoparticles endows them with properties that can be very useful in <a href="https://en.wikipedia.org/wiki/Oncology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Oncology">oncology</a>, particularly in imaging. Quantum dots (nanoparticles with quantum confinement properties, such as size-tunable light emission), when used in conjunction with MRI (magnetic resonance imaging), can produce exceptional images of tumor sites. <a href="https://en.wikipedia.org/wiki/Nanoparticle" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoparticle">Nanoparticles</a> of <a href="https://en.wikipedia.org/wiki/Cadmium_selenide" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Cadmium selenide">cadmium selenide</a>(<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Quantum_dots" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Quantum dots">quantum dots</a>) glow when exposed to ultraviolet light. When injected, they seep into cancer <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Tumors" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Tumors">tumors</a>. The surgeon can see the glowing tumor, and use it as a guide for more accurate tumor removal.These nanoparticles are much brighter than organic dyes and only need one light source for excitation. This means that the use of fluorescent quantum dots could produce a higher contrast image and at a lower cost than today’s organic dyes used as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Contrast_media" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Contrast media">contrast media</a>. The downside, however, is that quantum dots are usually made of quite toxic elements.</div>
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<img alt="" src="http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/Articleimage/2011/JM/c0jm03851b/c0jm03851b-f9.gif" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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Tracking movement can help determine how well drugs are being distributed or how substances are metabolized. It is difficult to track a small group of cells throughout the body, so scientists used to dye the cells. These dyes needed to be excited by light of a certain wavelength in order for them to light up. While different color dyes absorb different frequencies of light, there was a need for as many light sources as cells. A way around this problem is with luminescent tags. These tags are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Quantum_dots" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Quantum dots">quantum dots</a> attached to proteins that penetrate cell membranes. The dots can be random in size, can be made of bio-inert material, and they demonstrate the nanoscale property that color is size-dependent. As a result, sizes are selected so that the frequency of light used to make a group of quantum dots fluoresce is an even multiple of the frequency required to make another group incandesce. Then both groups can be lit with a single light source. They have also found a way to insert <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nanoparticles" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoparticles">nanoparticles</a><span class="reference" id="cite_ref-47" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-47" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[47]</a></span> into the affected parts of the body so that those parts of the body will glow showing the tumor growth or shrinkage or also organ trouble.<span class="reference" id="cite_ref-48" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-48" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[48]</a></span></div>
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<span class="mw-headline" id="Sensing" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">Sensing</span></h2>
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Nanotechnology-on-a-chip is one more dimension of <a href="https://en.wikipedia.org/wiki/Lab-on-a-chip" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Lab-on-a-chip">lab-on-a-chip</a> technology. Magnetic nanoparticles, bound to a suitable antibody, are used to label specific molecules, structures or microorganisms. Gold nanoparticles tagged with short segments of <a href="https://en.wikipedia.org/wiki/DNA" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="DNA">DNA</a> can be used for detection of genetic sequence in a sample. Multicolor optical coding for biological assays has been achieved by embedding different-sized<a href="https://en.wikipedia.org/wiki/Quantum_dot" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Quantum dot">quantum dots</a> into polymeric microbeads. Nanopore technology for analysis of nucleic acids converts strings of nucleotides directly into electronic signatures.<span class="noprint Inline-Template Template-Fact" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">[<i style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;"><a href="https://en.wikipedia.org/wiki/Wikipedia:Citation_needed" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Wikipedia:Citation needed"><span style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;" title="This claim needs references to reliable sources. (January 2013)">citation needed</span></a></i>]</span></div>
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Sensor test chips containing thousands of nanowires, able to detect proteins and other biomarkers left behind by cancer cells, could enable the detection and diagnosis of cancer in the early stages from a few drops of a patient’s blood.<span class="reference" id="cite_ref-49" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-49" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[49]</a></span> <a href="https://en.wikipedia.org/wiki/Nanotechnology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanotechnology">Nanotechnology</a> is helping to advance the use of <a href="https://en.wikipedia.org/wiki/Arthroscopy" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Arthroscopy">arthroscopes</a>, which are pencil-sized devices that are used in surgeries with lights and cameras so surgeons can do the surgeries with smaller incisions. The smaller the incisions the faster the healing time which is better for the patients. It is also helping to find a way to make an arthroscope smaller than a strand of hair.<span class="reference" id="cite_ref-50" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-50" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[50]</a></span></div>
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<img alt="" class="" src="http://www.spacedaily.com/images/nanotech-bodyinternal-bg.jpg" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="490" /></div>
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<span class="mw-headline" id="Blood_purification" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">Blood purification</span></h2>
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Magnetic micro particles are proven research instruments for the separation of cells and proteins from complex media. The technology is available under the name <a href="https://en.wikipedia.org/wiki/Magnetic-activated_cell_sorting" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Magnetic-activated cell sorting">Magnetic-activated cell sorting</a> or <a href="https://en.wikipedia.org/wiki/Dynabeads" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Dynabeads">Dynabeads</a> among others. More recently it was shown in animal models that<a href="https://en.wikipedia.org/wiki/Magnetic_nanoparticles" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Magnetic nanoparticles">magnetic nanoparticles</a> can be used for the removal of various noxious compounds including <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Toxins" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Toxins">toxins</a>, <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Pathogens" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Pathogens">pathogens</a>, and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Proteins" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Proteins">proteins</a> from whole blood in an <a href="https://en.wikipedia.org/wiki/Extracorporeal" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Extracorporeal">extracorporeal</a> circuit similar to <a href="https://en.wikipedia.org/wiki/Dialysis" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Dialysis">dialysis</a>.<span class="reference" id="cite_ref-Herrmann.282013.29_51-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Herrmann.282013.29-51" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[51]</a></span><span class="reference" id="cite_ref-Kang.282014.29_52-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Kang.282014.29-52" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[52]</a></span> In contrast to dialysis, which works on the principle of the size related <a href="https://en.wikipedia.org/wiki/Diffusion" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Diffusion">diffusion</a> of solutes and <a href="https://en.wikipedia.org/wiki/Ultrafiltration" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Ultrafiltration">ultrafiltration</a> of fluid across a <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Semi-permeable_membrane" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Semi-permeable membrane">semi-permeable membrane</a>, the purification with nanoparticles allows specific targeting of substances. Additionally larger compounds which are commonly not dialyzable can be removed.</div>
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The purification process is based on functionalized iron oxide or carbon coated metal nanoparticles with <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ferromagnetic" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Ferromagnetic">ferromagnetic</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Superparamagnetic" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Superparamagnetic">superparamagnetic</a>properties.<span class="reference" id="cite_ref-53" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-53" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[53]</a></span> Binding agents such as <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Proteins" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Proteins">proteins</a>,<span class="reference" id="cite_ref-Kang.282014.29_52-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Kang.282014.29-52" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[52]</a></span> <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Antibodies" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Antibodies">antibodies</a>,<span class="reference" id="cite_ref-Herrmann.282013.29_51-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Herrmann.282013.29-51" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[51]</a></span> <a href="https://en.wikipedia.org/wiki/Antibiotics" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Antibiotics">antibiotics</a>,<span class="reference" id="cite_ref-Herrmann.282013.292_54-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Herrmann.282013.292-54" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[54]</a></span> or synthetic <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Ligands" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Ligands">ligands</a><span class="reference" id="cite_ref-55" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-55" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[55]</a></span> are <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Covalently" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Covalently">covalently</a> linked to the particle surface. These binding agents are able to interact with target species forming an agglomerate. Applying an external <a href="https://en.wikipedia.org/wiki/Magnetic_field" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Magnetic field">magnetic field</a> gradient allows exerting a force on the nanoparticles. Hence the particles can be separated from the bulk fluid, thereby cleaning it from the contaminants.<span class="reference" id="cite_ref-56" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-56" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[56]</a></span><span class="reference" id="cite_ref-57" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-57" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[57]</a></span></div>
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The small size (< 100 nm) and large surface area of functionalized nanomagnets leads to advantageous properties compared to<a href="https://en.wikipedia.org/wiki/Hemoperfusion" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Hemoperfusion">hemoperfusion</a>, which is a clinically used technique for the purification of blood and is based on surface <a href="https://en.wikipedia.org/wiki/Adsorption" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Adsorption">adsorption</a>. These advantages are high loading and accessibility of the binding agents, high selectivity towards the target compound, fast diffusion, small hydrodynamic resistance, and low dosage.<span class="reference" id="cite_ref-58" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-58" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[58]</a></span></div>
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This approach offers new therapeutic possibilities for the treatment of systemic infections such as <a href="https://en.wikipedia.org/wiki/Sepsis" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Sepsis">sepsis</a> by directly removing the pathogen. It can also be used to selectively remove <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Cytokines" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Cytokines">cytokines</a> or <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Endotoxins" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Endotoxins">endotoxins</a><span class="reference" id="cite_ref-Herrmann.282013.292_54-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Herrmann.282013.292-54" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[54]</a></span> or for the dialysis of compounds which are not accessible by traditional dialysis methods. However the technology is still in a preclinical phase and first clinical trials are not expected before 2017.<span class="reference" id="cite_ref-59" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-59" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[59]</a></span></div>
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<span class="mw-headline" id="Tissue_engineering" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">Tissue engineering</span></h2>
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Nanotechnology may be used as part of <a href="https://en.wikipedia.org/wiki/Tissue_engineering" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Tissue engineering">tissue engineering</a> to help reproduce or repair damaged tissue using suitable nanomaterial-based scaffolds and growth factors. Tissue engineering if successful may replace conventional treatments like organ transplants or artificial implants. Nanoparticles such as graphene, carbon nanotubes, molybdenum disulfide and tungsten disulfide are being used as reinforcing agents to fabricate mechanically strong biodegradable polymeric nanocomposites for bone tissue engineering applications. The addition of these nanoparticles in the polymer matrix at low concentrations (~0.2 weight %) leads to significant improvements in the compressive and flexural mechanical properties of polymeric nanocomposites.<span class="reference" id="cite_ref-60" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-60" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[60]</a></span><span class="reference" id="cite_ref-61" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-61" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[61]</a></span> Potentially, these nanocomposites may be used as a novel, mechanically strong, light weight composite as bone implants.</div>
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For example, a flesh welder was demonstrated to fuse two pieces of chicken meat into a single piece using a suspension of gold-coated<a class="mw-redirect" href="https://en.wikipedia.org/wiki/Nanoshells" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanoshells">nanoshells</a> activated by an infrared laser. This could be used to weld arteries during surgery.<span class="reference" id="cite_ref-62" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-62" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[62]</a></span> Another example is <a href="https://en.wikipedia.org/wiki/Nanonephrology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanonephrology">nanonephrology</a>, the use of nanomedicine on the kidney.</div>
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<span class="mw-headline" id="Medical_devices" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">Medical devices</span></h2>
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Neuro-electronic interfacing is a visionary goal dealing with the construction of nanodevices that will permit computers to be joined and linked to the nervous system. This idea requires the building of a molecular structure that will permit control and detection of nerve impulses by an external computer. A refuelable strategy implies energy is refilled continuously or periodically with external sonic, chemical, tethered, magnetic, or biological electrical sources, while a nonrefuelable strategy implies that all power is drawn from internal energy storage which would stop when all energy is drained. A nanoscale <a href="https://en.wikipedia.org/wiki/Enzymatic_biofuel_cell" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Enzymatic biofuel cell">enzymatic biofuel cell</a> for self-powered nanodevices have been developed that uses glucose from biofluids including human <a href="https://en.wikipedia.org/wiki/Blood" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Blood">blood</a> and watermelons.<span class="reference" id="cite_ref-63" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-63" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[63]</a></span> One limitation to this innovation is the fact that electrical interference or leakage or overheating from power consumption is possible. The wiring of the structure is extremely difficult because they must be positioned precisely in the nervous system. The structures that will provide the interface must also be compatible with the body’s immune system.<span class="reference" id="cite_ref-Nanomed2_64-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Nanomed2-64" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[64]</a></span></div>
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<a href="https://en.wikipedia.org/wiki/Molecular_nanotechnology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Molecular nanotechnology">Molecular nanotechnology</a> is a <a href="https://en.wikipedia.org/wiki/Futures_studies" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Futures studies">speculative</a> subfield of nanotechnology regarding the possibility of engineering <a href="https://en.wikipedia.org/wiki/Molecular_assembler" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Molecular assembler">molecular assemblers</a>, machines which could re-order matter at a molecular or atomic scale. Nanomedicine would make use of these <a href="https://en.wikipedia.org/wiki/Nanorobotics" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanorobotics">nanorobots</a>, introduced into the body, to repair or detect damages and infections. Molecular nanotechnology is highly theoretical, seeking to anticipate what inventions nanotechnology might yield and to propose an agenda for future inquiry. The proposed elements of molecular nanotechnology, such as molecular assemblers and <a href="https://en.wikipedia.org/wiki/Nanorobotics" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanorobotics">nanorobots</a> are far beyond current capabilities.<span class="reference" id="cite_ref-Nanomed1_1-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Nanomed1-1" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[1]</a></span><span class="reference" id="cite_ref-Nanomed2_64-1" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-Nanomed2-64" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[64]</a></span><span class="reference" id="cite_ref-65" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-65" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[65]</a></span><span class="reference" id="cite_ref-nanofactory_66-0" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-nanofactory-66" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[66]</a></span> Future advances in nanomedicine could give rise to <a href="https://en.wikipedia.org/wiki/Life_extension" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Life extension">life extension</a>through the repair of many processes thought to be responsible for aging. <a href="https://en.wikipedia.org/wiki/K._Eric_Drexler" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="K. Eric Drexler">K. Eric Drexler</a>, one of the founders of nanotechnology, postulated cell repair machines, including ones operating within cells and utilizing as yet hypothetical <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Molecular_machines" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Molecular machines">molecular machines</a>, in his 1986 book<a href="https://en.wikipedia.org/wiki/Engines_of_Creation" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Engines of Creation">Engines of Creation</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Raymond_Kurzweil" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Raymond Kurzweil">Raymond Kurzweil</a>, a <a href="https://en.wikipedia.org/wiki/Futurist" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Futurist">futurist</a> and <a class="mw-redirect" href="https://en.wikipedia.org/wiki/Transhumanist" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Transhumanist">transhumanist</a>, stated in his book <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a href="https://en.wikipedia.org/wiki/The_Singularity_Is_Near" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="The Singularity Is Near">The Singularity Is Near</a></i> that he believes that advanced medical <a href="https://en.wikipedia.org/wiki/Nanorobotics" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanorobotics">nanorobotics</a> could completely remedy the effects of aging by 2030.<span class="reference" id="cite_ref-67" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-67" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[67]</a></span> According to <a href="https://en.wikipedia.org/wiki/Richard_Feynman" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Richard Feynman">Richard Feynman</a>, it was his former graduate student and collaborator <a href="https://en.wikipedia.org/wiki/Albert_Hibbs" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Albert Hibbs">Albert Hibbs</a> who originally suggested to him (circa 1959) the idea of a <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">medical</i> use for Feynman’s theoretical micromachines (see <a href="https://en.wikipedia.org/wiki/Nanotechnology" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Nanotechnology">nanotechnology</a>). Hibbs suggested that certain repair machines might one day be reduced in size to the point that it would, in theory, be possible to (as Feynman put it) “<a href="https://en.wikipedia.org/wiki/Molecular_machine#Biological" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Molecular machine">swallow the doctor</a>“. The idea was incorporated into Feynman’s 1959 essay<i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a href="https://en.wikipedia.org/wiki/There%27s_Plenty_of_Room_at_the_Bottom" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="There's Plenty of Room at the Bottom">There’s Plenty of Room at the Bottom</a>.</i><span class="reference" id="cite_ref-68" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_note-68" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">[68]</a></span></div>
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<span class="mw-headline" id="References" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">References</span></h2>
<div class="reflist columns references-column-width" style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin: 0px; outline: 0px; padding: 0px;">
<ol class="references" style="border: 0px; font-size: 13.9200000762939px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li id="cite_note-Nanomed1-1" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="external text" href="http://www.nanomedicine.com/NMI.htm" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Nanomedicine, Volume I: Basic Capabilities</a>, by Robert A. Freitas Jr. 1999, <a class="internal mw-magiclink-isbn" href="https://en.wikipedia.org/wiki/Special:BookSources/157059645X" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">ISBN 1-57059-645-X</a></span></li>
<li id="cite_note-2" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Wagner V; Dullaart A; Bock AK; Zweck A. (2006). <a class="external text" href="http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&uid=17033654&cmd=showdetailview" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“The emerging nanomedicine landscape”</a>. <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nat. Biotechnol.</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">24</b> (10): 1211–1217.<a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1038%2Fnbt1006-1211" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1038/nbt1006-1211</a>.<a class="mw-redirect" href="https://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/17033654" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">17033654</a>.</cite></span></li>
<li id="cite_note-3" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Freitas RA Jr. (2005). <a class="external text" href="http://www.nanomedicine.com/Papers/WhatIsNMMar05.pdf" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“What is Nanomedicine?”</a> (PDF). <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nanomedicine: Nanotechnology, Biology and Medicine</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">1</b> (1): 2–9.<a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1016%2Fj.nano.2004.11.003" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1016/j.nano.2004.11.003</a>.<a class="mw-redirect" href="https://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/17292052" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">17292052</a>.</cite></span></li>
<li id="cite_note-4" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="external text" href="http://www.amazon.com/dp/2884490809" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Nanotechnology in Medicine and the Biosciences</a>, by Coombs RRH, Robinson DW. 1996, <a class="internal mw-magiclink-isbn" href="https://en.wikipedia.org/wiki/Special:BookSources/2884490809" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">ISBN 2-88449-080-9</a></span></li>
<li id="cite_note-5" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="external text" href="http://www.amazon.com/dp/0131014005" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Nanotechnology: A Gentle Introduction to the Next Big Idea</a>, by MA Ratner, D Ratner. 2002, <a class="internal mw-magiclink-isbn" href="https://en.wikipedia.org/wiki/Special:BookSources/0131014005" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">ISBN 0-13-101400-5</a></span></li>
<li id="cite_note-6" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Editorial. (2006). <a class="external text" href="http://www.nature.com/nmat/journal/v5/n4/full/nmat1625.html" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Nanomedicine: A matter of rhetoric?”</a>. <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nat Materials.</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">5</b> (4): 243.<a href="https://en.wikipedia.org/wiki/Bibcode" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Bibcode">Bibcode</a>:<a class="external text" href="http://adsabs.harvard.edu/abs/2006NatMa...5..243." rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">2006NatMa…5..243.</a>.<a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1038%2Fnmat1625" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1038/nmat1625</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/16582920" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">16582920</a>.</cite></span></li>
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<li id="cite_note-46" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span class="mw-cite-backlink" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_ref-46" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><span class="cite-accessibility-label" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Jump up</span>^</a></b></span> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Conde J, Tian F, Hernández Y, Bao C, Cui D, Janssen KP, Ibarra MR, Baptista PV, Stoeger T, de la Fuente JM. In vivo tumor targeting via nanoparticle-mediated therapeutic siRNA coupled to inflammatory response in lung cancer mouse models.<i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Biomaterials</i>. 2013;34(31):7744-53. <a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1016%2Fj.biomaterials.2013.06.041" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1016/j.biomaterials.2013.06.041</a></span></li>
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<li id="cite_note-49" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Zheng G; Patolsky F; Cui Y; Wang WU; Lieber CM (2005). <a class="external text" href="http://www.nature.com/nbt/journal/v23/n10/abs/nbt1138.html" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Multiplexed electrical detection of cancer markers with nanowire sensor arrays”</a>. <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nat. Biotechnol.</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">23</b> (10): 1294–1301. <a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1038%2Fnbt1138" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1038/nbt1138</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/16170313" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">16170313</a>.</cite></span></li>
<li id="cite_note-50" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation book" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Hall, J. Storrs (2005). <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nanofuture : what’s next for nanotechnology</i>. Amherst, NY: Prometheus Books. <a href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="International Standard Book Number">ISBN</a> <a href="https://en.wikipedia.org/wiki/Special:BookSources/978-1591022879" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Special:BookSources/978-1591022879">978-1591022879</a>.</cite></span></li>
<li id="cite_note-Herrmann.282013.29-51" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Herrmann, I. K. et al. Nanomagnet-based removal of lead and digoxin from living rats. Nanoscale 5, 8718–8723 (2013).</span></li>
<li id="cite_note-Kang.282014.29-52" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span class="mw-cite-backlink" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">^ <a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_ref-Kang.282014.29_52-0" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><span class="cite-accessibility-label" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Jump up to:</span><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><i style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;"><b style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;">a</b></i></span></a> <a href="https://en.wikipedia.org/wiki/Nanomedicine#cite_ref-Kang.282014.29_52-1" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;"><i style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;"><b style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;">b</b></i></span></a></span> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Kang J. H.; et al. (2014). “An extracorporeal blood-cleansing device for sepsis therapy”. <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nat. Med</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">20</b>: 1211–1216.<a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1038%2Fnm.3640" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1038/nm.3640</a>.</cite></span></li>
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<li id="cite_note-57" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Yung C. W.; Fiering J.; Mueller A. J.; Ingber D. E. (2009). “Micromagnetic–microfluidic blood cleansing device”. <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Lab. Chip</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">9</b>: 1171–7.<a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1039%2Fb816986a" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1039/b816986a</a>.<a class="mw-redirect" href="https://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/19370233" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">19370233</a>.</cite></span></li>
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<li id="cite_note-61" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Lalwani, Gaurav (September 2013). <a class="external text" href="https://www.researchgate.net/publication/237003479_Tungsten_Disulfide_Nanotubes_Reinforced_Biodegradable_Polymers_for_Bone_Tissue_Engineering?ev=prf_pub/" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Tungsten disulfide nanotubes reinforced biodegradable polymers for bone tissue engineering”</a>.<i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Acta Biomaterialia</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">9</b> (9): 8365–8373. <a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1016%2Fj.actbio.2013.05.018" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1016/j.actbio.2013.05.018</a>. <a href="https://en.wikipedia.org/wiki/PubMed_Central" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Central">PMC</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732565" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">3732565</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/23727293" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">23727293</a>.</cite></span></li>
<li id="cite_note-62" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Gobin AM; O’Neal DP; Watkins DM; Halas NJ; Drezek RA; West JL (2005). <a class="external text" href="http://www.pubmed.com/16047329" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Near infrared laser-tissue welding using nanoshells as an exogenous absorber”</a>. <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Lasers Surg Med.</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">37</b> (2): 123–9. <a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1002%2Flsm.20206" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1002/lsm.20206</a>. <a class="mw-redirect" href="https://en.wikipedia.org/wiki/PubMed_Identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="PubMed Identifier">PMID</a> <a class="external text" href="https://www.ncbi.nlm.nih.gov/pubmed/16047329" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">16047329</a>.</cite></span></li>
<li id="cite_note-63" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="external free" href="http://www.nanowerk.com/spotlight/spotid=19573.php" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">http://www.nanowerk.com/spotlight/spotid=19573.php</a></span></li>
<li id="cite_note-Nanomed2-64" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="external text" href="http://www.nanomedicine.com/NMIIA.htm" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Nanomedicine, Volume IIA: Biocompatibility</a>, by Robert A. Freitas Jr. 2003, <a class="internal mw-magiclink-isbn" href="https://en.wikipedia.org/wiki/Special:BookSources/1570597006" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">ISBN 1-57059-700-6</a></span></li>
<li id="cite_note-65" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation journal" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Freitas, Robert A., Jr.; Havukkala, Ilkka (2005). <a class="external text" href="http://www.nanomedicine.com/Papers/NMRevMar05.pdf" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“Current Status of Nanomedicine and Medical Nanorobotics”</a> (PDF). <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Journal of Computational and Theoretical Nanoscience</i> <b style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">2</b>(4): 1–25. <a href="https://en.wikipedia.org/wiki/Digital_object_identifier" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Digital object identifier">doi</a>:<a class="external text" href="https://dx.doi.org/10.1166%2Fjctn.2005.001" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">10.1166/jctn.2005.001</a>.</cite></span></li>
<li id="cite_note-nanofactory-66" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="external text" href="http://www.molecularassembler.com/Nanofactory" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Nanofactory Collaboration</a></span></li>
<li id="cite_note-67" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation book" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="mw-redirect" href="https://en.wikipedia.org/wiki/Raymond_Kurzweil" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Raymond Kurzweil">Kurzweil, Ray</a> (2005). <i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a href="https://en.wikipedia.org/wiki/The_Singularity_Is_Near" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="The Singularity Is Near">The Singularity Is Near</a></i>. <a href="https://en.wikipedia.org/wiki/New_York_City" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="New York City">New York City</a>: <a href="https://en.wikipedia.org/wiki/Viking_Press" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Viking Press">Viking Press</a>. <a href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="International Standard Book Number">ISBN</a> <a href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-670-03384-3" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Special:BookSources/978-0-670-03384-3">978-0-670-03384-3</a>. <a href="https://en.wikipedia.org/wiki/OCLC" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="OCLC">OCLC</a> <a class="external text" href="https://www.worldcat.org/oclc/57201348" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">57201348</a>.</cite><span class="noprint Inline-Template" style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">[<i style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;"><a href="https://en.wikipedia.org/wiki/Wikipedia:Citing_sources" style="border: 0px; color: #227ad1; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Wikipedia:Citing sources"><span style="border: 0px; font-size: 9.74400043487549px; margin: 0px; outline: 0px; padding: 0px;" title="This citation requires a reference to the specific page or range of pages in which the material appears. (September 2010)">page needed</span></a></i>]</span></span></li>
<li id="cite_note-68" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"> <span class="reference-text" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation web" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Richard P. Feynman (December 1959). <a class="external text" href="http://www.its.caltech.edu/~feynman/plenty.html" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">“There’s Plenty of Room at the Bottom”</a><span class="reference-accessdate" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">. Retrieved March 2010</span>.</cite></span></li>
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<span class="mw-headline" id="Further_reading" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">Further reading</span></h2>
<ul style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><cite class="citation book" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Institute of Medicine, United States (2011). <a class="external text" href="http://www.nap.edu/catalog.php?record_id=13037" rel="nofollow" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><i style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nanotechnology and Oncology: Workshop Summary</i></a>. Washington, DC: The National Academies Press. <a href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="International Standard Book Number">ISBN</a> <a href="https://en.wikipedia.org/wiki/Special:BookSources/978-0-309-16321-7" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Special:BookSources/978-0-309-16321-7">978-0-309-16321-7</a><span class="reference-accessdate" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">. Retrieved <span class="nowrap" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">16 August</span> 2014</span>.</cite></li>
</ul>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-569892385714118127.post-71614996535142424852016-05-23T11:41:00.001+05:302016-05-23T11:41:43.243+05:30Chelation-Controlled Bergman Cyclization: Synthesis and Reactivity of Enediynyl Ligands<div dir="ltr" style="text-align: left;" trbidi="on">
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<strong>Chelation-Controlled Bergman Cyclization: Synthesis and Reactivity of Enediynyl Ligands</strong></div>
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<strong>● </strong>Basak, Amit; Mandal, Subrata; <strong><u>Bag, Subhendu Sekhar</u></strong><strong>●</strong></div>
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<em>Chemical Reviews</em><strong>2003</strong>, <em>103(10)</em>, 4077-4094.</div>
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<strong> Abstract: </strong>A review with 150 references.</div>
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see</div>
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<a data-mce-href="http://pubs.acs.org/doi/abs/10.1021/cr020069k" href="http://pubs.acs.org/doi/abs/10.1021/cr020069k">http://pubs.acs.org/doi/abs/10.1021/cr020069k</a></div>
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////////////Bergman Cyclization, Enediynyl Ligands</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-91589813178298483722016-05-13T09:12:00.000+05:302016-05-13T09:12:05.498+05:30Printing with Collagen<div dir="ltr" style="text-align: left;" trbidi="on">
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Printing with Collagen</h2>
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Addition of collagen to hydrogels in 3D printing improves stem cell differentiation in osteogenesis</div>
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<a data-mce-href="http://dmmsclick.wiley.com/click.asp?p=20563155&m=96603&u=2508997" href="http://dmmsclick.wiley.com/click.asp?p=20563155&m=96603&u=2508997">Read more</a></div>
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<a data-mce-href="http://www.chemistryviews.org/details/news/9268521/Printing_with_Collagen.html" href="http://www.chemistryviews.org/details/news/9268521/Printing_with_Collagen.html">http://www.chemistryviews.org/details/news/9268521/Printing_with_Collagen.html</a></div>
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<li><a data-mce-href="http://onlinelibrary.wiley.com/doi/10.1002/adhm.201501033/abstract" href="http://onlinelibrary.wiley.com/doi/10.1002/adhm.201501033/abstract" target="_blank">Bioprinting Organotypic Hydrogels with Improved Mesenchymal Stem Cell Remodeling and Mineralization Properties for Bone Tissue Engineering</a>,<br />Daniela Filipa Duarte Campos, Andreas Blaeser, Kate Buellesbach, Kshama Shree Sen, Weiwei Xun, Walter Tillmann, Horst Fischer,<br /><i>Adv. Healthcare Mater.</i> <b>2016</b>.<br /><a data-mce-href="http://onlinelibrary.wiley.com/doi/10.1002/adhm.201501033/abstract" href="http://onlinelibrary.wiley.com/doi/10.1002/adhm.201501033/abstract" target="_blank">DOI: 10.1002/adhm.201501033</a></li>
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MORE ON</h1>
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Collagen</h1>
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<img alt="" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d1/Collagentriplehelix.png/150px-Collagentriplehelix.png" src="https://upload.wikimedia.org/wikipedia/commons/thumb/d/d1/Collagentriplehelix.png/150px-Collagentriplehelix.png" style="height: auto; max-width: 100%;" /></div>
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Tropocollagen molecule: three left-handed procollagens (red, green, blue) join to form a right handed triple helical tropocollagen.</div>
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<img alt="" data-mce-src="http://www.medicalnewstoday.com/content/images/articles/262/262881/collagen.jpg" src="http://www.medicalnewstoday.com/content/images/articles/262/262881/collagen.jpg" style="height: auto; max-width: 100%;" /></div>
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<em>Collagen is the most common protein found in mammals.</em></div>
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<img alt="" data-mce-src="http://static1.squarespace.com/static/53703175e4b074a1fbd01dee/t/54ee7fc8e4b0ae0904d8d502/1424916438794/increase+the+skins+collagen+by+eating+the+right+foods" src="http://static1.squarespace.com/static/53703175e4b074a1fbd01dee/t/54ee7fc8e4b0ae0904d8d502/1424916438794/increase+the+skins+collagen+by+eating+the+right+foods" style="height: auto; max-width: 100%;" /></div>
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<b>Collagen</b> <span class="nowrap"><span class="IPA nopopups"><a data-mce-href="https://en.wikipedia.org/wiki/Help:IPA_for_English" href="https://en.wikipedia.org/wiki/Help:IPA_for_English" title="Help:IPA for English">/<span title="/ˈ/ primary stress follows">ˈ</span><span title="'k' in 'kind'">k</span><span title="/ɒ/ short 'o' in 'body'">ɒ</span><span title="'l' in 'lie'">l</span><span title="/ə/ 'a' in 'about'">ə</span><span title="/dʒ/ 'j' in 'jam'">dʒ</span><span title="/ɪ/ or /ə/ 'e' in 'roses'">ᵻ</span><span title="'n' in 'no'">n</span>/</a></span></span> is the main structural <a data-mce-href="https://en.wikipedia.org/wiki/Protein" href="https://en.wikipedia.org/wiki/Protein" title="Protein">protein</a> in the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Extracellular_space" href="https://en.wikipedia.org/wiki/Extracellular_space" title="Extracellular space">extracellular space</a> in the various <a data-mce-href="https://en.wikipedia.org/wiki/Connective_tissue" href="https://en.wikipedia.org/wiki/Connective_tissue" title="Connective tissue">connective tissues</a> in animal bodies. As the main component of connective tissue, it is the most abundant protein in mammals,<sup class="reference" id="cite_ref-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-1" href="https://en.wikipedia.org/wiki/Collagen#cite_note-1">[1]</a></sup> making up from 25% to 35% of the whole-body protein content. Depending upon the degree of mineralization, collagen tissues may be rigid (bone), compliant (tendon), or have a gradient from rigid to compliant (cartilage).<sup class="reference" id="cite_ref-Sherman_2015_22.E2.80.9350_2-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Sherman_2015_22.E2.80.9350-2" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Sherman_2015_22.E2.80.9350-2">[2]</a></sup> Collagen, in the form of elongated <a data-mce-href="https://en.wikipedia.org/wiki/Fibril" href="https://en.wikipedia.org/wiki/Fibril" title="Fibril">fibrils</a>, is mostly found in <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Fibrous_connective_tissue" href="https://en.wikipedia.org/wiki/Fibrous_connective_tissue" title="Fibrous connective tissue">fibrous tissues</a> such as <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Tendons" href="https://en.wikipedia.org/wiki/Tendons" title="Tendons">tendons</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Ligament" href="https://en.wikipedia.org/wiki/Ligament" title="Ligament">ligaments</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Skin" href="https://en.wikipedia.org/wiki/Skin" title="Skin">skin</a>. It is also abundant in<a data-mce-href="https://en.wikipedia.org/wiki/Cornea" href="https://en.wikipedia.org/wiki/Cornea" title="Cornea">corneas</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Cartilage" href="https://en.wikipedia.org/wiki/Cartilage" title="Cartilage">cartilage</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Bone" href="https://en.wikipedia.org/wiki/Bone" title="Bone">bones</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Blood_vessel" href="https://en.wikipedia.org/wiki/Blood_vessel" title="Blood vessel">blood vessels</a>, the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Gut_(anatomy)" href="https://en.wikipedia.org/wiki/Gut_(anatomy)" title="Gut (anatomy)">gut</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Intervertebral_disc" href="https://en.wikipedia.org/wiki/Intervertebral_disc" title="Intervertebral disc">intervertebral discs</a> and the <a data-mce-href="https://en.wikipedia.org/wiki/Dentin" href="https://en.wikipedia.org/wiki/Dentin" title="Dentin">dentin</a> in teeth.<sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-3" href="https://en.wikipedia.org/wiki/Collagen#cite_note-3">[3]</a></sup> In <a data-mce-href="https://en.wikipedia.org/wiki/Muscle_tissue" href="https://en.wikipedia.org/wiki/Muscle_tissue" title="Muscle tissue">muscle tissue</a>, it serves as a major component of the <a data-mce-href="https://en.wikipedia.org/wiki/Endomysium" href="https://en.wikipedia.org/wiki/Endomysium" title="Endomysium">endomysium</a>. Collagen constitutes one to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous muscles.<sup class="reference" id="cite_ref-4"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-4" href="https://en.wikipedia.org/wiki/Collagen#cite_note-4">[4]</a></sup> The<a data-mce-href="https://en.wikipedia.org/wiki/Fibroblast" href="https://en.wikipedia.org/wiki/Fibroblast" title="Fibroblast">fibroblast</a> is the most common cell that creates collagen.</div>
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<a data-mce-href="https://en.wikipedia.org/wiki/Gelatin" href="https://en.wikipedia.org/wiki/Gelatin" title="Gelatin">Gelatin</a>, which is used in food and industry, is collagen that has been irreversibly <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Hydrolyzed" href="https://en.wikipedia.org/wiki/Hydrolyzed" title="Hydrolyzed">hydrolyzed</a>.<sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-5" href="https://en.wikipedia.org/wiki/Collagen#cite_note-5">[5]</a></sup> Collagen also has many medical uses in treating complications of the bones and skin.</div>
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The name <i>collagen</i> comes from the Greek <a class="extiw" data-mce-href="https://en.wiktionary.org/wiki/%CE%BA%CF%8C%CE%BB%CE%BB%CE%B1#Ancient_Greek" href="https://en.wiktionary.org/wiki/%CE%BA%CF%8C%CE%BB%CE%BB%CE%B1#Ancient_Greek" title="wikt:κόλλα">κόλλα</a> (<i>kólla</i>), meaning "<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Glue" href="https://en.wikipedia.org/wiki/Glue" title="Glue">glue</a>", and suffix -γέν, <i>-gen</i>, denoting "producing".<sup class="reference" id="cite_ref-6"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-6" href="https://en.wikipedia.org/wiki/Collagen#cite_note-6">[6]</a></sup><sup class="reference" id="cite_ref-7"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-7" href="https://en.wikipedia.org/wiki/Collagen#cite_note-7">[7]</a></sup> This refers to the compound's early use in the process of boiling the skin and <a data-mce-href="https://en.wikipedia.org/wiki/Tendon" href="https://en.wikipedia.org/wiki/Tendon" title="Tendon">sinews</a> of <a data-mce-href="https://en.wikipedia.org/wiki/Horse" href="https://en.wikipedia.org/wiki/Horse" title="Horse">horses</a> and other animals to obtain glue.</div>
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<strong><img alt="woman receiving injection to forehead" data-mce-src="http://cdn1.medicalnewstoday.com/content/images/articles/262/262881/woman-receiving-injection-to-forehead.jpg" data-src="http://cdn1.medicalnewstoday.com/content/images/articles/262/262881/woman-receiving-injection-to-forehead.jpg" src="http://cdn1.medicalnewstoday.com/content/images/articles/262/262881/woman-receiving-injection-to-forehead.jpg" style="height: auto; max-width: 100%;" /><br /><em>Collagen injections can be used in cosmetic procedures to improve the contours of aging skin.</em></strong></div>
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<img alt="" data-mce-src="http://thumbs.dreamstime.com/z/collagen-medical-illustration-role-process-skin-regeneration-35919208.jpg" src="http://thumbs.dreamstime.com/z/collagen-medical-illustration-role-process-skin-regeneration-35919208.jpg" style="height: auto; max-width: 100%;" /></div>
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<span class="mw-headline" id="Types_of_collagen">Types of collagen</span></h2>
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Collagen occurs in many places throughout the body. Over 90% of the collagen in the <a data-mce-href="https://en.wikipedia.org/wiki/Human_body" href="https://en.wikipedia.org/wiki/Human_body" title="Human body">human body</a>, however, is type I.<sup class="reference" id="cite_ref-8"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-8" href="https://en.wikipedia.org/wiki/Collagen#cite_note-8">[8]</a></sup></div>
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So far, 28 types of collagen have been identified and described. They can be divided into several groups according to the structure they form:<sup class="reference" id="cite_ref-Sherman_2015_22.E2.80.9350_2-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Sherman_2015_22.E2.80.9350-2" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Sherman_2015_22.E2.80.9350-2">[2]</a></sup></div>
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<li>Fibrillar (Type I, II, III, V, XI)</li>
<li>Non-fibrillar<ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/FACIT_collagen" href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">FACIT</a> (Fibril Associated Collagens with Interrupted Triple Helices) (Type IX, XII, XIV, XVI, XIX)</li>
<li>Short chain (Type VIII, X)</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Basement_membrane" href="https://en.wikipedia.org/wiki/Basement_membrane" title="Basement membrane">Basement membrane</a> (Type IV)</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Multiplexin" href="https://en.wikipedia.org/wiki/Multiplexin" title="Multiplexin">Multiplexin</a> (Multiple Triple Helix domains with Interruptions) (Type XV, XVIII)</li>
<li>MACIT (Membrane Associated Collagens with Interrupted Triple Helices) (Type XIII, XVII)</li>
<li>Other (Type VI, VII)</li>
</ul>
</li>
</ul>
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The five most common types are:</div>
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<li>Type I: <a data-mce-href="https://en.wikipedia.org/wiki/Skin" href="https://en.wikipedia.org/wiki/Skin" title="Skin">skin</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Tendon" href="https://en.wikipedia.org/wiki/Tendon" title="Tendon">tendon</a>, vascular ligature, organs, <a data-mce-href="https://en.wikipedia.org/wiki/Bone" href="https://en.wikipedia.org/wiki/Bone" title="Bone">bone</a> (main component of the organic part of bone)</li>
<li>Type II: <a data-mce-href="https://en.wikipedia.org/wiki/Cartilage" href="https://en.wikipedia.org/wiki/Cartilage" title="Cartilage">cartilage</a> (main collagenous component of cartilage)</li>
<li>Type III: reticulate (main component of <a data-mce-href="https://en.wikipedia.org/wiki/Reticular_fiber" href="https://en.wikipedia.org/wiki/Reticular_fiber" title="Reticular fiber">reticular fibers</a>), commonly found alongside type I.</li>
<li>Type IV: forms basal lamina, the epithelium-secreted layer of the <a data-mce-href="https://en.wikipedia.org/wiki/Basement_membrane" href="https://en.wikipedia.org/wiki/Basement_membrane" title="Basement membrane">basement membrane</a>.</li>
<li>Type V: cell surfaces, <a data-mce-href="https://en.wikipedia.org/wiki/Hair" href="https://en.wikipedia.org/wiki/Hair" title="Hair">hair</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Placenta" href="https://en.wikipedia.org/wiki/Placenta" title="Placenta">placenta</a></li>
</ul>
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<img alt="wrinkled mouth with cigarette" data-mce-src="http://cdn1.medicalnewstoday.com/content/images/articles/262/262881/wrinkled-mouth-with-cigarette.jpg" data-src="http://cdn1.medicalnewstoday.com/content/images/articles/262/262881/wrinkled-mouth-with-cigarette.jpg" src="http://cdn1.medicalnewstoday.com/content/images/articles/262/262881/wrinkled-mouth-with-cigarette.jpg" style="height: auto; max-width: 100%;" /><br /><em>Tobacco contains chemicals that damage collagen</em></div>
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<img alt="" data-mce-src="http://bayareapelleve.com/wp-content/uploads/2015/07/Collagen-Human-Molecule-1.png" src="http://bayareapelleve.com/wp-content/uploads/2015/07/Collagen-Human-Molecule-1.png" style="height: auto; max-width: 100%;" /></h2>
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<span class="mw-headline" id="Medical_uses">Medical uses</span></h2>
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<span class="mw-headline" id="Cardiac_applications">Cardiac applications</span></h3>
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The collagenous <a data-mce-href="https://en.wikipedia.org/wiki/Cardiac_skeleton" href="https://en.wikipedia.org/wiki/Cardiac_skeleton" title="Cardiac skeleton">cardiac skeleton</a> which includes the four <a data-mce-href="https://en.wikipedia.org/wiki/Heart_valve" href="https://en.wikipedia.org/wiki/Heart_valve" title="Heart valve">heart valve</a> rings, is histologically and uniquely bound to cardiac muscle. The cardiac skeleton also includes the separating septa of the heart chambers – the <a data-mce-href="https://en.wikipedia.org/wiki/Interventricular_septum" href="https://en.wikipedia.org/wiki/Interventricular_septum" title="Interventricular septum">interventricular septum</a> and the <a data-mce-href="https://en.wikipedia.org/wiki/Atrioventricular_septum" href="https://en.wikipedia.org/wiki/Atrioventricular_septum" title="Atrioventricular septum">atrioventricular septum</a>. Collagen contribution to the measure of <a data-mce-href="https://en.wikipedia.org/wiki/Cardiac_stress_test" href="https://en.wikipedia.org/wiki/Cardiac_stress_test" title="Cardiac stress test">cardiac performance</a> summarily represents a continuous torsional force opposed to the <a data-mce-href="https://en.wikipedia.org/wiki/Fluid_mechanics" href="https://en.wikipedia.org/wiki/Fluid_mechanics" title="Fluid mechanics">fluid mechanics</a> of <a data-mce-href="https://en.wikipedia.org/wiki/Blood" href="https://en.wikipedia.org/wiki/Blood" title="Blood">blood</a> pressure emitted from the heart. The collagenous structure that divides the upper chambers of the heart from the lower chambers is an impermeable membrane that excludes both blood and electrical impulses through typical physiological means. With support from collagen, <a data-mce-href="https://en.wikipedia.org/wiki/Atrial_fibrillation" href="https://en.wikipedia.org/wiki/Atrial_fibrillation" title="Atrial fibrillation">atrial fibrillation</a> should never deteriorate to <a data-mce-href="https://en.wikipedia.org/wiki/Ventricular_fibrillation" href="https://en.wikipedia.org/wiki/Ventricular_fibrillation" title="Ventricular fibrillation">ventricular fibrillation</a>. Collagen is layered in variable densities with cardiac muscle mass. The mass, distribution, age and density of collagen all contribute to the <a data-mce-href="https://en.wikipedia.org/wiki/Compliance_(physiology)" href="https://en.wikipedia.org/wiki/Compliance_(physiology)" title="Compliance (physiology)">compliance</a> required to move blood back and forth. Individual cardiac valvular leaflets are folded into shape by specialized collagen under variable <a data-mce-href="https://en.wikipedia.org/wiki/Pressure" href="https://en.wikipedia.org/wiki/Pressure" title="Pressure">pressure</a>. Gradual <a data-mce-href="https://en.wikipedia.org/wiki/Calcium" href="https://en.wikipedia.org/wiki/Calcium" title="Calcium">calcium</a> deposition within collagen occurs as a natural function of aging. Calcified points within collagen matrices show contrast in a moving display of blood and muscle, enabling methods of <a data-mce-href="https://en.wikipedia.org/wiki/Cardiac_imaging" href="https://en.wikipedia.org/wiki/Cardiac_imaging" title="Cardiac imaging">cardiac imaging</a> technology to arrive at ratios essentially stating blood in (<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Cardiac_input" href="https://en.wikipedia.org/wiki/Cardiac_input" title="Cardiac input">cardiac input</a>) and blood out (<a data-mce-href="https://en.wikipedia.org/wiki/Cardiac_output" href="https://en.wikipedia.org/wiki/Cardiac_output" title="Cardiac output">cardiac output</a>). Pathology of the collagen underpinning of the heart is understood within the category of <a data-mce-href="https://en.wikipedia.org/wiki/Connective_tissue_disease" href="https://en.wikipedia.org/wiki/Connective_tissue_disease" title="Connective tissue disease">connective tissue disease</a>.</div>
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<img alt="" class="" data-mce-src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcQ7Lw6M0J2xrFG23C3kgfOC64J5AzZuhl9IJPK15CL4JWCYEXaz" height="409" src="https://encrypted-tbn2.gstatic.com/images?q=tbn:ANd9GcQ7Lw6M0J2xrFG23C3kgfOC64J5AzZuhl9IJPK15CL4JWCYEXaz" style="height: auto; max-width: 100%;" width="879" /></div>
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<span class="mw-headline" id="Hydrolyzed_type_II_collagen_and_osteoarthritis">Hydrolyzed type II collagen and osteoarthritis</span></h3>
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A published study<sup class="reference" id="cite_ref-9"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-9" href="https://en.wikipedia.org/wiki/Collagen#cite_note-9">[9]</a></sup> reports that ingestion of a novel low molecular weight hydrolyzed chicken sternal cartilage extract, containing a matrix of hydrolyzed <a data-mce-href="https://en.wikipedia.org/wiki/Type_II_collagen" href="https://en.wikipedia.org/wiki/Type_II_collagen" title="Type II collagen">type II collagen</a>,<a data-mce-href="https://en.wikipedia.org/wiki/Chondroitin_sulfate" href="https://en.wikipedia.org/wiki/Chondroitin_sulfate" title="Chondroitin sulfate">chondroitin sulfate</a>, and <a data-mce-href="https://en.wikipedia.org/wiki/Hyaluronic_acid" href="https://en.wikipedia.org/wiki/Hyaluronic_acid" title="Hyaluronic acid">hyaluronic acid</a>, relieves joint discomfort associated with <a data-mce-href="https://en.wikipedia.org/wiki/Osteoarthritis" href="https://en.wikipedia.org/wiki/Osteoarthritis" title="Osteoarthritis">osteoarthritis</a>. A <a data-mce-href="https://en.wikipedia.org/wiki/Randomized_controlled_trial" href="https://en.wikipedia.org/wiki/Randomized_controlled_trial" title="Randomized controlled trial">randomized controlled trial</a> (RCT) enrolling 80 subjects demonstrated that it was well tolerated with no serious <a data-mce-href="https://en.wikipedia.org/wiki/Adverse_event" href="https://en.wikipedia.org/wiki/Adverse_event" title="Adverse event">adverse event</a> and led to a significant improvement in joint mobility compared to the placebo group on days 35 (p = 0.007) and 70 (p < 0.001).</div>
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<strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Fast facts on collagen</em></span></strong></div>
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<strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Here are some key points about collagen. More detail and supporting information is in the main article.<sup>25-27</sup></em></span></strong></div>
<ul style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Protein makes up around 20% of the body's mass, and collagen makes up around 30% of the protein in the human body.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>There are at least 16 types of collagen, but 80-90% of the collagen in the body consists of types I, II, and III.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Type I collagen fibrils are stronger than steel (gram for gram).</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Collagen is most commonly found within the body in the skin, bones and connective tissues.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>The word "collagen" is derived from the Greek "kolla," meaning glue.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Collagen gives the skin its strength and structure, and also plays a role in the replacement of dead skin cells.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Collagen production declines with age (as part of intrinsic aging), and is reduced by exposure to ultraviolet light and other environmental factors (extrinsic aging).</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Collagen in medical products can be derived from human, bovine, porcine and ovine sources.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Collagen dressings attract new skin cells to wound sites.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Cosmetic products such as revitalizing lotions that claim to increase collagen levels are unlikely to do so, as collagen molecules are too large to be absorbed through the skin.</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Collagen production can be stimulated through the use of laser therapy and the use of all-trans retinoic acid (a form of<a class="keywords" data-mce-href="http://www.medicalnewstoday.com/articles/195878.php" data-mce-style="color: #ff0000;" href="http://www.medicalnewstoday.com/articles/195878.php" style="color: red;" title="What are vitamins? What vitamins do I need?">vitamin</a> A).</em></span></strong></li>
<li><strong><span data-mce-style="color: #ff0000;" style="color: red;"><em>Controllable factors that damage the production of collagen include sunlight, smoking and high sugar consumption.</em></span></strong></li>
</ul>
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<img alt="" data-mce-src="http://bayareapelleve.com/wp-content/uploads/2015/07/collagen-skin-fibers.jpg" src="http://bayareapelleve.com/wp-content/uploads/2015/07/collagen-skin-fibers.jpg" style="height: auto; max-width: 100%;" /></div>
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<span class="mw-headline" id="Cosmetic_surgery">Cosmetic surgery</span></h3>
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Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and a wide variety of dental, orthopedic, and surgical purposes. Both human and bovine collagen is widely used as dermal fillers for treatment of wrinkles and skin aging.<sup class="reference" id="cite_ref-pharmax2_10-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-pharmax2-10" href="https://en.wikipedia.org/wiki/Collagen#cite_note-pharmax2-10">[10]</a></sup> Some points of interest are:</div>
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<li>When used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be virtually eliminated by simple and inconspicuous <a data-mce-href="https://en.wikipedia.org/wiki/Patch_test" href="https://en.wikipedia.org/wiki/Patch_test" title="Patch test">patch testing</a> prior to cosmetic use.</li>
<li>Most medical collagen is derived from young beef cattle (bovine) from certified <a data-mce-href="https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy" href="https://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy" title="Bovine spongiform encephalopathy">BSE</a>-free animals. Most manufacturers use donor animals from either "closed herds", or from countries which have never had a reported case of BSE such as Australia, Brazil, and New Zealand.</li>
</ol>
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<span class="mw-headline" id="Bone_grafts">Bone grafts</span></h3>
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As the skeleton forms the structure of the body, it is vital that it maintains its strength, even after breaks and injuries. Collagen is used in bone grafting as it has a triple helical structure, making it a very strong molecule. It is ideal for use in bones, as it does not compromise the structural integrity of the skeleton. The triple helical structure of collagen prevents it from being broken down by enzymes, it enables adhesiveness of cells and it is important for the proper assembly of the extracellular matrix.<sup class="reference" id="cite_ref-11"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-11" href="https://en.wikipedia.org/wiki/Collagen#cite_note-11">[11]</a></sup></div>
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<span class="mw-headline" id="Tissue_regeneration">Tissue regeneration</span></h3>
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Collagen scaffolds are used in tissue regeneration, whether in sponges, thin sheets, or gels. Collagen has the correct properties for tissue regeneration such as pore structure, permeability, hydrophilicity and it is stable in vivo. Collagen scaffolds are also ideal for the deposition of cells, such as <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Osteoblasts" href="https://en.wikipedia.org/wiki/Osteoblasts" title="Osteoblasts">osteoblasts</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Fibroblast" href="https://en.wikipedia.org/wiki/Fibroblast" title="Fibroblast">fibroblasts</a> and once inserted, growth is able to continue as normal in the tissue.<sup class="reference" id="cite_ref-Oliveira_12-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Oliveira-12" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Oliveira-12">[12]</a></sup></div>
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<span class="mw-headline" id="Reconstructive_surgical_uses">Reconstructive surgical uses</span></h3>
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Collagens are widely employed in the construction of the <a data-mce-href="https://en.wikipedia.org/wiki/Artificial_skin" href="https://en.wikipedia.org/wiki/Artificial_skin" title="Artificial skin">artificial skin</a> substitutes used in the management of severe <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Burn_(injury)" href="https://en.wikipedia.org/wiki/Burn_(injury)" title="Burn (injury)">burns</a>. These collagens may be derived from bovine, equine, porcine, or even human sources; and are sometimes used in combination with <a data-mce-href="https://en.wikipedia.org/wiki/Silicone" href="https://en.wikipedia.org/wiki/Silicone" title="Silicone">silicones</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Glycosaminoglycan" href="https://en.wikipedia.org/wiki/Glycosaminoglycan" title="Glycosaminoglycan">glycosaminoglycans</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Fibroblast" href="https://en.wikipedia.org/wiki/Fibroblast" title="Fibroblast">fibroblasts</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Growth_factor" href="https://en.wikipedia.org/wiki/Growth_factor" title="Growth factor">growth factors</a> and other substances.</div>
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Collagen is also sold commercially in pill form as a supplement to aid joint mobility. However, because proteins are broken down into amino acids before absorption, there is no reason for orally ingested collagen to affect connective tissue in the body, except through the effect of individual amino acid supplementation.</div>
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Collagen is also frequently used in scientific research applications for cell culture, studying cell behavior and cellular interactions with the extracellular environment.<sup class="reference" id="cite_ref-13"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-13" href="https://en.wikipedia.org/wiki/Collagen#cite_note-13">[13]</a></sup></div>
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<span class="mw-headline" id="Wound_care">Wound care</span></h3>
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Collagen is one of the body’s key natural resources and a component of skin tissue that can benefit all stages of the wound healing process.<sup class="reference" id="cite_ref-scr_14-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-scr-14" href="https://en.wikipedia.org/wiki/Collagen#cite_note-scr-14">[14]</a></sup> When collagen is made available to the wound bed, closure can occur. Wound deterioration, followed sometimes by procedures such as amputation, can thus be avoided.</div>
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Collagen is a natural product, therefore it is used as a natural wound dressing and has properties that artificial wound dressings do not have. It is resistant against bacteria, which is of vital importance in a wound dressing. It helps to keep the wound sterile, because of its natural ability to fight infection. When collagen is used as a burn dressing, healthy<a data-mce-href="https://en.wikipedia.org/wiki/Granulation_tissue" href="https://en.wikipedia.org/wiki/Granulation_tissue" title="Granulation tissue">granulation tissue</a> is able to form very quickly over the burn, helping it to heal rapidly.<sup class="reference" id="cite_ref-15"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-15" href="https://en.wikipedia.org/wiki/Collagen#cite_note-15">[15]</a></sup></div>
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Throughout the 4 phases of wound healing, collagen performs the following functions in wound healing:</div>
<ul style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li>Guiding function: Collagen fibers serve to guide fibroblasts. Fibroblasts migrate along a connective tissue matrix.</li>
<li>Chemotactic properties: The large surface area available on collagen fibers can attract fibrogenic cells which help in healing.</li>
<li>Nucleation: Collagen, in the presence of certain neutral salt molecules can act as a nucleating agent causing formation of fibrillar structures. A collagen wound dressing might serve as a guide for orienting new collagen deposition and capillary growth.</li>
<li>Hemostatic properties: Blood <a data-mce-href="https://en.wikipedia.org/wiki/Platelet" href="https://en.wikipedia.org/wiki/Platelet" title="Platelet">platelets</a> interact with the collagen to make a hemostatic plug.</li>
</ul>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="Chemistry">Chemistry</span></h2>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
The collagen protein is composed of a triple helix, which generally consists of two identical chains (α1) and an additional chain that differs slightly in its chemical composition (α2).<sup class="reference" id="cite_ref-SzpakJAS_16-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16" href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16">[16]</a></sup> The amino acid composition of collagen is atypical for proteins, particularly with respect to its high <a data-mce-href="https://en.wikipedia.org/wiki/Hydroxyproline" href="https://en.wikipedia.org/wiki/Hydroxyproline" title="Hydroxyproline">hydroxyproline</a> content. The most common motifs in the amino acid sequence of collagen are <a data-mce-href="https://en.wikipedia.org/wiki/Glycine" href="https://en.wikipedia.org/wiki/Glycine" title="Glycine">glycine</a>-<a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">proline</a>-X and glycine-X-hydroxyproline, where X is any amino acid other than glycine, proline or hydroxyproline. The average amino acid composition for fish and mammal skin is given.<sup class="reference" id="cite_ref-SzpakJAS_16-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16" href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16">[16]</a></sup></div>
<table class="wikitable sortable jquery-tablesorter mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;"><thead>
<tr><th class="headerSort" data-mce-tabindex="0" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" title="Sort ascending">Amino acid</th><th class="headerSort" data-mce-tabindex="0" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" title="Sort ascending">Abundance in mammal skin<br />(<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Residue_(biochemistry)" href="https://en.wikipedia.org/wiki/Residue_(biochemistry)" title="Residue (biochemistry)">residues</a>/1000)</th><th class="headerSort" data-mce-tabindex="0" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" title="Sort ascending">Abundance in fish skin<br />(residues/1000)</th></tr>
</thead><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Glycine" href="https://en.wikipedia.org/wiki/Glycine" title="Glycine">Glycine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">329</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">339</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">Proline</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">126</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">108</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Alanine" href="https://en.wikipedia.org/wiki/Alanine" title="Alanine">Alanine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">109</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">114</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Hydroxyproline" href="https://en.wikipedia.org/wiki/Hydroxyproline" title="Hydroxyproline">Hydroxyproline</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">95</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">67</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Glutamic_acid" href="https://en.wikipedia.org/wiki/Glutamic_acid" title="Glutamic acid">Glutamic acid</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">74</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">76</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Arginine" href="https://en.wikipedia.org/wiki/Arginine" title="Arginine">Arginine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">49</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">52</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Aspartic_acid" href="https://en.wikipedia.org/wiki/Aspartic_acid" title="Aspartic acid">Aspartic acid</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">47</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">47</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Serine" href="https://en.wikipedia.org/wiki/Serine" title="Serine">Serine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">36</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">46</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Lysine" href="https://en.wikipedia.org/wiki/Lysine" title="Lysine">Lysine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">29</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Leucine" href="https://en.wikipedia.org/wiki/Leucine" title="Leucine">Leucine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">24</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">23</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Valine" href="https://en.wikipedia.org/wiki/Valine" title="Valine">Valine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">22</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Threonine" href="https://en.wikipedia.org/wiki/Threonine" title="Threonine">Threonine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">19</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Phenylalanine" href="https://en.wikipedia.org/wiki/Phenylalanine" title="Phenylalanine">Phenylalanine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">14</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Isoleucine" href="https://en.wikipedia.org/wiki/Isoleucine" title="Isoleucine">Isoleucine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">11</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">11</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Hydroxylysine" href="https://en.wikipedia.org/wiki/Hydroxylysine" title="Hydroxylysine">Hydroxylysine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Methionine" href="https://en.wikipedia.org/wiki/Methionine" title="Methionine">Methionine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">13</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Histidine" href="https://en.wikipedia.org/wiki/Histidine" title="Histidine">Histidine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Tyrosine" href="https://en.wikipedia.org/wiki/Tyrosine" title="Tyrosine">Tyrosine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Cysteine" href="https://en.wikipedia.org/wiki/Cysteine" title="Cysteine">Cysteine</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">1</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Tryptophan" href="https://en.wikipedia.org/wiki/Tryptophan" title="Tryptophan">Tryptophan</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0</td></tr>
</tbody><tfoot></tfoot></table>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="Synthesis">Synthesis</span></h2>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
First, a three-dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal components. This is not yet collagen but its precursor, procollagen. Procollagen is then modified by the addition of <a data-mce-href="https://en.wikipedia.org/wiki/Hydroxyl" href="https://en.wikipedia.org/wiki/Hydroxyl" title="Hydroxyl">hydroxyl</a> groups to the amino acids <a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">proline</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Lysine" href="https://en.wikipedia.org/wiki/Lysine" title="Lysine">lysine</a>. This step is important for later <a data-mce-href="https://en.wikipedia.org/wiki/Glycosylation" href="https://en.wikipedia.org/wiki/Glycosylation" title="Glycosylation">glycosylation</a> and the formation of the triple helix structure of collagen. The hydroxylase enzymes that perform these reactions require <a data-mce-href="https://en.wikipedia.org/wiki/Vitamin_C" href="https://en.wikipedia.org/wiki/Vitamin_C" title="Vitamin C">Vitamin C</a> as a cofactor, and a deficiency in this vitamin results in impaired collagen synthesis and the resulting disease <a data-mce-href="https://en.wikipedia.org/wiki/Scurvy" href="https://en.wikipedia.org/wiki/Scurvy" title="Scurvy">scurvy</a><sup class="reference" id="cite_ref-17"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-17" href="https://en.wikipedia.org/wiki/Collagen#cite_note-17">[17]</a></sup> These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase<sup class="reference" id="cite_ref-18"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-18" href="https://en.wikipedia.org/wiki/Collagen#cite_note-18">[18]</a></sup> and lysyl-hydroxylase. Vitamin C also serves with them in inducing these reactions. In this service, one molecule of vitamin C is destroyed for each H replaced by OH. <sup class="reference" id="cite_ref-19"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-19" href="https://en.wikipedia.org/wiki/Collagen#cite_note-19">[19]</a></sup> The synthesis of collagen occurs inside and outside of the cell. The formation of collagen which results in fibrillary collagen (most common form) is discussed here. Meshwork collagen, which is often involved in the formation of filtration systems, is the other form of collagen. All types of collagens are triple helices, and the differences lie in the make-up of the alpha peptides created in step 2.</div>
<ol style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li><b>Transcription of mRNA</b>: About 34 genes are associated with collagen formation, each coding for a specific mRNA sequence, and typically have the "<i>COL</i>" prefix. The beginning of collagen synthesis begins with turning on genes which are associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3).</li>
<li><b>Pre-pro-peptide formation</b>: Once the final mRNA exits from the cell nucleus and enters into the cytoplasm, it links with the ribosomal subunits and the process of translation occurs. The early/first part of the new peptide is known as the signal sequence. The signal sequence on the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/N-terminal" href="https://en.wikipedia.org/wiki/N-terminal" title="N-terminal">N-terminal</a> of the peptide is recognized by a <a data-mce-href="https://en.wikipedia.org/wiki/Signal_recognition_particle" href="https://en.wikipedia.org/wiki/Signal_recognition_particle" title="Signal recognition particle">signal recognition particle</a> on the endoplasmic reticulum, which will be responsible for directing the pre-pro-peptide into the endoplasmic reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the endoplasmic reticulum for post-translational processing. It is now known as pre-pro-collagen.</li>
<li><b>Pre-pro-peptide to pro-collagen</b>: Three modifications of the pre-pro-peptide occur leading to the formation of the alpha peptide:<ol>
<li>The signal peptide on the N-terminal is dissolved, and the molecule is now known as <i>propeptide</i> (not procollagen).</li>
<li>Hydroxylation of lysines and prolines on propeptide by the enzymes 'prolyl hydroxylase' and 'lysyl hydroxylase' (to produce hydroxyproline and hydroxylysine) occurs to aid cross-linking of the alpha peptides. This enzymatic step requires <a data-mce-href="https://en.wikipedia.org/wiki/Vitamin_C" href="https://en.wikipedia.org/wiki/Vitamin_C" title="Vitamin C">vitamin C</a> as a cofactor. In <a data-mce-href="https://en.wikipedia.org/wiki/Scurvy" href="https://en.wikipedia.org/wiki/Scurvy" title="Scurvy">scurvy</a>, the lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by three alpha peptides).</li>
<li>Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxyl groups that were placed onto lysines, but not on prolines.</li>
<li>Once these modifications have taken place, three of the hydroxylated and glycosylated propeptides twist into a triple helix forming procollagen. Procollagen still has unwound ends, which will be later trimmed. At this point, the procollagen is packaged into a transfer vesicle destined for the Golgi apparatus.</li>
</ol>
</li>
<li><b>Golgi apparatus modification</b>: In the Golgi apparatus, the procollagen goes through one last post-translational modification before being secreted out of the cell. In this step, oligosaccharides (not monosaccharides as in step 3) are added, and then the procollagen is packaged into a secretory vesicle destined for the extracellular space.</li>
<li><b>Formation of tropocollagen</b>: Once outside the cell, membrane bound enzymes known as 'collagen peptidases', remove the "loose ends" of the procollagen molecule. What is left is known as tropocollagen. Defects in this step produce one of the many collagenopathies known as <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Ehlers-Danlos_syndrome" href="https://en.wikipedia.org/wiki/Ehlers-Danlos_syndrome" title="Ehlers-Danlos syndrome">Ehlers-Danlos syndrome</a>. This step is absent when synthesizing type III, a type of fibrilar collagen.</li>
<li><b>Formation of the collagen fibril</b>: 'Lysyl oxidase', an extracellular enzyme, produces the final step in the collagen synthesis pathway. This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which will eventually undergo covalent bonding between tropocollagen molecules. This polymer of tropocollogen is known as a collagen fibril.</li>
</ol>
<div class="thumb tright" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div class="thumbinner">
<a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Tropocollagen_cross-linkage_lysyl_oxidase_(EN).svg" href="https://en.wikipedia.org/wiki/File:Tropocollagen_cross-linkage_lysyl_oxidase_(EN).svg"><img alt="" class="thumbimage" data-file-height="1093" data-file-width="592" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f3/Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg/220px-Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg.png" height="640" src="https://upload.wikimedia.org/wikipedia/commons/thumb/f/f3/Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg/220px-Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/f/f3/Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg/330px-Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/f/f3/Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg/440px-Tropocollagen_cross-linkage_lysyl_oxidase_%28EN%29.svg.png 2x" style="height: auto; max-width: 100%;" width="346" /></a><br />
<div class="thumbcaption">
<div class="magnify">
</div>
Action of <a data-mce-href="https://en.wikipedia.org/wiki/Lysyl_oxidase" href="https://en.wikipedia.org/wiki/Lysyl_oxidase" title="Lysyl oxidase">lysyl oxidase</a></div>
</div>
</div>
<h3 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="Amino_acids">Amino acids</span></h3>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
Collagen has an unusual <a data-mce-href="https://en.wikipedia.org/wiki/Amino_acid" href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acid</a> composition and sequence:</div>
<ul style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li><a data-mce-href="https://en.wikipedia.org/wiki/Glycine" href="https://en.wikipedia.org/wiki/Glycine" title="Glycine">Glycine</a> is found at almost every third <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Residue_(biochemistry)" href="https://en.wikipedia.org/wiki/Residue_(biochemistry)" title="Residue (biochemistry)">residue</a>.</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">Proline</a> makes up about 17% of collagen.</li>
<li>Collagen contains two uncommon derivative amino acids not directly inserted during <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Translation_(genetics)" href="https://en.wikipedia.org/wiki/Translation_(genetics)" title="Translation (genetics)">translation</a>. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require <a data-mce-href="https://en.wikipedia.org/wiki/Vitamin_C" href="https://en.wikipedia.org/wiki/Vitamin_C" title="Vitamin C">vitamin C</a> as a<a data-mce-href="https://en.wikipedia.org/wiki/Cofactor_(biochemistry)" href="https://en.wikipedia.org/wiki/Cofactor_(biochemistry)" title="Cofactor (biochemistry)">cofactor</a>.<ul>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Hydroxyproline" href="https://en.wikipedia.org/wiki/Hydroxyproline" title="Hydroxyproline">Hydroxyproline</a> derived from proline</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Hydroxylysine" href="https://en.wikipedia.org/wiki/Hydroxylysine" title="Hydroxylysine">Hydroxylysine</a> derived from <a data-mce-href="https://en.wikipedia.org/wiki/Lysine" href="https://en.wikipedia.org/wiki/Lysine" title="Lysine">lysine</a> - depending on the type of collagen, varying numbers of hydroxylysines are <a data-mce-href="https://en.wikipedia.org/wiki/Glycosylation" href="https://en.wikipedia.org/wiki/Glycosylation" title="Glycosylation">glycosylated</a> (mostly having <a data-mce-href="https://en.wikipedia.org/wiki/Disaccharide" href="https://en.wikipedia.org/wiki/Disaccharide" title="Disaccharide">disaccharides</a> attached).</li>
</ul>
</li>
</ul>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="https://en.wikipedia.org/wiki/Cortisol" href="https://en.wikipedia.org/wiki/Cortisol" title="Cortisol">Cortisol</a> stimulates <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Amide_hydrolysis" href="https://en.wikipedia.org/wiki/Amide_hydrolysis" title="Amide hydrolysis">degradation</a> of (skin) collagen into amino acids.<sup class="reference" id="cite_ref-20"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-20" href="https://en.wikipedia.org/wiki/Collagen#cite_note-20">[20]</a></sup></div>
<h3 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="Collagen_I_formation">Collagen I formation</span></h3>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
Most collagen forms in a similar manner, but the following process is typical for type I:</div>
<ol style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li>Inside the cell<ol>
<li>Two types of alpha chains are formed during <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Translation_(genetics)" href="https://en.wikipedia.org/wiki/Translation_(genetics)" title="Translation (genetics)">translation</a> on ribosomes along the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Rough_endoplasmic_reticulum" href="https://en.wikipedia.org/wiki/Rough_endoplasmic_reticulum" title="Rough endoplasmic reticulum">rough endoplasmic reticulum</a> (RER): alpha-1 and alpha-2 chains. These peptide chains (known as <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=Preprocollagen&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=Preprocollagen&action=edit&redlink=1" title="Preprocollagen (page does not exist)">preprocollagen</a>) have <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=Registration_peptide&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=Registration_peptide&action=edit&redlink=1" title="Registration peptide (page does not exist)">registration peptides</a> on each end and a <a data-mce-href="https://en.wikipedia.org/wiki/Signal_peptide" href="https://en.wikipedia.org/wiki/Signal_peptide" title="Signal peptide">signal peptide</a>.</li>
<li>Polypeptide chains are released into the lumen of the RER.</li>
<li>Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Hydroxylation" href="https://en.wikipedia.org/wiki/Hydroxylation" title="Hydroxylation">Hydroxylation</a> of <a data-mce-href="https://en.wikipedia.org/wiki/Lysine" href="https://en.wikipedia.org/wiki/Lysine" title="Lysine">lysine</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">proline</a> amino acids occurs inside the lumen. This process is dependent on <a data-mce-href="https://en.wikipedia.org/wiki/Ascorbic_acid" href="https://en.wikipedia.org/wiki/Ascorbic_acid" title="Ascorbic acid">ascorbic acid</a> (vitamin C) as a <a data-mce-href="https://en.wikipedia.org/wiki/Cofactor_(biochemistry)" href="https://en.wikipedia.org/wiki/Cofactor_(biochemistry)" title="Cofactor (biochemistry)">cofactor</a>.</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Glycosylation" href="https://en.wikipedia.org/wiki/Glycosylation" title="Glycosylation">Glycosylation</a> of specific hydroxylysine residues occurs.</li>
<li>Triple alpha helical structure is formed inside the endoplasmic reticulum from two alpha-1 chains and one alpha-2 chain.</li>
<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Procollagen" href="https://en.wikipedia.org/wiki/Procollagen" title="Procollagen">Procollagen</a> is shipped to the <a data-mce-href="https://en.wikipedia.org/wiki/Golgi_apparatus" href="https://en.wikipedia.org/wiki/Golgi_apparatus" title="Golgi apparatus">Golgi apparatus</a>, where it is packaged and secreted by <a data-mce-href="https://en.wikipedia.org/wiki/Exocytosis" href="https://en.wikipedia.org/wiki/Exocytosis" title="Exocytosis">exocytosis</a>.</li>
</ol>
</li>
<li>Outside the cell<ol>
<li>Registration peptides are cleaved and tropocollagen is formed by <a data-mce-href="https://en.wikipedia.org/wiki/Procollagen_peptidase" href="https://en.wikipedia.org/wiki/Procollagen_peptidase" title="Procollagen peptidase">procollagen peptidase</a>.</li>
<li>Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (<a data-mce-href="https://en.wikipedia.org/wiki/Aldol_reaction" href="https://en.wikipedia.org/wiki/Aldol_reaction" title="Aldol reaction">aldol reaction</a>) by <a data-mce-href="https://en.wikipedia.org/wiki/Lysyl_oxidase" href="https://en.wikipedia.org/wiki/Lysyl_oxidase" title="Lysyl oxidase">lysyl oxidase</a> which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.</li>
<li>Collagen may be attached to cell membranes via several types of protein, including <a data-mce-href="https://en.wikipedia.org/wiki/Fibronectin" href="https://en.wikipedia.org/wiki/Fibronectin" title="Fibronectin">fibronectin</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Integrin" href="https://en.wikipedia.org/wiki/Integrin" title="Integrin">integrin</a>.</li>
</ol>
</li>
</ol>
<h3 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="Synthetic_pathogenesis">Synthetic pathogenesis</span></h3>
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Vitamin C deficiency causes <a data-mce-href="https://en.wikipedia.org/wiki/Scurvy" href="https://en.wikipedia.org/wiki/Scurvy" title="Scurvy">scurvy</a>, a serious and painful disease in which defective collagen prevents the formation of strong <a data-mce-href="https://en.wikipedia.org/wiki/Connective_tissue" href="https://en.wikipedia.org/wiki/Connective_tissue" title="Connective tissue">connective tissue</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Gingiva" href="https://en.wikipedia.org/wiki/Gingiva" title="Gingiva">Gums</a> deteriorate and bleed, with loss of teeth; skin discolors, and <a data-mce-href="https://en.wikipedia.org/wiki/Wound" href="https://en.wikipedia.org/wiki/Wound" title="Wound">wounds</a> do not heal. Prior to the 18th century, this condition was notorious among long-duration military, particularly naval, expeditions during which participants were deprived of foods containing vitamin C.</div>
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An <a data-mce-href="https://en.wikipedia.org/wiki/Autoimmune_disease" href="https://en.wikipedia.org/wiki/Autoimmune_disease" title="Autoimmune disease">autoimmune disease</a> such as <a data-mce-href="https://en.wikipedia.org/wiki/Lupus_erythematosus" href="https://en.wikipedia.org/wiki/Lupus_erythematosus" title="Lupus erythematosus">lupus erythematosus</a> or <a data-mce-href="https://en.wikipedia.org/wiki/Rheumatoid_arthritis" href="https://en.wikipedia.org/wiki/Rheumatoid_arthritis" title="Rheumatoid arthritis">rheumatoid arthritis</a><sup class="reference" id="cite_ref-21"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-21" href="https://en.wikipedia.org/wiki/Collagen#cite_note-21">[21]</a></sup> may attack healthy collagen fibers.</div>
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Many bacteria and viruses secrete <a data-mce-href="https://en.wikipedia.org/wiki/Virulence_factor" href="https://en.wikipedia.org/wiki/Virulence_factor" title="Virulence factor">virulence factors</a>, such as the enzyme <a data-mce-href="https://en.wikipedia.org/wiki/Collagenase" href="https://en.wikipedia.org/wiki/Collagenase" title="Collagenase">collagenase</a>, which destroys collagen or interferes with its production.</div>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="Molecular_structure">Molecular structure</span></h2>
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A single collagen molecule, tropocollagen, is used to make up larger collagen aggregates, such as fibrils. It is approximately 300 <a data-mce-href="https://en.wikipedia.org/wiki/Nanometre" href="https://en.wikipedia.org/wiki/Nanometre" title="Nanometre">nm</a> long and 1.5 nm in diameter, and it is made up of three <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Polypeptide" href="https://en.wikipedia.org/wiki/Polypeptide" title="Polypeptide">polypeptide</a> strands (called alpha peptides, see step 2), each of which has the conformation of a left-handed <a data-mce-href="https://en.wikipedia.org/wiki/Helix" href="https://en.wikipedia.org/wiki/Helix" title="Helix">helix</a> – this should not be confused with the right-handed<a data-mce-href="https://en.wikipedia.org/wiki/Alpha_helix" href="https://en.wikipedia.org/wiki/Alpha_helix" title="Alpha helix">alpha helix</a>. These three left-handed helices are twisted together into a right-handed triple helix or "super helix", a cooperative <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Quaternary_structure" href="https://en.wikipedia.org/wiki/Quaternary_structure" title="Quaternary structure">quaternary structure</a> stabilized by many <a data-mce-href="https://en.wikipedia.org/wiki/Hydrogen_bond" href="https://en.wikipedia.org/wiki/Hydrogen_bond" title="Hydrogen bond">hydrogen bonds</a>. With type I collagen and possibly all fibrillar collagens, if not all collagens, each triple-helix associates into a right-handed super-super-coil referred to as the collagen microfibril. Each microfibril is <a class="extiw" data-mce-href="https://en.wiktionary.org/wiki/interdigitate" href="https://en.wiktionary.org/wiki/interdigitate" title="wikt:interdigitate">interdigitated</a> with its neighboring microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so well ordered as to be crystalline.</div>
<div class="thumb tright" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<div class="thumbinner">
<a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:Collagen_biosynthesis_(en).png" href="https://en.wikipedia.org/wiki/File:Collagen_biosynthesis_(en).png"><img alt="" class="thumbimage" data-file-height="459" data-file-width="701" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/2/2f/Collagen_biosynthesis_%28en%29.png" height="459" src="https://upload.wikimedia.org/wikipedia/commons/2/2f/Collagen_biosynthesis_%28en%29.png" style="height: auto; max-width: 100%;" width="701" /></a><br />
<div class="thumbcaption">
Three <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Polypeptide" href="https://en.wikipedia.org/wiki/Polypeptide" title="Polypeptide">polypeptides</a> coil to form tropocollagen. Many tropocollagens then bind together to form a fibril, and many of these then form a fibre.</div>
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</div>
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A distinctive feature of collagen is the regular arrangement of<a data-mce-href="https://en.wikipedia.org/wiki/Amino_acid" href="https://en.wikipedia.org/wiki/Amino_acid" title="Amino acid">amino acids</a> in each of the three chains of these collagen subunits. The sequence often follows the pattern <a data-mce-href="https://en.wikipedia.org/wiki/Glycine" href="https://en.wikipedia.org/wiki/Glycine" title="Glycine">Gly</a>-<a data-mce-href="https://en.wikipedia.org/wiki/Proline" href="https://en.wikipedia.org/wiki/Proline" title="Proline">Pro</a>-X or Gly-X-<a data-mce-href="https://en.wikipedia.org/wiki/Hydroxyproline" href="https://en.wikipedia.org/wiki/Hydroxyproline" title="Hydroxyproline">Hyp</a>, where X may be any of various other amino acid residues.<sup class="reference" id="cite_ref-SzpakJAS_16-2"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16" href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16">[16]</a></sup> Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline or hydroxyproline, a fact often missed due to the distraction of the unusual GX<sub>1</sub>X<sub>2</sub> character of collagen alpha-peptides. The high glycine content of collagen is important with respect to stabilization of the collagen helix as this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and the formation of intermolecular cross-links.<sup class="reference" id="cite_ref-SzpakJAS_16-3"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16" href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16">[16]</a></sup>This kind of regular repetition and high glycine content is found in only a few other fibrous proteins, such as <a data-mce-href="https://en.wikipedia.org/wiki/Silk" href="https://en.wikipedia.org/wiki/Silk" title="Silk">silk</a> <a data-mce-href="https://en.wikipedia.org/wiki/Fibroin" href="https://en.wikipedia.org/wiki/Fibroin" title="Fibroin">fibroin</a>.</div>
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Collagen is not only a structural protein. Due to its key role in the determination of cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its non-proline-rich regions have cell or matrix association / regulation roles. The relatively high content of proline and hydroxyproline rings, with their geometrically constrained <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Carboxyl" href="https://en.wikipedia.org/wiki/Carboxyl" title="Carboxyl">carboxyl</a> and (secondary) <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Amino" href="https://en.wikipedia.org/wiki/Amino" title="Amino">amino</a> groups, along with the rich abundance of glycine, accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without any intrachain hydrogen bonding.</div>
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Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the interior (axis) of the helix, where there is no space for a larger side group than glycine’s single <a data-mce-href="https://en.wikipedia.org/wiki/Hydrogen" href="https://en.wikipedia.org/wiki/Hydrogen" title="Hydrogen">hydrogen atom</a>. For the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple helix—Hyp even more so than Pro; a lower concentration of them is required in animals such as <a data-mce-href="https://en.wikipedia.org/wiki/Fish" href="https://en.wikipedia.org/wiki/Fish" title="Fish">fish</a>, whose <a data-mce-href="https://en.wikipedia.org/wiki/Thermoregulation" href="https://en.wikipedia.org/wiki/Thermoregulation" title="Thermoregulation">body temperatures</a> are lower than most warm-blooded animals. Lower proline and hydroxyproline contents are characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline contents to mammals.<sup class="reference" id="cite_ref-SzpakJAS_16-4"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16" href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16">[16]</a></sup> The lower proline and hydroxproline contents of cold-water fish and other <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Poikilothermic" href="https://en.wikipedia.org/wiki/Poikilothermic" title="Poikilothermic">poikilotherm</a> animals leads to their collagen having a lower thermal stability than mammalian collagen.<sup class="reference" id="cite_ref-SzpakJAS_16-5"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16" href="https://en.wikipedia.org/wiki/Collagen#cite_note-SzpakJAS-16">[16]</a></sup> This lower thermal stability means that <a data-mce-href="https://en.wikipedia.org/wiki/Gelatin" href="https://en.wikipedia.org/wiki/Gelatin" title="Gelatin">gelatin</a> derived from fish collagen is not suitable for many food and industrial applications.</div>
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The tropocollagen <a data-mce-href="https://en.wikipedia.org/wiki/Protein_subunit" href="https://en.wikipedia.org/wiki/Protein_subunit" title="Protein subunit">subunits</a> spontaneously <a data-mce-href="https://en.wikipedia.org/wiki/Molecular_self-assembly" href="https://en.wikipedia.org/wiki/Molecular_self-assembly" title="Molecular self-assembly">self-assemble</a>, with regularly staggered ends, into even larger arrays in the <a data-mce-href="https://en.wikipedia.org/wiki/Extracellular" href="https://en.wikipedia.org/wiki/Extracellular" title="Extracellular">extracellular</a> spaces of tissues.<sup class="reference" id="cite_ref-22"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-22" href="https://en.wikipedia.org/wiki/Collagen#cite_note-22">[22]</a></sup><sup class="reference" id="cite_ref-Hulmes.2C_D.J._1992._p._49_23-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes.2C_D.J._1992._p._49-23" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes.2C_D.J._1992._p._49-23">[23]</a></sup> Additional assembly of fibrils is guided by fibroblasts, which deposit fully formed fibrils from fibripositors.<sup class="reference" id="cite_ref-Sherman_2015_22.E2.80.9350_2-2"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Sherman_2015_22.E2.80.9350-2" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Sherman_2015_22.E2.80.9350-2">[2]</a></sup> In the fibrillar collagens, the molecules are staggered from each other by about 67 <a data-mce-href="https://en.wikipedia.org/wiki/Nanometre" href="https://en.wikipedia.org/wiki/Nanometre" title="Nanometre">nm</a> (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each D-period contains four plus a fraction collagen molecules, because 300 nm divided by 67 nm does not give an integer (the length of the collagen molecule divided by the stagger distance D). Therefore, in each D-period repeat of the microfibril, there is a part containing five molecules in cross-section, called the “overlap”, and a part containing only four molecules, called the "gap".<sup class="reference" id="cite_ref-Orgel_24-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Orgel-24" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Orgel-24">[24]</a></sup> The triple-helices are also arranged in a hexagonal or quasihexagonal array in cross-section, in both the gap and overlap regions.<sup class="reference" id="cite_ref-Orgel_24-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Orgel-24" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Orgel-24">[24]</a></sup><sup class="reference" id="cite_ref-Hulmes_Miller_1979_25-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes_Miller_1979-25" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes_Miller_1979-25">[25]</a></sup></div>
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There is some <a data-mce-href="https://en.wikipedia.org/wiki/Covalent_bond" href="https://en.wikipedia.org/wiki/Covalent_bond" title="Covalent bond">covalent</a> crosslinking within the triple helices, and a variable amount of covalent crosslinking between tropocollagen helices forming well organized aggregates (such as fibrils).<sup class="reference" id="cite_ref-26"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-26" href="https://en.wikipedia.org/wiki/Collagen#cite_note-26">[26]</a></sup> Larger fibrillar bundles are formed with the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans to form the different types of mature tissues from alternate combinations of the same key players.<sup class="reference" id="cite_ref-Hulmes.2C_D.J._1992._p._49_23-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes.2C_D.J._1992._p._49-23" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes.2C_D.J._1992._p._49-23">[23]</a></sup> Collagen's <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Soluble" href="https://en.wikipedia.org/wiki/Soluble" title="Soluble">insolubility</a> was a barrier to the study of monomeric collagen until it was found that tropocollagen from young animals can be extracted because it is not yet fully <a data-mce-href="https://en.wikipedia.org/wiki/Cross-link" href="https://en.wikipedia.org/wiki/Cross-link" title="Cross-link">crosslinked</a>. However, advances in microscopy techniques (i.e. electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to obtain increasingly detailed images of collagen structure <i>in situ</i>. These later advances are particularly important to better understanding the way in which collagen structure affects cell–cell and cell–matrix communication, and how tissues are constructed in growth and repair, and changed in development and disease.<sup class="reference" id="cite_ref-27"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-27" href="https://en.wikipedia.org/wiki/Collagen#cite_note-27">[27]</a></sup><sup class="reference" id="cite_ref-28"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-28" href="https://en.wikipedia.org/wiki/Collagen#cite_note-28">[28]</a></sup> For example, using AFM–based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its different molecular organizations in these two regions.<sup class="reference" id="cite_ref-29"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-29" href="https://en.wikipedia.org/wiki/Collagen#cite_note-29">[29]</a></sup></div>
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Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for the deposition of long, hard, fine crystals of the mineral component, which is (approximately) Ca<sub>10</sub>(OH)<sub>2</sub>(PO<sub>4</sub>)<sub>6</sub>.<sup class="reference" id="cite_ref-30"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-30" href="https://en.wikipedia.org/wiki/Collagen#cite_note-30">[30]</a></sup> Type I collagen gives bone its <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Tensile_strength" href="https://en.wikipedia.org/wiki/Tensile_strength" title="Tensile strength">tensile strength</a>.</div>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="Associated_disorders">Associated disorders</span></h2>
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Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen production.</div>
<table class="wikitable mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><b>Genetic Defects of Collagen Genes</b></caption><tbody>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Type</b></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Notes</b></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b>Gene(s)</b></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen_disease" href="https://en.wikipedia.org/wiki/Collagen_disease" title="Collagen disease">Disorders</a></b></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Type-I_collagen" href="https://en.wikipedia.org/wiki/Type-I_collagen" title="Type-I collagen">I</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">This is the most abundant collagen of the human body. It is present in <a data-mce-href="https://en.wikipedia.org/wiki/Scar" href="https://en.wikipedia.org/wiki/Scar" title="Scar">scar tissue</a>, the end product when tissue <a data-mce-href="https://en.wikipedia.org/wiki/Healing" href="https://en.wikipedia.org/wiki/Healing" title="Healing">heals</a> by repair. It is found in <a data-mce-href="https://en.wikipedia.org/wiki/Tendon" href="https://en.wikipedia.org/wiki/Tendon" title="Tendon">tendons</a>, skin, artery walls, cornea, the <a data-mce-href="https://en.wikipedia.org/wiki/Endomysium" href="https://en.wikipedia.org/wiki/Endomysium" title="Endomysium">endomysium</a>surrounding muscle fibers, fibrocartilage, and the organic part of bones and teeth.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL1A1" href="https://en.wikipedia.org/wiki/COL1A1" title="COL1A1">COL1A1</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL1A2" href="https://en.wikipedia.org/wiki/COL1A2" title="COL1A2">COL1A2</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Osteogenesis_imperfecta" href="https://en.wikipedia.org/wiki/Osteogenesis_imperfecta" title="Osteogenesis imperfecta">Osteogenesis imperfecta</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" title="Ehlers–Danlos syndrome">Ehlers–Danlos syndrome</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Infantile_cortical_hyperostosis" href="https://en.wikipedia.org/wiki/Infantile_cortical_hyperostosis" title="Infantile cortical hyperostosis">Infantile cortical hyperostosis</a> a.k.a. Caffey's disease</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Type-II_collagen" href="https://en.wikipedia.org/wiki/Type-II_collagen" title="Type-II collagen">II</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Hyaline_cartilage" href="https://en.wikipedia.org/wiki/Hyaline_cartilage" title="Hyaline cartilage">Hyaline cartilage</a>, makes up 50% of all cartilage protein. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Vitreous_humour" href="https://en.wikipedia.org/wiki/Vitreous_humour" title="Vitreous humour">Vitreous humour</a> of the eye.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL2A1" href="https://en.wikipedia.org/wiki/COL2A1" title="COL2A1">COL2A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Collagenopathy,_types_II_and_XI" href="https://en.wikipedia.org/wiki/Collagenopathy,_types_II_and_XI" title="Collagenopathy, types II and XI">Collagenopathy, types II and XI</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Type-III_collagen" href="https://en.wikipedia.org/wiki/Type-III_collagen" title="Type-III collagen">III</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">This is the collagen of <a data-mce-href="https://en.wikipedia.org/wiki/Granulation_tissue" href="https://en.wikipedia.org/wiki/Granulation_tissue" title="Granulation tissue">granulation tissue</a>, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. <a data-mce-href="https://en.wikipedia.org/wiki/Reticular_fiber" href="https://en.wikipedia.org/wiki/Reticular_fiber" title="Reticular fiber">Reticular fiber</a>. Also found in artery walls, skin, intestines and the uterus</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL3A1" href="https://en.wikipedia.org/wiki/COL3A1" title="COL3A1">COL3A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" title="Ehlers–Danlos syndrome">Ehlers–Danlos syndrome</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Dupuytren%27s_contracture" href="https://en.wikipedia.org/wiki/Dupuytren%27s_contracture" title="Dupuytren's contracture">Dupuytren's contracture</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Type-IV_collagen" href="https://en.wikipedia.org/wiki/Type-IV_collagen" title="Type-IV collagen">IV</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Basal_lamina" href="https://en.wikipedia.org/wiki/Basal_lamina" title="Basal lamina">Basal lamina</a>; <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Eye_lens" href="https://en.wikipedia.org/wiki/Eye_lens" title="Eye lens">eye lens</a>. Also serves as part of the filtration system in <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Capillaries" href="https://en.wikipedia.org/wiki/Capillaries" title="Capillaries">capillaries</a> and the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Glomeruli" href="https://en.wikipedia.org/wiki/Glomeruli" title="Glomeruli">glomeruli</a> of<a data-mce-href="https://en.wikipedia.org/wiki/Nephron" href="https://en.wikipedia.org/wiki/Nephron" title="Nephron">nephron</a> in the <a data-mce-href="https://en.wikipedia.org/wiki/Kidney" href="https://en.wikipedia.org/wiki/Kidney" title="Kidney">kidney</a>.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen,_type_IV,_alpha_1" href="https://en.wikipedia.org/wiki/Collagen,_type_IV,_alpha_1" title="Collagen, type IV, alpha 1">COL4A1</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL4A2" href="https://en.wikipedia.org/wiki/COL4A2" title="COL4A2">COL4A2</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL4A3" href="https://en.wikipedia.org/wiki/COL4A3" title="COL4A3">COL4A3</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL4A4" href="https://en.wikipedia.org/wiki/COL4A4" title="COL4A4">COL4A4</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL4A5" href="https://en.wikipedia.org/wiki/COL4A5" title="COL4A5">COL4A5</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL4A6" href="https://en.wikipedia.org/wiki/COL4A6" title="COL4A6">COL4A6</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Alport_syndrome" href="https://en.wikipedia.org/wiki/Alport_syndrome" title="Alport syndrome">Alport syndrome</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Goodpasture%27s_syndrome" href="https://en.wikipedia.org/wiki/Goodpasture%27s_syndrome" title="Goodpasture's syndrome">Goodpasture's syndrome</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">V</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Most interstitial tissue, assoc. with type I, associated with <a data-mce-href="https://en.wikipedia.org/wiki/Placenta" href="https://en.wikipedia.org/wiki/Placenta" title="Placenta">placenta</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL5A1" href="https://en.wikipedia.org/wiki/COL5A1" title="COL5A1">COL5A1</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL5A2" href="https://en.wikipedia.org/wiki/COL5A2" title="COL5A2">COL5A2</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL5A3" href="https://en.wikipedia.org/wiki/COL5A3" title="COL5A3">COL5A3</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" href="https://en.wikipedia.org/wiki/Ehlers%E2%80%93Danlos_syndrome" title="Ehlers–Danlos syndrome">Ehlers–Danlos syndrome</a> (Classical)</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">VI</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Most interstitial tissue, assoc. with type I</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL6A1" href="https://en.wikipedia.org/wiki/COL6A1" title="COL6A1">COL6A1</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL6A2" href="https://en.wikipedia.org/wiki/COL6A2" title="COL6A2">COL6A2</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL6A3" href="https://en.wikipedia.org/wiki/COL6A3" title="COL6A3">COL6A3</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL6A5" href="https://en.wikipedia.org/wiki/COL6A5" title="COL6A5">COL6A5</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Ulrich_myopathy" href="https://en.wikipedia.org/wiki/Ulrich_myopathy" title="Ulrich myopathy">Ulrich myopathy</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Bethlem_myopathy" href="https://en.wikipedia.org/wiki/Bethlem_myopathy" title="Bethlem myopathy">Bethlem myopathy</a>,<a data-mce-href="https://en.wikipedia.org/wiki/Atopic_dermatitis" href="https://en.wikipedia.org/wiki/Atopic_dermatitis" title="Atopic dermatitis">Atopic dermatitis</a><sup class="reference" id="cite_ref-31"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-31" href="https://en.wikipedia.org/wiki/Collagen#cite_note-31">[31]</a></sup></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">VII</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Forms <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Anchoring_fibril" href="https://en.wikipedia.org/wiki/Anchoring_fibril" title="Anchoring fibril">anchoring fibrils</a> in <a data-mce-href="https://en.wikipedia.org/wiki/Dermoepidermal_junction" href="https://en.wikipedia.org/wiki/Dermoepidermal_junction" title="Dermoepidermal junction">dermoepidermal junctions</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL7A1" href="https://en.wikipedia.org/wiki/COL7A1" title="COL7A1">COL7A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Epidermolysis_bullosa_dystrophica" href="https://en.wikipedia.org/wiki/Epidermolysis_bullosa_dystrophica" title="Epidermolysis bullosa dystrophica">Epidermolysis bullosa dystrophica</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">VIII</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Some <a data-mce-href="https://en.wikipedia.org/wiki/Endothelium" href="https://en.wikipedia.org/wiki/Endothelium" title="Endothelium">endothelial</a> cells</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL8A1" href="https://en.wikipedia.org/wiki/COL8A1" title="COL8A1">COL8A1</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL8A2" href="https://en.wikipedia.org/wiki/COL8A2" title="COL8A2">COL8A2</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Posterior_polymorphous_corneal_dystrophy_2" href="https://en.wikipedia.org/wiki/Posterior_polymorphous_corneal_dystrophy_2" title="Posterior polymorphous corneal dystrophy 2">Posterior polymorphous corneal dystrophy 2</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">IX</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/FACIT_collagen" href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">FACIT collagen</a>, cartilage, assoc. with type II and XI fibrils</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL9A1" href="https://en.wikipedia.org/wiki/COL9A1" title="COL9A1">COL9A1</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL9A2" href="https://en.wikipedia.org/wiki/COL9A2" title="COL9A2">COL9A2</a>,<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL9A3" href="https://en.wikipedia.org/wiki/COL9A3" title="COL9A3">COL9A3</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/EDM2" href="https://en.wikipedia.org/wiki/EDM2" title="EDM2">EDM2</a> and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/EDM3" href="https://en.wikipedia.org/wiki/EDM3" title="EDM3">EDM3</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">X</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Hypertrophic" href="https://en.wikipedia.org/wiki/Hypertrophic" title="Hypertrophic">Hypertrophic</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Mineralization_(biology)" href="https://en.wikipedia.org/wiki/Mineralization_(biology)" title="Mineralization (biology)">mineralizing</a> cartilage</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL10A1" href="https://en.wikipedia.org/wiki/COL10A1" title="COL10A1">COL10A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Schmid_metaphyseal_dysplasia" href="https://en.wikipedia.org/wiki/Schmid_metaphyseal_dysplasia" title="Schmid metaphyseal dysplasia">Schmid metaphyseal dysplasia</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XI</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Cartilage</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL11A1" href="https://en.wikipedia.org/wiki/COL11A1" title="COL11A1">COL11A1</a>, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL11A2" href="https://en.wikipedia.org/wiki/COL11A2" title="COL11A2">COL11A2</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Collagenopathy,_types_II_and_XI" href="https://en.wikipedia.org/wiki/Collagenopathy,_types_II_and_XI" title="Collagenopathy, types II and XI">Collagenopathy, types II and XI</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XII</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/FACIT_collagen" href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">FACIT collagen</a>, interacts with type I containing fibrils, <a data-mce-href="https://en.wikipedia.org/wiki/Decorin" href="https://en.wikipedia.org/wiki/Decorin" title="Decorin">decorin</a> and glycosaminoglycans</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL12A1" href="https://en.wikipedia.org/wiki/COL12A1" title="COL12A1">COL12A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XIII</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Transmembrane collagen, interacts with integrin a1b1, <a data-mce-href="https://en.wikipedia.org/wiki/Fibronectin" href="https://en.wikipedia.org/wiki/Fibronectin" title="Fibronectin">fibronectin</a> and components of basement membranes like <a data-mce-href="https://en.wikipedia.org/wiki/Nidogen" href="https://en.wikipedia.org/wiki/Nidogen" title="Nidogen">nidogen</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Perlecan" href="https://en.wikipedia.org/wiki/Perlecan" title="Perlecan">perlecan</a>.</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL13A1" href="https://en.wikipedia.org/wiki/COL13A1" title="COL13A1">COL13A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XIV</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/FACIT_collagen" href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">FACIT collagen</a>, also known as undulin</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL14A1" href="https://en.wikipedia.org/wiki/COL14A1" title="COL14A1">COL14A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XV</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL15A1" href="https://en.wikipedia.org/wiki/COL15A1" title="COL15A1">COL15A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XVI</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL16A1" href="https://en.wikipedia.org/wiki/COL16A1" title="COL16A1">COL16A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Collagen_XVII" href="https://en.wikipedia.org/wiki/Collagen_XVII" title="Collagen XVII">XVII</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Transmembrane collagen, also known as BP180, a 180 kDa protein</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL17A1" href="https://en.wikipedia.org/wiki/COL17A1" title="COL17A1">COL17A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Bullous_pemphigoid" href="https://en.wikipedia.org/wiki/Bullous_pemphigoid" title="Bullous pemphigoid">Bullous pemphigoid</a> and certain forms of junctional <a data-mce-href="https://en.wikipedia.org/wiki/Epidermolysis_bullosa" href="https://en.wikipedia.org/wiki/Epidermolysis_bullosa" title="Epidermolysis bullosa">epidermolysis bullosa</a></td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Type_XVIII_collagen" href="https://en.wikipedia.org/wiki/Type_XVIII_collagen" title="Type XVIII collagen">XVIII</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Source of <a data-mce-href="https://en.wikipedia.org/wiki/Endostatin" href="https://en.wikipedia.org/wiki/Endostatin" title="Endostatin">endostatin</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL18A1" href="https://en.wikipedia.org/wiki/COL18A1" title="COL18A1">COL18A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XIX</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/FACIT_collagen" href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">FACIT collagen</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL19A1" href="https://en.wikipedia.org/wiki/COL19A1" title="COL19A1">COL19A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XX</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL20A1" href="https://en.wikipedia.org/wiki/COL20A1" title="COL20A1">COL20A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XXI</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/FACIT_collagen" href="https://en.wikipedia.org/wiki/FACIT_collagen" title="FACIT collagen">FACIT collagen</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL21A1" href="https://en.wikipedia.org/wiki/COL21A1" title="COL21A1">COL21A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XXII</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL22A1" href="https://en.wikipedia.org/wiki/COL22A1" title="COL22A1">COL22A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen,_type_XXIII,_alpha_1" href="https://en.wikipedia.org/wiki/Collagen,_type_XXIII,_alpha_1" title="Collagen, type XXIII, alpha 1">XXIII</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">MACIT collagen</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL23A1" href="https://en.wikipedia.org/wiki/COL23A1" title="COL23A1">COL23A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XXIV</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/COL24A1" href="https://en.wikipedia.org/wiki/COL24A1" title="COL24A1">COL24A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XXV</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL25A1" href="https://en.wikipedia.org/wiki/COL25A1" title="COL25A1">COL25A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XXVI</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/EMID2" href="https://en.wikipedia.org/wiki/EMID2" title="EMID2">EMID2</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XXVII</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL27A1" href="https://en.wikipedia.org/wiki/COL27A1" title="COL27A1">COL27A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">XXVIII</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL28A1" href="https://en.wikipedia.org/wiki/COL28A1" title="COL28A1">COL28A1</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">–</td></tr>
</tbody></table>
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In addition to the above-mentioned disorders, excessive deposition of collagen occurs in <a data-mce-href="https://en.wikipedia.org/wiki/Scleroderma" href="https://en.wikipedia.org/wiki/Scleroderma" title="Scleroderma">scleroderma</a>.</div>
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<span class="mw-headline" id="Diseases">Diseases</span></h2>
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One thousand mutations have been identified in twelve out of more than twenty types of collagen. These mutations can lead to various diseases at the tissue level.<sup class="reference" id="cite_ref-Mahajan.2C_VB_2010_32-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Mahajan.2C_VB_2010-32" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Mahajan.2C_VB_2010-32">[32]</a></sup></div>
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<a data-mce-href="https://en.wikipedia.org/wiki/Osteogenesis_imperfecta" href="https://en.wikipedia.org/wiki/Osteogenesis_imperfecta" title="Osteogenesis imperfecta">Osteogenesis imperfecta</a> – Caused by a mutation in <b>type 1 collagen</b>, dominant autosomal disorder, results in weak bones and irregular connective tissue, some cases can be mild while others can be lethal, mild cases have lowered levels of collagen type 1 while severe cases have structural defects in collagen.<sup class="reference" id="cite_ref-33"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-33" href="https://en.wikipedia.org/wiki/Collagen#cite_note-33">[33]</a></sup></div>
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<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Chondrodysplasia" href="https://en.wikipedia.org/wiki/Chondrodysplasia" title="Chondrodysplasia">Chondrodysplasias</a> – Skeletal disorder believed to be caused by a mutation in <b>type 2 collagen</b>, further research is being conducted to confirm this.<sup class="reference" id="cite_ref-34"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-34" href="https://en.wikipedia.org/wiki/Collagen#cite_note-34">[34]</a></sup></div>
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<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Ehlers-Danlos_Syndrome" href="https://en.wikipedia.org/wiki/Ehlers-Danlos_Syndrome" title="Ehlers-Danlos Syndrome">Ehlers-Danlos Syndrome</a> – Six different types of this disorder, which lead to deformities in connective tissue. Some types can be lethal, leading to the rupture of arteries. Each syndrome is caused by a different mutation, for example type four of this disorder is caused by a mutation in <b>collagen type 3</b>.<sup class="reference" id="cite_ref-Hamel_35-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hamel-35" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hamel-35">[35]</a></sup></div>
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<a data-mce-href="https://en.wikipedia.org/wiki/Alport_syndrome" href="https://en.wikipedia.org/wiki/Alport_syndrome" title="Alport syndrome">Alport syndrome</a> – Can be passed on genetically, usually as X-linked dominant, but also as both an autosomal dominant and autosomal recessive disorder, sufferers have problems with their kidneys and eyes, loss of hearing can also develop in during the childhood or adolescent years.<sup class="reference" id="cite_ref-36"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-36" href="https://en.wikipedia.org/wiki/Collagen#cite_note-36">[36]</a></sup></div>
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<a data-mce-href="https://en.wikipedia.org/wiki/Osteoporosis" href="https://en.wikipedia.org/wiki/Osteoporosis" title="Osteoporosis">Osteoporosis</a> – Not inherited genetically, brought on with age, associated with reduced levels of collagen in the skin and bones, growth hormone injections are being researched as a possible treatment to counteract any loss of collagen.<sup class="reference" id="cite_ref-37"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-37" href="https://en.wikipedia.org/wiki/Collagen#cite_note-37">[37]</a></sup></div>
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<a data-mce-href="https://en.wikipedia.org/wiki/Knobloch_syndrome" href="https://en.wikipedia.org/wiki/Knobloch_syndrome" title="Knobloch syndrome">Knobloch syndrome</a> – Caused by a mutation in the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/COL18A1" href="https://en.wikipedia.org/wiki/COL18A1" title="COL18A1">COL18A1</a> gene that codes for the production of collagen XVIII. Patients present with protrusion of the brain tissue and degeneration of the retina, an individual who has family members suffering from the disorder are at an increased risk of developing it themselves as there is a hereditary link.<sup class="reference" id="cite_ref-Mahajan.2C_VB_2010_32-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Mahajan.2C_VB_2010-32" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Mahajan.2C_VB_2010-32">[32]</a></sup></div>
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<span class="mw-headline" id="Characteristics">Characteristics</span></h2>
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Collagen is one of the long, <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Fibrous_protein" href="https://en.wikipedia.org/wiki/Fibrous_protein" title="Fibrous protein">fibrous structural proteins</a> whose functions are quite different from those of <a data-mce-href="https://en.wikipedia.org/wiki/Globular_protein" href="https://en.wikipedia.org/wiki/Globular_protein" title="Globular protein">globular proteins</a>, such as <a data-mce-href="https://en.wikipedia.org/wiki/Enzyme" href="https://en.wikipedia.org/wiki/Enzyme" title="Enzyme">enzymes</a>. Tough bundles of collagen called<i>collagen fibers</i> are a major component of the <a data-mce-href="https://en.wikipedia.org/wiki/Extracellular_matrix" href="https://en.wikipedia.org/wiki/Extracellular_matrix" title="Extracellular matrix">extracellular matrix</a> that supports most tissues and gives cells structure from the outside, but collagen is also found inside certain cells. Collagen has great <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Tensile_strength" href="https://en.wikipedia.org/wiki/Tensile_strength" title="Tensile strength">tensile strength</a>, and is the main component of <a data-mce-href="https://en.wikipedia.org/wiki/Fascia" href="https://en.wikipedia.org/wiki/Fascia" title="Fascia">fascia</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Cartilage" href="https://en.wikipedia.org/wiki/Cartilage" title="Cartilage">cartilage</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Ligament" href="https://en.wikipedia.org/wiki/Ligament" title="Ligament">ligaments</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Tendon" href="https://en.wikipedia.org/wiki/Tendon" title="Tendon">tendons</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Bone" href="https://en.wikipedia.org/wiki/Bone" title="Bone">bone</a> and skin.<sup class="reference" id="cite_ref-38"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-38" href="https://en.wikipedia.org/wiki/Collagen#cite_note-38">[38]</a></sup><sup class="reference" id="cite_ref-39"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-39" href="https://en.wikipedia.org/wiki/Collagen#cite_note-39">[39]</a></sup> Along with <a data-mce-href="https://en.wikipedia.org/wiki/Elastin" href="https://en.wikipedia.org/wiki/Elastin" title="Elastin">elastin</a> and soft <a data-mce-href="https://en.wikipedia.org/wiki/Keratin" href="https://en.wikipedia.org/wiki/Keratin" title="Keratin">keratin</a>, it is responsible for <a data-mce-href="https://en.wikipedia.org/wiki/Human_skin" href="https://en.wikipedia.org/wiki/Human_skin" title="Human skin">skin</a> strength and elasticity, and its degradation leads to <a data-mce-href="https://en.wikipedia.org/wiki/Wrinkle" href="https://en.wikipedia.org/wiki/Wrinkle" title="Wrinkle">wrinkles</a> that accompany <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Aging" href="https://en.wikipedia.org/wiki/Aging" title="Aging">aging</a>.<sup class="reference" id="cite_ref-pharmax2_10-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-pharmax2-10" href="https://en.wikipedia.org/wiki/Collagen#cite_note-pharmax2-10">[10]</a></sup> It strengthens <a data-mce-href="https://en.wikipedia.org/wiki/Blood_vessel" href="https://en.wikipedia.org/wiki/Blood_vessel" title="Blood vessel">blood vessels</a> and plays a role in <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Biological_tissue" href="https://en.wikipedia.org/wiki/Biological_tissue" title="Biological tissue">tissue</a> development. It is present in the <a data-mce-href="https://en.wikipedia.org/wiki/Cornea" href="https://en.wikipedia.org/wiki/Cornea" title="Cornea">cornea</a> and lens of the <a data-mce-href="https://en.wikipedia.org/wiki/Human_eye" href="https://en.wikipedia.org/wiki/Human_eye" title="Human eye">eye</a> in <a data-mce-href="https://en.wikipedia.org/wiki/Crystal" href="https://en.wikipedia.org/wiki/Crystal" title="Crystal">crystalline</a> form. It may be one of the most abundant proteins in the fossil record, given that it appears to fossilize frequently, even in bones from the <a data-mce-href="https://en.wikipedia.org/wiki/Mesozoic" href="https://en.wikipedia.org/wiki/Mesozoic" title="Mesozoic">Mesozoic</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Paleozoic" href="https://en.wikipedia.org/wiki/Paleozoic" title="Paleozoic">Paleozoic</a>.<sup class="reference" id="cite_ref-ZL11_40-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-ZL11-40" href="https://en.wikipedia.org/wiki/Collagen#cite_note-ZL11-40">[40]</a></sup></div>
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<span class="mw-headline" id="Uses">Uses</span></h3>
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Collagen has a wide variety of applications, from food to medical. For instance, it is used in <a data-mce-href="https://en.wikipedia.org/wiki/Plastic_surgery" href="https://en.wikipedia.org/wiki/Plastic_surgery" title="Plastic surgery">cosmetic surgery</a> and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Burn_(injury)" href="https://en.wikipedia.org/wiki/Burn_(injury)" title="Burn (injury)">burn surgery</a>. It is widely used in the form of collagen <a data-mce-href="https://en.wikipedia.org/wiki/Casing_(sausage)" href="https://en.wikipedia.org/wiki/Casing_(sausage)" title="Casing (sausage)">casings</a> for sausages, which are also used in the manufacture of <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Strings_(music)#Gut" href="https://en.wikipedia.org/wiki/Strings_(music)#Gut" title="Strings (music)">musical strings</a>.</div>
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If collagen is subject to sufficient <a data-mce-href="https://en.wikipedia.org/wiki/Denaturation_(biochemistry)" href="https://en.wikipedia.org/wiki/Denaturation_(biochemistry)" title="Denaturation (biochemistry)">denaturation</a>, e.g. by heating, the three tropocollagen strands separate partially or completely into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII), e.g. <a data-mce-href="https://en.wikipedia.org/wiki/Random_coil" href="https://en.wikipedia.org/wiki/Random_coil" title="Random coil">random coils</a>. This process describes the formation of <a data-mce-href="https://en.wikipedia.org/wiki/Gelatin" href="https://en.wikipedia.org/wiki/Gelatin" title="Gelatin">gelatin</a>, which is used in many <a data-mce-href="https://en.wikipedia.org/wiki/Food" href="https://en.wikipedia.org/wiki/Food" title="Food">foods</a>, including flavored<a data-mce-href="https://en.wikipedia.org/wiki/Gelatin_dessert" href="https://en.wikipedia.org/wiki/Gelatin_dessert" title="Gelatin dessert">gelatin desserts</a>. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.<sup class="reference" id="cite_ref-41"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-41" href="https://en.wikipedia.org/wiki/Collagen#cite_note-41">[41]</a></sup> From a nutritional point of view, collagen and gelatin are a poor-quality sole source of protein since they do not contain all the <a data-mce-href="https://en.wikipedia.org/wiki/Essential_amino_acid" href="https://en.wikipedia.org/wiki/Essential_amino_acid" title="Essential amino acid">essential amino acids</a> in the proportions that the human body requires—they are not '<a data-mce-href="https://en.wikipedia.org/wiki/Complete_protein" href="https://en.wikipedia.org/wiki/Complete_protein" title="Complete protein">complete proteins</a>' (as defined by food science, not that they are partially structured). Manufacturers of collagen-based <a data-mce-href="https://en.wikipedia.org/wiki/Dietary_supplement" href="https://en.wikipedia.org/wiki/Dietary_supplement" title="Dietary supplement">dietary supplements</a> usually containing <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Hydrolyzed_collagen" href="https://en.wikipedia.org/wiki/Hydrolyzed_collagen" title="Hydrolyzed collagen">hydrolyzed collagen</a> claim that their products can improve skin and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Fingernail" href="https://en.wikipedia.org/wiki/Fingernail" title="Fingernail">fingernail</a> quality as well as joint health. However, mainstream scientific research has not shown strong evidence to support these claims.<sup class="reference" id="cite_ref-42"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-42" href="https://en.wikipedia.org/wiki/Collagen#cite_note-42">[42]</a></sup>Individuals with problems in these areas are more likely to be suffering from some other underlying condition (such as normal aging, dry skin, arthritis etc.) rather than just a protein deficiency.</div>
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From the Greek for glue, <i>kolla</i>, the word collagen means "<a data-mce-href="https://en.wikipedia.org/wiki/Animal_glue" href="https://en.wikipedia.org/wiki/Animal_glue" title="Animal glue">glue</a> producer" and refers to the early process of boiling the skin and <a data-mce-href="https://en.wikipedia.org/wiki/Tendon" href="https://en.wikipedia.org/wiki/Tendon" title="Tendon">sinews</a> of <a data-mce-href="https://en.wikipedia.org/wiki/Horse" href="https://en.wikipedia.org/wiki/Horse" title="Horse">horses</a> and other animals to obtain glue. Collagen adhesive was used by <a data-mce-href="https://en.wikipedia.org/wiki/Egypt" href="https://en.wikipedia.org/wiki/Egypt" title="Egypt">Egyptians</a> about 4,000 years ago, and <a data-mce-href="https://en.wikipedia.org/wiki/Native_Americans_in_the_United_States" href="https://en.wikipedia.org/wiki/Native_Americans_in_the_United_States" title="Native Americans in the United States">Native Americans</a> used it in <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Bow_(weapon)" href="https://en.wikipedia.org/wiki/Bow_(weapon)" title="Bow (weapon)">bows</a> about 1,500 years ago. The oldest glue in the world, <a data-mce-href="https://en.wikipedia.org/wiki/Radiocarbon_dating" href="https://en.wikipedia.org/wiki/Radiocarbon_dating" title="Radiocarbon dating">carbon-dated</a> as more than 8,000 years old, was found to be collagen—used as a protective lining on rope baskets and <a data-mce-href="https://en.wikipedia.org/wiki/Embroidery" href="https://en.wikipedia.org/wiki/Embroidery" title="Embroidery">embroidered</a> <a data-mce-href="https://en.wikipedia.org/wiki/Textile" href="https://en.wikipedia.org/wiki/Textile" title="Textile">fabrics</a>, and to hold <a data-mce-href="https://en.wikipedia.org/wiki/List_of_eating_utensils" href="https://en.wikipedia.org/wiki/List_of_eating_utensils" title="List of eating utensils">utensils</a> together; also in crisscross decorations on <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Human_skull" href="https://en.wikipedia.org/wiki/Human_skull" title="Human skull">human skulls</a>.<sup class="reference" id="cite_ref-43"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-43" href="https://en.wikipedia.org/wiki/Collagen#cite_note-43">[43]</a></sup> Collagen normally converts to gelatin, but survived due to dry conditions. Animal glues are <a data-mce-href="https://en.wikipedia.org/wiki/Thermoplastic" href="https://en.wikipedia.org/wiki/Thermoplastic" title="Thermoplastic">thermoplastic</a>, softening again upon reheating, and so they are still used in making <a data-mce-href="https://en.wikipedia.org/wiki/Musical_instrument" href="https://en.wikipedia.org/wiki/Musical_instrument" title="Musical instrument">musical instruments</a> such as fine <a data-mce-href="https://en.wikipedia.org/wiki/Violin" href="https://en.wikipedia.org/wiki/Violin" title="Violin">violins</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Guitar" href="https://en.wikipedia.org/wiki/Guitar" title="Guitar">guitars</a>, which may have to be reopened for repairs—an application incompatible with tough, <a data-mce-href="https://en.wikipedia.org/wiki/Chemical_synthesis" href="https://en.wikipedia.org/wiki/Chemical_synthesis" title="Chemical synthesis">synthetic</a><a data-mce-href="https://en.wikipedia.org/wiki/Plastic" href="https://en.wikipedia.org/wiki/Plastic" title="Plastic">plastic</a> adhesives, which are permanent. Animal sinews and skins, including <a data-mce-href="https://en.wikipedia.org/wiki/Leather" href="https://en.wikipedia.org/wiki/Leather" title="Leather">leather</a>, have been used to make useful articles for millennia.</div>
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Gelatin-<a data-mce-href="https://en.wikipedia.org/wiki/Resorcinol" href="https://en.wikipedia.org/wiki/Resorcinol" title="Resorcinol">resorcinol</a>-<a data-mce-href="https://en.wikipedia.org/wiki/Formaldehyde" href="https://en.wikipedia.org/wiki/Formaldehyde" title="Formaldehyde">formaldehyde</a> glue (and with formaldehyde replaced by less-toxic pentanedial and <a data-mce-href="https://en.wikipedia.org/wiki/Glyoxal" href="https://en.wikipedia.org/wiki/Glyoxal" title="Glyoxal">ethanedial</a>) has been used to repair experimental incisions in <a data-mce-href="https://en.wikipedia.org/wiki/Rabbit" href="https://en.wikipedia.org/wiki/Rabbit" title="Rabbit">rabbit</a> <a data-mce-href="https://en.wikipedia.org/wiki/Lung" href="https://en.wikipedia.org/wiki/Lung" title="Lung">lungs</a>.<sup class="reference" id="cite_ref-44"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-44" href="https://en.wikipedia.org/wiki/Collagen#cite_note-44">[44]</a></sup></div>
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<span class="mw-headline" id="History">History</span></h2>
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The molecular and packing structures of collagen have eluded scientists over decades of research. The first evidence that it possesses a regular structure at the molecular level was presented in the mid-1930s.<sup class="reference" id="cite_ref-45"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-45" href="https://en.wikipedia.org/wiki/Collagen#cite_note-45">[45]</a></sup><sup class="reference" id="cite_ref-46"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-46" href="https://en.wikipedia.org/wiki/Collagen#cite_note-46">[46]</a></sup> Since that time, many prominent scholars, including Nobel laureates <a data-mce-href="https://en.wikipedia.org/wiki/Francis_Crick" href="https://en.wikipedia.org/wiki/Francis_Crick" title="Francis Crick">Crick</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Linus_Pauling" href="https://en.wikipedia.org/wiki/Linus_Pauling" title="Linus Pauling">Pauling</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Alexander_Rich" href="https://en.wikipedia.org/wiki/Alexander_Rich" title="Alexander Rich">Rich</a> and <a data-mce-href="https://en.wikipedia.org/wiki/Ada_Yonath" href="https://en.wikipedia.org/wiki/Ada_Yonath" title="Ada Yonath">Yonath</a>, and others, including <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=Barbara_Brodsky&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=Barbara_Brodsky&action=edit&redlink=1" title="Barbara Brodsky (page does not exist)">Brodsky</a>,<a data-mce-href="https://en.wikipedia.org/wiki/Helen_M._Berman" href="https://en.wikipedia.org/wiki/Helen_M._Berman" title="Helen M. Berman">Berman</a>, and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Gopalasamudram_Narayana_Iyer_Ramachandran" href="https://en.wikipedia.org/wiki/Gopalasamudram_Narayana_Iyer_Ramachandran" title="Gopalasamudram Narayana Iyer Ramachandran">Ramachandran</a>, concentrated on the conformation of the collagen <a data-mce-href="https://en.wikipedia.org/wiki/Monomer" href="https://en.wikipedia.org/wiki/Monomer" title="Monomer">monomer</a>. Several competing models, although correctly dealing with the conformation of each individual peptide chain, gave way to the triple-helical "Madras" model of Ramachandran, which provided an essentially correct model of the molecule's <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Quaternary_structure" href="https://en.wikipedia.org/wiki/Quaternary_structure" title="Quaternary structure">quaternary structure</a><sup class="reference" id="cite_ref-47"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-47" href="https://en.wikipedia.org/wiki/Collagen#cite_note-47">[47]</a></sup><sup class="reference" id="cite_ref-48"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-48" href="https://en.wikipedia.org/wiki/Collagen#cite_note-48">[48]</a></sup><sup class="reference" id="cite_ref-49"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-49" href="https://en.wikipedia.org/wiki/Collagen#cite_note-49">[49]</a></sup> although this model still required some refinement.<sup class="reference" id="cite_ref-Saad_1994_50-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Saad_1994-50" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Saad_1994-50">[50]</a></sup> <sup class="noprint Inline-Template">[<i><a data-mce-href="https://en.wikipedia.org/wiki/Wikipedia:Please_clarify" href="https://en.wikipedia.org/wiki/Wikipedia:Please_clarify" title="Wikipedia:Please clarify"><span title="What refinement? (February 2015)">clarification needed</span></a></i>]</sup> <sup class="reference" id="cite_ref-51"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-51" href="https://en.wikipedia.org/wiki/Collagen#cite_note-51">[51]</a></sup><sup class="reference" id="cite_ref-52"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-52" href="https://en.wikipedia.org/wiki/Collagen#cite_note-52">[52]</a></sup><sup class="reference" id="cite_ref-53"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-53" href="https://en.wikipedia.org/wiki/Collagen#cite_note-53">[53]</a></sup><sup class="reference" id="cite_ref-54"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-54" href="https://en.wikipedia.org/wiki/Collagen#cite_note-54">[54]</a></sup> The packing structure of collagen has not been defined to the same degree outside of the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Fibrillar" href="https://en.wikipedia.org/wiki/Fibrillar" title="Fibrillar">fibrillar</a> collagen types, although it has been long known to be hexagonal or quasi-hexagonal.<sup class="reference" id="cite_ref-Hulmes_Miller_1979_25-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes_Miller_1979-25" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Hulmes_Miller_1979-25">[25]</a></sup><sup class="reference" id="cite_ref-55"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-55" href="https://en.wikipedia.org/wiki/Collagen#cite_note-55">[55]</a></sup><sup class="reference" id="cite_ref-56"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-56" href="https://en.wikipedia.org/wiki/Collagen#cite_note-56">[56]</a></sup> As with its monomeric structure, several conflicting models alleged that either the packing arrangement of collagen molecules is 'sheet-like' or <a data-mce-href="https://en.wikipedia.org/wiki/Microfibril" href="https://en.wikipedia.org/wiki/Microfibril" title="Microfibril">microfibrillar</a>.<sup class="reference" id="cite_ref-Saad_1994_50-1"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Saad_1994-50" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Saad_1994-50">[50]</a></sup><sup class="reference" id="cite_ref-57"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-57" href="https://en.wikipedia.org/wiki/Collagen#cite_note-57">[57]</a></sup><sup class="reference" id="cite_ref-58"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-58" href="https://en.wikipedia.org/wiki/Collagen#cite_note-58">[58]</a></sup> The microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron microscopy.<sup class="reference" id="cite_ref-59"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-59" href="https://en.wikipedia.org/wiki/Collagen#cite_note-59">[59]</a></sup><sup class="reference" id="cite_ref-60"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-60" href="https://en.wikipedia.org/wiki/Collagen#cite_note-60">[60]</a></sup><sup class="reference" id="cite_ref-61"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-61" href="https://en.wikipedia.org/wiki/Collagen#cite_note-61">[61]</a></sup> The microfibrillar structure of tail tendon, as described by Fraser, Miller, and Wess (amongst others), was modeled as being closest to the observed structure,<sup class="reference" id="cite_ref-Saad_1994_50-2"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Saad_1994-50" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Saad_1994-50">[50]</a></sup> although it oversimplified the topological progression of neighboring collagen molecules, and hence did not predict the correct conformation of the discontinuous D-periodic pentameric arrangement termed simply: the microfibril.<sup class="reference" id="cite_ref-Orgel_24-2"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Orgel-24" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Orgel-24">[24]</a></sup><sup class="reference" id="cite_ref-Okuyama_62-0"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-Okuyama-62" href="https://en.wikipedia.org/wiki/Collagen#cite_note-Okuyama-62">[62]</a></sup> Various <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Cross-linking_agent" href="https://en.wikipedia.org/wiki/Cross-linking_agent" title="Cross-linking agent">cross linking agents</a> like <a data-mce-href="https://en.wikipedia.org/wiki/L-Dopaquinone" href="https://en.wikipedia.org/wiki/L-Dopaquinone" title="L-Dopaquinone">L-Dopaquinone</a>, embeline, potassium embelate and 5-O-methyl embelin could be developed as potential cross-linking/stabilization agents of collagen preparation and its application as wound dressing sheet in clinical applications is enhanced.<sup class="reference" id="cite_ref-63"><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_note-63" href="https://en.wikipedia.org/wiki/Collagen#cite_note-63">[63]</a></sup></div>
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<span class="mw-headline" id="See_also">See also</span></h2>
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<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Hydrolyzed_collagen" href="https://en.wikipedia.org/wiki/Hydrolyzed_collagen" title="Hydrolyzed collagen">Hydrolyzed collagen</a>, a common form in which collagen is sold as a supplement.</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Animal_glue" href="https://en.wikipedia.org/wiki/Animal_glue" title="Animal glue">Animal glue</a></li>
<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Gelatine" href="https://en.wikipedia.org/wiki/Gelatine" title="Gelatine">Gelatine</a></li>
<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Fibrous_protein" href="https://en.wikipedia.org/wiki/Fibrous_protein" title="Fibrous protein">Fibrous protein</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Osteoid" href="https://en.wikipedia.org/wiki/Osteoid" title="Osteoid">Osteoid</a>, collagen containing component of bone</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Lysyl_oxidase" href="https://en.wikipedia.org/wiki/Lysyl_oxidase" title="Lysyl oxidase">Lysyl oxidase</a> and <a data-mce-href="https://en.wikipedia.org/wiki/LOXL1" href="https://en.wikipedia.org/wiki/LOXL1" title="LOXL1">LOXL1</a>, <a data-mce-href="https://en.wikipedia.org/wiki/LOXL2" href="https://en.wikipedia.org/wiki/LOXL2" title="LOXL2">LOXL2</a>, <a data-mce-href="https://en.wikipedia.org/wiki/LOXL3" href="https://en.wikipedia.org/wiki/LOXL3" title="LOXL3">LOXL3</a>, <a data-mce-href="https://en.wikipedia.org/wiki/LOXL4" href="https://en.wikipedia.org/wiki/LOXL4" title="LOXL4">LOXL4</a> in collagen formation</li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Collagenase" href="https://en.wikipedia.org/wiki/Collagenase" title="Collagenase">Collagenase</a>, the enzyme involved in collagen breakdown and remodelling. For more on other <a data-mce-href="https://en.wikipedia.org/wiki/Protease" href="https://en.wikipedia.org/wiki/Protease" title="Protease">proteases</a> that target collagen see <a data-mce-href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" title="The Proteolysis Map">The Proteolysis Map</a></li>
<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Ehlers-Danlos_Syndrome" href="https://en.wikipedia.org/wiki/Ehlers-Danlos_Syndrome" title="Ehlers-Danlos Syndrome">Ehlers-Danlos Syndrome</a></li>
<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Hypermobility_Syndrome" href="https://en.wikipedia.org/wiki/Hypermobility_Syndrome" title="Hypermobility Syndrome">Hypermobility Syndrome</a></li>
<li><a data-mce-href="https://en.wikipedia.org/wiki/Sponge" href="https://en.wikipedia.org/wiki/Sponge" title="Sponge">Sponge</a> - Cell types</li>
<li><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Drug_discovery_and_development_of_MMP_inhibitors" href="https://en.wikipedia.org/wiki/Drug_discovery_and_development_of_MMP_inhibitors" title="Drug discovery and development of MMP inhibitors">Drug discovery and development of MMP inhibitors</a></li>
</ul>
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<span class="mw-headline" id="References">References</span></h2>
<div class="reflist columns references-column-width" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<ol class="references">
<li id="cite_note-1"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-1"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Di Lullo, Gloria A.; Sweeney, Shawn M.; Körkkö, Jarmo; Ala-Kokko, Leena & San Antonio, James D. (2002). "Mapping the Ligand-binding Sites and Disease-associated Mutations on the Most Abundant Protein in the Human, Type I Collagen". <i><a data-mce-href="https://en.wikipedia.org/wiki/Journal_of_Biological_Chemistry" href="https://en.wikipedia.org/wiki/Journal_of_Biological_Chemistry" title="Journal of Biological Chemistry">J. Biol. Chem.</a></i><b>277</b> (6): 4223–4231. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1074%2Fjbc.M110709200" href="https://dx.doi.org/10.1074%2Fjbc.M110709200" rel="nofollow">10.1074/jbc.M110709200</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/11704682" href="https://www.ncbi.nlm.nih.gov/pubmed/11704682" rel="nofollow">11704682</a>.</cite></span></li>
<li id="cite_note-Sherman_2015_22.E2.80.9350-2"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Sherman_2015_22.E2.80.9350_2-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Sherman_2015_22.E2.80.9350_2-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Sherman_2015_22.E2.80.9350_2-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Sherman_2015_22.E2.80.9350_2-1"><sup><i><b>b</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Sherman_2015_22.E2.80.9350_2-2" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Sherman_2015_22.E2.80.9350_2-2"><sup><i><b>c</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Sherman, Vincent R. (2015). "The materials science of collagen". <i>Journal of the Mechanical Behavior of Biomedical Materials</i> <b>52</b>: 22–50.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2Fj.jmbbm.2015.05.023" href="https://dx.doi.org/10.1016%2Fj.jmbbm.2015.05.023" rel="nofollow">10.1016/j.jmbbm.2015.05.023</a>.</cite></span></li>
<li id="cite_note-3"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-3" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-3"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">Britannica Concise Encyclopedia 2007</span></li>
<li id="cite_note-4"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-4" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-4"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation book">Sikorski, Zdzisław E. (2001). <i>Chemical and Functional Properties of Food Proteins</i>. Boca Raton: CRC Press. p. 242. <a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a data-mce-href="https://en.wikipedia.org/wiki/Special:BookSources/1-56676-960-4" href="https://en.wikipedia.org/wiki/Special:BookSources/1-56676-960-4" title="Special:BookSources/1-56676-960-4">1-56676-960-4</a>.</cite></span></li>
<li id="cite_note-5"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-5" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-5"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Bogue, Robert H. (1923). "Conditions Affecting the Hydrolysis of Collagen to Gelatin".<i>Industrial and Engineering Chemistry</i> <b>15</b> (11): 1154–1159. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1021%2Fie50167a018" href="https://dx.doi.org/10.1021%2Fie50167a018" rel="nofollow">10.1021/ie50167a018</a>.</cite></span></li>
<li id="cite_note-6"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-6" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-6"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">O.E.D. 2nd Edition 2005</span></li>
<li id="cite_note-7"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-7" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-7"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Müller, Werner E. G. (2003). "The Origin of Metazoan Complexity: Porifera as Integrated Animals". <i>Integrative and Comparative Biology</i> <b>43</b> (1): 3–10. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1093%2Ficb%2F43.1.3" href="https://dx.doi.org/10.1093%2Ficb%2F43.1.3" rel="nofollow">10.1093/icb/43.1.3</a>.</cite></span></li>
<li id="cite_note-8"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-8" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-8"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">Sabiston textbook of surgery board review, 7th edition. Chapter 5 wound healing, question 14</span></li>
<li id="cite_note-9"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-9" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-9"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Schauss, A., Stenehjem, J., Park, J., Endres, J., and Clewell, A. (2012). "Effect of the novel low molecular weight hydrolyzed chicken sternal cartilage extract, BioCell Collagen, on improving osteoarthritis-related symptoms: A randomized, double-blind, placebo-controlled trial". <i>Journal of Agricultural and Food Chemistry</i> <b>60</b> (16): 4096–101.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1021%2Fjf205295u" href="https://dx.doi.org/10.1021%2Fjf205295u" rel="nofollow">10.1021/jf205295u</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/22486722" href="https://www.ncbi.nlm.nih.gov/pubmed/22486722" rel="nofollow">22486722</a>.</cite></span></li>
<li id="cite_note-pharmax2-10"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-pharmax2_10-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-pharmax2_10-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-pharmax2_10-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-pharmax2_10-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><a class="external text" data-mce-href="http://pharmaxchange.info/press/2011/03/the-ageing-skin-part-4e-dermal-fillers/" href="http://pharmaxchange.info/press/2011/03/the-ageing-skin-part-4e-dermal-fillers/" rel="nofollow">Dermal Fillers | The Ageing Skin</a>. Pharmaxchange.info. Retrieved on 2013-04-21.</span></li>
<li id="cite_note-11"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-11" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-11"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Cunniffe, G; F O'Brien (2011). "Collagen scaffolds for orthopedic regenerative medicine".<i>The Journal of the Minerals, Metals and Materials Society</i> <b>63</b> (4): 66–73.<a data-mce-href="https://en.wikipedia.org/wiki/Bibcode" href="https://en.wikipedia.org/wiki/Bibcode" title="Bibcode">Bibcode</a>:<a class="external text" data-mce-href="http://adsabs.harvard.edu/abs/2011JOM....63d..66C" href="http://adsabs.harvard.edu/abs/2011JOM....63d..66C" rel="nofollow">2011JOM....63d..66C</a>. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1007%2Fs11837-011-0061-y" href="https://dx.doi.org/10.1007%2Fs11837-011-0061-y" rel="nofollow">10.1007/s11837-011-0061-y</a>.</cite></span></li>
<li id="cite_note-Oliveira-12"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Oliveira_12-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Oliveira_12-0"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Oliveira, S; R Ringshia; R Legeros; E Clark; L Terracio; C Teixeira M Yost (2009). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891373" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891373" rel="nofollow">"An improved collagen scaffold for skeletal regeneration"</a>. <i>Journal of Biomedical Materials</i> <b>94</b>(2): 371–379. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1002%2Fjbm.a.32694" href="https://dx.doi.org/10.1002%2Fjbm.a.32694" rel="nofollow">10.1002/jbm.a.32694</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891373" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891373" rel="nofollow">2891373</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/20186736" href="https://www.ncbi.nlm.nih.gov/pubmed/20186736" rel="nofollow">20186736</a>.</cite></span></li>
<li id="cite_note-13"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-13" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-13"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Blow, Nathan (2009). "Cell culture: building a better matrix". <i>Nature Methods</i> <b>6</b> (8): 619–622. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1038%2Fnmeth0809-619" href="https://dx.doi.org/10.1038%2Fnmeth0809-619" rel="nofollow">10.1038/nmeth0809-619</a>.</cite></span></li>
<li id="cite_note-scr-14"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-scr_14-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-scr_14-0"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Birbrair, Alexander; Zhang, Tan; Files, Daniel C.; Mannava, Sandeep; Smith, Thomas; Wang, Zhong-Min; Messi, Maria L.; Mintz, Akiva; Delbono, Osvaldo (2014-11-06). <a class="external text" data-mce-href="http://www.stemcellres.com/content/5/6/122" href="http://www.stemcellres.com/content/5/6/122" rel="nofollow">"Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner"</a>. <i>Stem Cell Research & Therapy</i> <b>5</b> (6): 122. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1186%2Fscrt512" href="https://dx.doi.org/10.1186%2Fscrt512" rel="nofollow">10.1186/scrt512</a>. <a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Serial_Number" href="https://en.wikipedia.org/wiki/International_Standard_Serial_Number" title="International Standard Serial Number">ISSN</a> <a class="external text" data-mce-href="https://www.worldcat.org/issn/1757-6512" href="https://www.worldcat.org/issn/1757-6512" rel="nofollow">1757-6512</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445991" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445991" rel="nofollow">4445991</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/25376879" href="https://www.ncbi.nlm.nih.gov/pubmed/25376879" rel="nofollow">25376879</a>.</cite></span></li>
<li id="cite_note-15"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-15" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-15"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Singh, O; SS Gupta; M Soni; S Moses; S Shukla; RK Mathur (2011). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081477" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081477" rel="nofollow">"Collagen dressing versus conventional dressings in burn and chronic wounds: a retrospective study"</a>.<i>Journal of Cutaneous and Aesthetic Surgery</i> <b>4</b> (1): 12–16. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.4103%2F0974-2077.79180" href="https://dx.doi.org/10.4103%2F0974-2077.79180" rel="nofollow">10.4103/0974-2077.79180</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081477" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081477" rel="nofollow">3081477</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/21572675" href="https://www.ncbi.nlm.nih.gov/pubmed/21572675" rel="nofollow">21572675</a>.</cite></span></li>
<li id="cite_note-SzpakJAS-16"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-1"><sup><i><b>b</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-2" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-2"><sup><i><b>c</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-3" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-3"><sup><i><b>d</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-4" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-4"><sup><i><b>e</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-5" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-SzpakJAS_16-5"><sup><i><b>f</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Szpak, Paul (2011). <a class="external text" data-mce-href="https://www.academia.edu/801925/Fish_Bone_Chemistry_and_Ultrastructure_Implications_for_Taphonomy_and_Stable_Isotope_Analysis" href="https://www.academia.edu/801925/Fish_Bone_Chemistry_and_Ultrastructure_Implications_for_Taphonomy_and_Stable_Isotope_Analysis" rel="nofollow">"Fish bone chemistry and ultrastructure: implications for taphonomy and stable isotope analysis"</a>. <i>Journal of Archaeological Science</i> <b>38</b> (12): 3358–3372. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2Fj.jas.2011.07.022" href="https://dx.doi.org/10.1016%2Fj.jas.2011.07.022" rel="nofollow">10.1016/j.jas.2011.07.022</a>.</cite></span></li>
<li id="cite_note-17"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-17" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-17"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation web">Diegelmann, Robert. <a class="external text" data-mce-href="http://www.medscape.com/viewarticle/423231_2" href="http://www.medscape.com/viewarticle/423231_2" rel="nofollow">"Collagen Metabolism"</a>. <i>Medscape.com</i>. Medscape<span class="reference-accessdate">. Retrieved<span class="nowrap">4 December</span> 2014</span>.</cite></span></li>
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<li id="cite_note-19"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-19" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-19"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Myllylä, R.; Majamaa, K.; Günzler, V.; Hanauske-Abel, H. M.; Kivirikko, K. I. (1984). "Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by propyl 4-hydroxylase and lysyl hydroxylase". <i>J. Biol. Chem.</i> <b>259</b> (9): 5403–5. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/6325436" href="https://www.ncbi.nlm.nih.gov/pubmed/6325436" rel="nofollow">6325436</a>.</cite></span></li>
<li id="cite_note-20"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-20" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-20"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Houck, J. C.; Sharma, V. K.; Patel, Y. M.; Gladner, J. A. (1968). "Induction of Collagenolytic and Proteolytic Activities by AntiInflammatory Drugs in the Skin and Fibroblasts". <i><a data-mce-href="https://en.wikipedia.org/wiki/Biochemical_Pharmacology_(journal)" href="https://en.wikipedia.org/wiki/Biochemical_Pharmacology_(journal)" title="Biochemical Pharmacology (journal)">Biochemical Pharmacology</a></i> <b>17</b> (10): 2081–2090. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2F0006-2952%2868%2990182-2" href="https://dx.doi.org/10.1016%2F0006-2952%2868%2990182-2" rel="nofollow">10.1016/0006-2952(68)90182-2</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/4301453" href="https://www.ncbi.nlm.nih.gov/pubmed/4301453" rel="nofollow">4301453</a>.</cite></span></li>
<li id="cite_note-21"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-21" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-21"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Al-Hadithy, H.; Isenberg, DA; et al. (1982). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1000860" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1000860" rel="nofollow">"Neutrophil function in systemic lupus erythematosus and other collagen diseases"</a>. <i>Ann Rheum Dis</i> <b>41</b> (1): 33–38.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1136%2Fard.41.1.33" href="https://dx.doi.org/10.1136%2Fard.41.1.33" rel="nofollow">10.1136/ard.41.1.33</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1000860" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1000860" rel="nofollow">1000860</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/7065727" href="https://www.ncbi.nlm.nih.gov/pubmed/7065727" rel="nofollow">7065727</a>.</cite></span></li>
<li id="cite_note-22"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-22" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-22"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Hulmes, D. J. (2002). "Building collagen molecules, fibrils, and suprafibrillar structures". <i>J Struct Biol</i> <b>137</b> (1–2): 2–10. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1006%2Fjsbi.2002.4450" href="https://dx.doi.org/10.1006%2Fjsbi.2002.4450" rel="nofollow">10.1006/jsbi.2002.4450</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/12064927" href="https://www.ncbi.nlm.nih.gov/pubmed/12064927" rel="nofollow">12064927</a>.</cite></span></li>
<li id="cite_note-Hulmes.2C_D.J._1992._p._49-23"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes.2C_D.J._1992._p._49_23-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes.2C_D.J._1992._p._49_23-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes.2C_D.J._1992._p._49_23-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes.2C_D.J._1992._p._49_23-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Hulmes, D. J. (1992). "The collagen superfamily—diverse structures and assemblies".<i>Essays Biochem</i> <b>27</b>: 49–67. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/1425603" href="https://www.ncbi.nlm.nih.gov/pubmed/1425603" rel="nofollow">1425603</a>.</cite></span></li>
<li id="cite_note-Orgel-24"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Orgel_24-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Orgel_24-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Orgel_24-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Orgel_24-1"><sup><i><b>b</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Orgel_24-2" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Orgel_24-2"><sup><i><b>c</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Orgel, J. P.; Irving, TC; et al. (2006). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1473175" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1473175" rel="nofollow">"Microfibrillar structure of type I collagen in situ"</a>. <i>PNAS</i> <b>103</b> (24): 9001–9005. <a data-mce-href="https://en.wikipedia.org/wiki/Bibcode" href="https://en.wikipedia.org/wiki/Bibcode" title="Bibcode">Bibcode</a>:<a class="external text" data-mce-href="http://adsabs.harvard.edu/abs/2006PNAS..103.9001O" href="http://adsabs.harvard.edu/abs/2006PNAS..103.9001O" rel="nofollow">2006PNAS..103.9001O</a>.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1073%2Fpnas.0502718103" href="https://dx.doi.org/10.1073%2Fpnas.0502718103" rel="nofollow">10.1073/pnas.0502718103</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1473175" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1473175" rel="nofollow">1473175</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/16751282" href="https://www.ncbi.nlm.nih.gov/pubmed/16751282" rel="nofollow">16751282</a>.</cite></span></li>
<li id="cite_note-Hulmes_Miller_1979-25"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes_Miller_1979_25-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes_Miller_1979_25-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes_Miller_1979_25-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Hulmes_Miller_1979_25-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Hulmes, D. J. & Miller, A. (1979). "Quasi-hexagonal molecular packing in collagen fibrils". <i>Nature</i> <b>282</b> (5741): 878–880. <a data-mce-href="https://en.wikipedia.org/wiki/Bibcode" href="https://en.wikipedia.org/wiki/Bibcode" title="Bibcode">Bibcode</a>:<a class="external text" data-mce-href="http://adsabs.harvard.edu/abs/1979Natur.282..878H" href="http://adsabs.harvard.edu/abs/1979Natur.282..878H" rel="nofollow">1979Natur.282..878H</a>.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1038%2F282878a0" href="https://dx.doi.org/10.1038%2F282878a0" rel="nofollow">10.1038/282878a0</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/514368" href="https://www.ncbi.nlm.nih.gov/pubmed/514368" rel="nofollow">514368</a>.</cite></span></li>
<li id="cite_note-26"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-26" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-26"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Perumal, S.; Antipova, O. & Orgel, J. P. (2008). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268544" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268544" rel="nofollow">"Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis"</a>. <i>PNAS</i> <b>105</b> (8): 2824–2829. <a data-mce-href="https://en.wikipedia.org/wiki/Bibcode" href="https://en.wikipedia.org/wiki/Bibcode" title="Bibcode">Bibcode</a>:<a class="external text" data-mce-href="http://adsabs.harvard.edu/abs/2008PNAS..105.2824P" href="http://adsabs.harvard.edu/abs/2008PNAS..105.2824P" rel="nofollow">2008PNAS..105.2824P</a>. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1073%2Fpnas.0710588105" href="https://dx.doi.org/10.1073%2Fpnas.0710588105" rel="nofollow">10.1073/pnas.0710588105</a>.<a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268544" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268544" rel="nofollow">2268544</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/18287018" href="https://www.ncbi.nlm.nih.gov/pubmed/18287018" rel="nofollow">18287018</a>.</cite></span></li>
<li id="cite_note-27"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-27" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-27"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Sweeney, S. M.; Orgel, JP; et al. (2008). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475701" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475701" rel="nofollow">"Candidate Cell and Matrix Interaction Domains on the Collagen Fibril, the Predominant Protein of Vertebrates"</a>. <i>J Biol Chem</i> <b>283</b> (30): 21187–21197. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1074%2Fjbc.M709319200" href="https://dx.doi.org/10.1074%2Fjbc.M709319200" rel="nofollow">10.1074/jbc.M709319200</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475701" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2475701" rel="nofollow">2475701</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/18487200" href="https://www.ncbi.nlm.nih.gov/pubmed/18487200" rel="nofollow">18487200</a>.</cite></span></li>
<li id="cite_note-28"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-28" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-28"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Twardowski, T.; Fertala, A.; et al. (2007). <a class="external text" data-mce-href="http://www.ingentaconnect.com/content/ben/cpd/2007/00000013/00000035/art00009" href="http://www.ingentaconnect.com/content/ben/cpd/2007/00000013/00000035/art00009" rel="nofollow">"Type I collagen and collagen mimetics as angiogenesis promoting superpolymers"</a>. <i><a data-mce-href="https://en.wikipedia.org/wiki/Current_Pharmaceutical_Design" href="https://en.wikipedia.org/wiki/Current_Pharmaceutical_Design" title="Current Pharmaceutical Design">Curr Pharm Des</a></i> <b>13</b> (35): 3608–3621.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.2174%2F138161207782794176" href="https://dx.doi.org/10.2174%2F138161207782794176" rel="nofollow">10.2174/138161207782794176</a>.</cite></span></li>
<li id="cite_note-29"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-29" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-29"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Minary-Jolandan, M; Yu, MF (2009). "Nanomechanical heterogeneity in the gap and overlap regions of type I collagen fibrils with implications for bone heterogeneity".<i>Biomacromolecules</i> <b>10</b> (9): 2565–70. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1021%2Fbm900519v" href="https://dx.doi.org/10.1021%2Fbm900519v" rel="nofollow">10.1021/bm900519v</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/19694448" href="https://www.ncbi.nlm.nih.gov/pubmed/19694448" rel="nofollow">19694448</a>.</cite></span></li>
<li id="cite_note-30"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-30" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-30"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">Ross, M. H. and Pawlina, W. (2011) <i>Histology</i>, 6th ed., Lippincott Williams & Wilkins, p. 218.</span></li>
<li id="cite_note-31"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-31" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-31"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Söderhäll, C.; Marenholz, I.; Kerscher, T.; Rüschendorf, F; Rüschendorf, F.; Esparza-Gordillo, J.; Mayr, G; et al. (2007). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1971127" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1971127" rel="nofollow">"Variants in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis"</a>. <i><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PLoS_Biology" href="https://en.wikipedia.org/wiki/PLoS_Biology" title="PLoS Biology">PLoS Biology</a></i> <b>5</b> (9): e242.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1371%2Fjournal.pbio.0050242" href="https://dx.doi.org/10.1371%2Fjournal.pbio.0050242" rel="nofollow">10.1371/journal.pbio.0050242</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1971127" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1971127" rel="nofollow">1971127</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/17850181" href="https://www.ncbi.nlm.nih.gov/pubmed/17850181" rel="nofollow">17850181</a>.</cite></span></li>
<li id="cite_note-Mahajan.2C_VB_2010-32"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Mahajan.2C_VB_2010_32-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Mahajan.2C_VB_2010_32-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Mahajan.2C_VB_2010_32-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Mahajan.2C_VB_2010_32-1"><sup><i><b>b</b></i></sup></a></span> <span class="reference-text"><cite class="citation journal">Mahajan, VB, Olney, AH, Garrett, P, Chary, A, Dragan, E, Lerner, G, Murray, J & Bassuk, AG; Olney; Garrett; Chary; Dragan; Lerner; Murray; Bassuk (2010). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965270" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965270" rel="nofollow">"Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia"</a>. <i>American journal of medical genetics. Part A</i> <b>152A</b> (11): 2875–9. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1002%2Fajmg.a.33621" href="https://dx.doi.org/10.1002%2Fajmg.a.33621" rel="nofollow">10.1002/ajmg.a.33621</a>.<a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965270" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965270" rel="nofollow">2965270</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/20799329" href="https://www.ncbi.nlm.nih.gov/pubmed/20799329" rel="nofollow">20799329</a>.</cite></span></li>
<li id="cite_note-33"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-33" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-33"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Gajko-Galicka, A (2002). <a class="external text" data-mce-href="http://www.actabp.pl/pdf/2_2002/433-441.pdf" href="http://www.actabp.pl/pdf/2_2002/433-441.pdf" rel="nofollow">"Mutations in type I collagen genes resulting in osteogenesis imperfecta in humans"</a> (PDF). <i>Acta biochimica Polonica</i> <b>49</b> (2): 433–41.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/12362985" href="https://www.ncbi.nlm.nih.gov/pubmed/12362985" rel="nofollow">12362985</a>.</cite></span></li>
<li id="cite_note-34"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-34" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-34"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Horton, WA, Campbell, D, Machado, MA & Chou, J; Campbell; Machado; Chou (1989). "Type II collagen screening in the human chondrodysplasias". <i>American Journal of Medical Genetics</i> <b>34</b> (4): 579–83. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1002%2Fajmg.1320340425" href="https://dx.doi.org/10.1002%2Fajmg.1320340425" rel="nofollow">10.1002/ajmg.1320340425</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/2624272" href="https://www.ncbi.nlm.nih.gov/pubmed/2624272" rel="nofollow">2624272</a>.</cite></span></li>
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<li id="cite_note-36"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-36" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-36"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text">Kashtan, CE (1993) "Collagen IV-Related Nephropathies (<a class="external text" data-mce-href="http://www.ncbi.nlm.nih.gov/books/NBK1207/" href="http://www.ncbi.nlm.nih.gov/books/NBK1207/" rel="nofollow">Alport Syndrome and Thin Basement Membrane Nephropathy</a>)", in RA Pagon, TD Bird, CR Dolan, K Stephens & MP Adam (eds), GeneReviews, University of Washington, Seattle, Seattle WA <a class="external mw-magiclink-pmid" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/20301386?dopt=Abstract" href="https://www.ncbi.nlm.nih.gov/pubmed/20301386?dopt=Abstract" rel="nofollow">PMID 20301386</a>.</span></li>
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<li id="cite_note-38"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-38" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-38"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation book">Fratzl, P. (2008). <i>Collagen: Structure and Mechanics</i>. New York: Springer. <a data-mce-href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" href="https://en.wikipedia.org/wiki/International_Standard_Book_Number" title="International Standard Book Number">ISBN</a> <a data-mce-href="https://en.wikipedia.org/wiki/Special:BookSources/0-387-73905-X" href="https://en.wikipedia.org/wiki/Special:BookSources/0-387-73905-X" title="Special:BookSources/0-387-73905-X">0-387-73905-X</a>.</cite></span></li>
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<li id="cite_note-ZL11-40"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-ZL11_40-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-ZL11_40-0"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Zylberberg, L.; Laurin, M. (2011). "Analysis of fossil bone organic matrix by transmission electron microscopy". <i>Comptes rendus Palevol</i> <b>11</b> (5–6): 357–366.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2Fj.crpv.2011.04.004" href="https://dx.doi.org/10.1016%2Fj.crpv.2011.04.004" rel="nofollow">10.1016/j.crpv.2011.04.004</a>.</cite></span></li>
<li id="cite_note-41"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-41" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-41"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="https://web.archive.org/web/20060505134337/http://www.gmap-gelatin.com/gelatin_adv.html" href="https://web.archive.org/web/20060505134337/http://www.gmap-gelatin.com/gelatin_adv.html" rel="nofollow">"Gelatin's Advantages: Health, Nutrition and Safety"</a>. <i>gmap-gelatin.com</i>. Archived from<a class="external text" data-mce-href="http://www.gmap-gelatin.com/gelatin_adv.html" href="http://www.gmap-gelatin.com/gelatin_adv.html" rel="nofollow">the original</a> on May 5, 2006.</cite></span></li>
<li id="cite_note-42"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-42" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-42"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><a data-mce-href="https://en.wikipedia.org/wiki/European_Food_Safety_Authority" href="https://en.wikipedia.org/wiki/European_Food_Safety_Authority" title="European Food Safety Authority">European Food Safety Authority</a> - EFSA Panel on Dietetic Products, Nutrition and Allergies. <a class="external text" data-mce-href="http://www.efsa.europa.eu/en/efsajournal/doc/2291.pdf" href="http://www.efsa.europa.eu/en/efsajournal/doc/2291.pdf" rel="nofollow">Scientific Opinion on the substantiation of a health claim related to collagen hydrolysate and maintenance of joints pursuant to Article 13(5) of Regulation (EC) No 1924/20061</a>. <i>EFSA Journal</i> 2011;9(7):2291.</span></li>
<li id="cite_note-43"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-43" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-43"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation web">Walker, Amélie A. (May 21, 1998). <a class="external text" data-mce-href="http://www.archaeology.org/online/news/glue.html" href="http://www.archaeology.org/online/news/glue.html" rel="nofollow">"Oldest Glue Discovered"</a>. <i>Archaeology</i>.</cite></span></li>
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<li id="cite_note-46"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-46" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-46"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Clark, G.; Parker, E.; Schaad, J. & Warren, W. J. (1935). "New measurements of previously unknown large interplanar spacings in natural materials". <i><a data-mce-href="https://en.wikipedia.org/wiki/Journal_of_the_American_Chemical_Society" href="https://en.wikipedia.org/wiki/Journal_of_the_American_Chemical_Society" title="Journal of the American Chemical Society">J. Amer. Chem. Soc</a></i> <b>57</b>(8): 1509. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1021%2Fja01311a504" href="https://dx.doi.org/10.1021%2Fja01311a504" rel="nofollow">10.1021/ja01311a504</a>.</cite></span></li>
<li id="cite_note-47"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-47" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-47"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Balasubramanian, D . (October 2001). <a class="external text" data-mce-href="http://www.ias.ac.in/resonance/php/toc.php?vol=06&issue=10" href="http://www.ias.ac.in/resonance/php/toc.php?vol=06&issue=10" rel="nofollow">"GNR — A Tribute"</a>. <i>Resonance</i> (Indian Academy of Sciences) <b>6</b> (10).</cite></span></li>
<li id="cite_note-48"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-48" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-48"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Leonidas, Demetres D.; Chavali, GB; et al. (2001). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374093" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374093" rel="nofollow">"Binding of Phosphate and pyrophosphate ions at the active site of human angiogenin as revealed by X-ray crystallography"</a>. <i>Protein Science</i> <b>10</b> (8): 1669–1676. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1110%2Fps.13601" href="https://dx.doi.org/10.1110%2Fps.13601" rel="nofollow">10.1110/ps.13601</a>.<a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374093" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374093" rel="nofollow">2374093</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/11468363" href="https://www.ncbi.nlm.nih.gov/pubmed/11468363" rel="nofollow">11468363</a>.</cite></span></li>
<li id="cite_note-49"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-49" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-49"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Subramanian, Easwara (2001). "Obituary: G.N. Ramachandran". <i><a data-mce-href="https://en.wikipedia.org/wiki/Nature_Structural_%26_Molecular_Biology" href="https://en.wikipedia.org/wiki/Nature_Structural_%26_Molecular_Biology" title="Nature Structural & Molecular Biology">Nature Structural & Molecular Biology</a></i> <b>8</b> (6): 489–491. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1038%2F88544" href="https://dx.doi.org/10.1038%2F88544" rel="nofollow">10.1038/88544</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/11373614" href="https://www.ncbi.nlm.nih.gov/pubmed/11373614" rel="nofollow">11373614</a>.</cite></span></li>
<li id="cite_note-Saad_1994-50"><span class="mw-cite-backlink">^ <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Saad_1994_50-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Saad_1994_50-0"><span class="cite-accessibility-label">Jump up to:</span><sup><i><b>a</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Saad_1994_50-1" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Saad_1994_50-1"><sup><i><b>b</b></i></sup></a> <a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Saad_1994_50-2" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Saad_1994_50-2"><sup><i><b>c</b></i></sup></a></span> <span class="reference-text"><cite class="citation book">Saad, Mohamed (Oct 1994). <a class="external text" data-mce-href="https://drive.google.com/open?id=0B3L_EN9hIuFTTkhuN2lrWEU4RDQ&authuser=0" href="https://drive.google.com/open?id=0B3L_EN9hIuFTTkhuN2lrWEU4RDQ&authuser=0" rel="nofollow"><i>Low resolution structure and packing investigations of collagen crystalline domains in tendon using Synchrotron Radiation X-rays, Structure factors determination, evaluation of Isomorphous Replacement methods and other modeling.</i></a> PhD Thesis, Université Joseph Fourier Grenoble I. pp. 1–221.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.13140%2F2.1.4776.7844" href="https://dx.doi.org/10.13140%2F2.1.4776.7844" rel="nofollow">10.13140/2.1.4776.7844</a>.</cite></span></li>
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<li id="cite_note-56"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-56" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-56"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Fraser, R. D. B. & MacRae, T. P. (1981). "Unit cell and molecular connectivity in tendon collagen". <i><a data-mce-href="https://en.wikipedia.org/wiki/International_Journal_of_Biological_Macromolecules" href="https://en.wikipedia.org/wiki/International_Journal_of_Biological_Macromolecules" title="International Journal of Biological Macromolecules">Int. J. Biol. Macromol.</a></i> <b>3</b> (3): 193–200. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2F0141-8130%2881%2990063-5" href="https://dx.doi.org/10.1016%2F0141-8130%2881%2990063-5" rel="nofollow">10.1016/0141-8130(81)90063-5</a>.</cite></span></li>
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<li id="cite_note-58"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-58" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-58"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Wess, T. J.; Hammersley, AP; et al. (1998). "Molecular packing of type I collagen in tendon". <i>J Mol Biol</i> <b>275</b> (2): 255–267. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1006%2Fjmbi.1997.1449" href="https://dx.doi.org/10.1006%2Fjmbi.1997.1449" rel="nofollow">10.1006/jmbi.1997.1449</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/9466908" href="https://www.ncbi.nlm.nih.gov/pubmed/9466908" rel="nofollow">9466908</a>.</cite></span></li>
<li id="cite_note-59"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-59" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-59"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Raspanti, M.; Ottani, V.; Ruggeri, A. (1990). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257211" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257211" rel="nofollow">"Subfibrillar architecture and functional properties of collagen: a comparative study in rat tendons"</a>. <i><a data-mce-href="https://en.wikipedia.org/wiki/Journal_of_Anatomy" href="https://en.wikipedia.org/wiki/Journal_of_Anatomy" title="Journal of Anatomy">J Anat.</a></i> <b>172</b>: 157–164.<a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257211" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1257211" rel="nofollow">1257211</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/2272900" href="https://www.ncbi.nlm.nih.gov/pubmed/2272900" rel="nofollow">2272900</a>.</cite></span></li>
<li id="cite_note-60"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-60" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-60"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Holmes, D. F.; Gilpin, C. J.; Baldock, C.; Ziese, U.; Koster, A. J.; Kadler, K. E. (2001).<a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC34664" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC34664" rel="nofollow">"Corneal collagen fibril structure in three dimensions: Structural insights into fibril assembly, mechanical properties, and tissue organization"</a>. <i><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Proceedings_of_the_National_Academy_of_Sciences" href="https://en.wikipedia.org/wiki/Proceedings_of_the_National_Academy_of_Sciences" title="Proceedings of the National Academy of Sciences">PNAS</a></i> <b>98</b> (13): 7307–7312.<a data-mce-href="https://en.wikipedia.org/wiki/Bibcode" href="https://en.wikipedia.org/wiki/Bibcode" title="Bibcode">Bibcode</a>:<a class="external text" data-mce-href="http://adsabs.harvard.edu/abs/2001PNAS...98.7307H" href="http://adsabs.harvard.edu/abs/2001PNAS...98.7307H" rel="nofollow">2001PNAS...98.7307H</a>. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1073%2Fpnas.111150598" href="https://dx.doi.org/10.1073%2Fpnas.111150598" rel="nofollow">10.1073/pnas.111150598</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC34664" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC34664" rel="nofollow">34664</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/11390960" href="https://www.ncbi.nlm.nih.gov/pubmed/11390960" rel="nofollow">11390960</a>.</cite></span></li>
<li id="cite_note-61"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-61" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-61"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Holmes, D. F.; Kadler, KE (2006). <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859918" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859918" rel="nofollow">"The 10+4 microfibril structure of thin cartilage fibrils"</a>. <i>PNAS</i> <b>103</b> (46): 17249–17254. <a data-mce-href="https://en.wikipedia.org/wiki/Bibcode" href="https://en.wikipedia.org/wiki/Bibcode" title="Bibcode">Bibcode</a>:<a class="external text" data-mce-href="http://adsabs.harvard.edu/abs/2006PNAS..10317249H" href="http://adsabs.harvard.edu/abs/2006PNAS..10317249H" rel="nofollow">2006PNAS..10317249H</a>.<a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1073%2Fpnas.0608417103" href="https://dx.doi.org/10.1073%2Fpnas.0608417103" rel="nofollow">10.1073/pnas.0608417103</a>. <a data-mce-href="https://en.wikipedia.org/wiki/PubMed_Central" href="https://en.wikipedia.org/wiki/PubMed_Central" title="PubMed Central">PMC</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859918" href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1859918" rel="nofollow">1859918</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/17088555" href="https://www.ncbi.nlm.nih.gov/pubmed/17088555" rel="nofollow">17088555</a>.</cite></span></li>
<li id="cite_note-Okuyama-62"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Okuyama_62-0" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-Okuyama_62-0"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Okuyama, K; Bächinger, HP; Mizuno, K; Boudko, SP; Engel, J; Berisio, R; Vitagliano, L (2009). "Comment on Microfibrillar structure of type I collagen in situ by Orgel et al. (2006), Proc. Natl Acad. Sci. USA, 103, 9001–9005". <i>Acta Crystallogr D Biol Crystallogr</i> <b>65</b> (Pt9): 1009–10. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1107%2FS0907444909023051" href="https://dx.doi.org/10.1107%2FS0907444909023051" rel="nofollow">10.1107/S0907444909023051</a>. <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/19690380" href="https://www.ncbi.nlm.nih.gov/pubmed/19690380" rel="nofollow">19690380</a>.</cite></span></li>
<li id="cite_note-63"><span class="mw-cite-backlink"><b><a data-mce-href="https://en.wikipedia.org/wiki/Collagen#cite_ref-63" href="https://en.wikipedia.org/wiki/Collagen#cite_ref-63"><span class="cite-accessibility-label">Jump up</span>^</a></b></span> <span class="reference-text"><cite class="citation journal">Narayanaswamy, Radhakrishnan; Shanmugasamy, Sangeetha; Shanmugasamy, Sangeetha; Gopal, Ramesh; Mandal, Asit (2011). "Bioinformatics in crosslinking chemistry of collagen with selective crosslinkers". <i>BMC Research Notes</i> <b>4</b>: 399. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1186%2F1756-0500-4-399" href="https://dx.doi.org/10.1186%2F1756-0500-4-399" rel="nofollow">10.1186/1756-0500-4-399</a>.</cite></span></li>
</ol>
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<span class="mw-headline" id="External_links">External links</span></h2>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<a class="external text" data-mce-href="http://themedicalbiochemistrypage.org/extracellularmatrix.html" href="http://themedicalbiochemistrypage.org/extracellularmatrix.html" rel="nofollow">12 types of collagen</a></h2>
<ul style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li><a class="external text" data-mce-href="http://www.le.ac.uk/genetics/collagen/" href="http://www.le.ac.uk/genetics/collagen/" rel="nofollow">Database of type I and type III collagen mutations</a></li>
<li><a class="external text" data-mce-href="http://science.dirbix.com/biology/collagen" href="http://science.dirbix.com/biology/collagen" rel="nofollow">Science.dirbix Collagen</a></li>
<li><a class="external text" data-mce-href="http://compbio.cs.princeton.edu/csc/" href="http://compbio.cs.princeton.edu/csc/" rel="nofollow">Collagen Stability Calculator</a></li>
<li><a class="external text" data-mce-href="http://www.mc.vanderbilt.edu/cmb/collagen/" href="http://www.mc.vanderbilt.edu/cmb/collagen/" rel="nofollow">Computer-generated animations of the assembly of Type I and Type IV Collagens</a></li>
<li><a class="external text" data-mce-href="https://www.youtube.com/watch?v=_a8q2OWrdvM" href="https://www.youtube.com/watch?v=_a8q2OWrdvM" rel="nofollow">Integrin-Collagen interface, PMAP</a> (<a data-mce-href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" title="The Proteolysis Map">The Proteolysis Map</a>)—animation</li>
<li><a class="external text" data-mce-href="https://www.youtube.com/watch?v=8BMFqRmbbes" href="https://www.youtube.com/watch?v=8BMFqRmbbes" rel="nofollow">Integrin-Collagen binding model, PMAP</a> (<a data-mce-href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" title="The Proteolysis Map">The Proteolysis Map</a>)—animation</li>
<li><a class="external text" data-mce-href="https://www.youtube.com/watch?v=8L3a7oqQPRY" href="https://www.youtube.com/watch?v=8L3a7oqQPRY" rel="nofollow">Collagen-Integrin atomic detail, PMAP</a> (<a data-mce-href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" href="https://en.wikipedia.org/wiki/The_Proteolysis_Map" title="The Proteolysis Map">The Proteolysis Map</a>)—animation</li>
<li><a class="external text" data-mce-href="https://drive.google.com/open?id=0B3L_EN9hIuFTTkhuN2lrWEU4RDQ&authuser=0" href="https://drive.google.com/open?id=0B3L_EN9hIuFTTkhuN2lrWEU4RDQ&authuser=0" rel="nofollow">Saad M. (1994) "Low resolution structure and packing investigations of collagen crystalline domains in tendon using Synchrotron Radiation X-rays, Structure factors determination, evaluation of Isomorphous Replacement methods and other modeling." PhD Thesis, Université Joseph Fourier Grenoble 1</a></li>
</ul>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com2tag:blogger.com,1999:blog-569892385714118127.post-50380766596367268752016-05-03T09:08:00.000+05:302016-05-03T09:07:59.990+05:30Elpamotide<div dir="ltr" style="text-align: left;" trbidi="on">
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1.png" href="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1.png" rel="attachment wp-att-6047"><img alt="STR1" class="alignnone size-full wp-image-6047" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1.png" height="286" src="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1.png" style="height: auto; max-width: 100%;" width="564" /></a></div>
<div class="good-title">
<img alt="" class="" data-mce-src="http://chem.sis.nlm.nih.gov/chemidplus/structure/673478-49-4" height="275" src="http://chem.sis.nlm.nih.gov/chemidplus/structure/673478-49-4" style="height: auto; max-width: 100%;" width="275" /></div>
<div class="good-title">
<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-5.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-5.jpg" rel="attachment wp-att-6048"><img alt="STR1" class="alignnone size-full wp-image-6048" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-5.jpg" height="491" src="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-5.jpg" style="height: auto; max-width: 100%;" width="781" /></a><span style="background-color: white;">Elpamotide str drawn bt worlddrugtracker</span></div>
<h1 class="good-title">
<span data-mce-style="color: #ff0000;" style="color: red;"><br /></span></h1>
<h1 class="good-title">
<span data-mce-style="color: #ff0000;" style="color: red;">Elpamotide</span></h1>
<h4 id="infoHeader">
<i id="yui_3_18_1_3_1462245037252_445">L-Arginyl-L-phenylalanyl-L-valyl-L-prolyl-L-alpha-aspartylglycyl-L-asparaginyl-L-arginyl-L-isoleucine human soluble (Vascular Endothelial Growth Factor Receptor) VEGFR2-(169-177)-peptide</i></h4>
<div class="molecularFormula">
MF C<sub>47</sub> H<sub>76</sub> N<sub>16</sub> O<sub>13</sub></div>
<div class="molecularFormula">
Molecular Weight, 1073.2164</div>
<div class="indexName">
L-Isoleucine, L-arginyl-L-phenylalanyl-L-valyl-L-prolyl-L-α-aspartylglycyl-L-asparaginyl-L-arginyl-</div>
<ul>
<li>10: PN: WO2008099908 SEQID: 10 claimed protein</li>
<li class="alt">14: PN: WO2009028150 SEQID: 1 claimed protein</li>
<li>18: PN: JP2013176368 SEQID: 18 claimed protein</li>
<li class="alt">1: PN: WO2009028150 SEQID: 1 claimed protein</li>
<li>2: PN: WO2010027107 TABLE: 1 claimed sequence</li>
</ul>
<ul class="" id="otherNames_673478-49-4">
<li class="alt">6: PN: WO2013133405 SEQID: 6 claimed protein</li>
<li>8: PN: US8574586 SEQID: 8 unclaimed protein</li>
<li class="alt">8: PN: WO2004024766 SEQID: 8 claimed sequence</li>
<li>8: PN: WO2010143435 SEQID: 8 claimed protein</li>
</ul>
<div class="clearfix">
<i class="pull-left icon-bq icon-blackRed icon-Red">Phase III</i></div>
A neoangiogenesis antagonist potentially for the treatment of pancreatic cancer and biliary cancer.<br />
<div class="pic-logo">
<img alt="" data-mce-src="http://47.89.55.71:82/drug/images/1688-logo-01.png" height="27" src="http://47.89.55.71:82/drug/images/1688-logo-01.png" style="height: auto; max-width: 100%;" width="189" /></div>
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<div class="addr yfdm">
<span class="f-red f_n">OTS-102</span></div>
<div class="addr">
<span class="f-red">CAS No.</span><span class="f-red f-cas">673478-49-4, </span><span id="yui_3_18_1_3_1462245037252_403">UNII: S68632MB2G</span></div>
<table border="1" cellpadding="10" cellspacing="0" class="generalInfo gvTables" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain" rules="all"><tbody>
<tr><td style="font-family: inherit; font-size: inherit;">Company</td><td style="font-family: inherit; font-size: inherit;">OncoTherapy Science Inc.</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Description</td><td style="font-family: inherit; font-size: inherit;">Angiogenesis inhibitor that incorporates the KDR169 epitope of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1; VEGFR-2)</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Molecular Target</td><td style="font-family: inherit; font-size: inherit;">Vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2) (KDR/Flk-1) <a class="company_link mce-item-anchor" href="https://www.blogger.com/null" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain_hlMolecularTarget2" style="-webkit-user-modify: read-only; -webkit-user-select: all; background: url(http://www.allfordrugs.com/wp-includes/js/tinymce/skins/lightgray/img/anchor.gif) 50% 50% no-repeat rgb(213, 213, 213); border: 1px dotted rgb(58, 58, 58); cursor: default; display: inline-block; height: 9px !important; width: 9px !important;"></a></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Mechanism of Action</td><td style="font-family: inherit; font-size: inherit;">Angiogenesis inhibitor; Vaccine</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Therapeutic Modality</td><td style="font-family: inherit; font-size: inherit;">Preventive vaccine: Peptide vaccine</td></tr>
</tbody></table>
</div>
<ul class="data-list__content" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li class="data-list__property" id="at-a-glance_origniator"><strong class="data-list__property-key">Originator </strong><span class="data-list__property-value">OncoTherapy Science</span></li>
<li class="data-list__property" id="at-a-glance_class"><strong class="data-list__property-key">Class </strong><span class="data-list__property-value">Cancer vaccines; Peptide vaccines</span></li>
<li class="data-list__property" id="at-a-glance_mechanismOfAction"><strong class="data-list__property-key">Mechanism of Action </strong><span class="data-list__property-value">Cytotoxic T lymphocyte stimulants</span></li>
</ul>
<ul class="data-list__content data-list__content--most-recent-events" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li class="data-list__property"><strong class="data-list__property-key">16 Jun 2015 </strong><span class="data-list__property-value property-value--event-details">No recent reports on development identified - Phase-II/III for Pancreatic cancer (Combination therapy) and Phase-II for Biliary cancer in Japan (SC)</span></li>
<li class="data-list__property"><strong class="data-list__property-key">09 Jan 2015 </strong><span class="data-list__property-value property-value--event-details">Otsuka Pharmaceutical announces termination of its license agreement with Fuso Pharmaceutical for elpamotide in Japan</span></li>
<li class="data-list__property"><strong class="data-list__property-key">01 Feb 2013 </strong><span class="data-list__property-value property-value--event-details">OncoTherapy Science and Fuso Pharmaceutical Industries complete a Phase-II trial in unresectable advanced Biliary cancer and recurrent Biliary cancer (combination therapy) in Japan (UMIN000002500)</span></li>
</ul>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-6.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-6.jpg" rel="attachment wp-att-6049"><img alt="STR1" class="alignnone size-full wp-image-6049" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-6.jpg" height="479" src="http://www.allfordrugs.com/wp-content/uploads/2016/05/STR1-6.jpg" style="height: auto; max-width: 100%;" width="538" /></a></div>
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<span style="background-color: white;">Elpamotide str drawn bt worlddrugtracker</span></div>
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<li class="data-list__property"><img alt="" data-mce-src="http://www.kegg.jp/Fig/drug_small/D09995.gif" src="http://www.kegg.jp/Fig/drug_small/D09995.gif" style="height: auto; max-width: 100%;" /></li>
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<h1 class="good-title" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span data-mce-style="color: #ff0000;" style="color: red;">Elpamotide , </span><span data-mce-style="color: #ff0000;" style="color: red;">credit kegg</span></h1>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
Elpamotide is a neoangiogenesis inhibitor in phase II clinical trials at OncoTherapy Science for the treatment of inoperable advanced or recurrent biliary cancer. Phase III clinical trials was also ongoing at the company for the treatment of pancreas cancer, but recent progress report for this indication are not available at present.</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
Consisting of VEGF-R2 protein, elpamotide is a neovascular inhibitor with a totally novel mechanism of action. Its antitumor effect is thought to work by inducing strong immunoreaction against new blood vessels which provide blood flow to tumors. The drug candidate only act against blood vessels involved in tumor growth and is associated with few adverse effects.</div>
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Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival</div>
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The vaccine candidate was originally developed by OncoTherapy Science. In January 2010, Fuso Pharmaceutical, which was granted the exclusive rights to manufacture and commercialize elpamotide in Japan from OncoTherapy Science, sublicensed the manufacturing and commercialization rights to Otsuka Pharmaceutical. In 2015, the license agreement between Fuso Pharmaceutical and OncoTherapy Science, and the license agreement between Fuso Pharmaceutical and Otsuka Pharmaceutical terminated.</div>
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WO 2010143435</div>
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US 8574586</div>
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WO 2012044577</div>
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WO 2009028150</div>
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WO 2008099908</div>
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PATENT</div>
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<a data-mce-href="https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9E6E0866FB1BCCC933CB34F606E13CCF.wapp2nB?docId=WO2013133405&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText" href="https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=9E6E0866FB1BCCC933CB34F606E13CCF.wapp2nB?docId=WO2013133405&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText">WO2013133405</a></div>
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The injectable formulation containing peptides, because peptides are unstable to heat, it is impossible to carry out terminal sterilization by autoclaving. Therefore, in order to achieve sterilization, sterile filtration step is essential. Sterile filtration step is carried out by passing through the 0.22 .mu.m following membrane filter typically absolute bore is guaranteed. Therefore, in the stage of pre-filtration, it is necessary to prepare a peptide solution in which the peptide is completely dissolved. However, peptides, since the solubility characteristics by its amino acid sequence differs, it is necessary to select an appropriate solvent depending on the solubility characteristics of the peptide. In particular, it is difficult to completely dissolve the highly hydrophobic peptide in a polar solvent, it requires a great deal of effort on the choice of solvent. It is also possible to increase the solubility by changing the pH, or depart from the proper pH range as an injectable formulation, in many cases the peptide may become unstable.</div>
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In recent years, not only one type of peptide, the peptide vaccine formulation containing multiple kinds of peptides as an active ingredient has been noted. Such a peptide vaccine formulation is especially considered to be advantageous for the treatment of cancer.</div>
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The peptide vaccine formulation for the treatment of cancer, to induce a specific immune response to the cancer cells, containing the T cell epitope peptides of the tumor-specific antigen as an active ingredient (e.g., Patent Document 1). Tumor-specific antigens these T-cell epitope peptide is derived, by exhaustive expression analysis using clinical samples of cancer patients, for each type of cancer, specifically overexpressed in cancer cells, only rarely expressed in normal cells It never is one which has been identified as an antigen (e.g., Patent Document 2). However, even in tumor-specific antigens identified in this way, by a variety of having the cancer cells, in all patients and all cancer cells, not necessarily the same as being highly expressed. That is, there may be a case in which the cancer in different patients can be an antigen that is highly expressed cancer in a patient not so expressed. Further, even in the same patient, in the cellular level, cancer cells are known to be a heterogeneous population of cells (non-patent document 1), another even antigens expressed in certain cancer cells in cancer cells may be the case that do not express. Therefore, in one type of T-cell epitope peptide vaccine formulations containing only, there is a possibility that the patient can not be obtained a sufficient antitumor effect is present. Further, even in patients obtained an anti-tumor effect, the cancer cells can not kill may be present. On the other hand, if the vaccine preparation comprising a plurality of T-cell epitope peptide, it is likely that the cancer cells express any antigen. Therefore, it is possible to obtain an anti-tumor effect in a wider patient, the lower the possibility that cancer cells can not kill exists.</div>
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The effect of the vaccine formulation containing multiple types of T-cell epitope peptide as described above, the higher the more kinds of T-cell epitope peptides formulated. However, if try to include an effective amount of a plurality of types of T cell peptide, because the peptide content of the per unit amount is increased, to completely dissolve the entire peptide becomes more difficult. Further, because it would plurality of peptides having different properties coexist, it becomes more difficult to maintain all of the peptide stability.</div>
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For example, in European Patent Publication No. 2111867 (Patent Document 3), freeze-dried preparation of the vaccine formulation for the treatment of cancer comprising a plurality of T-cell epitope peptides have been disclosed. This freeze-dried preparation, in the preparation of peptide solution before freeze drying, each peptide depending on its solubility properties, are dissolved in a suitable solvent for each peptide. Furthermore, when mixing the peptide solution prepared in order to prevent the precipitation of the peptide, it is described that mixing the peptide solution in determined order. Thus, to select a suitable solvent for each peptide, possible to consider the order of mixing each peptide solution is laborious as the type of peptide increases.</div>
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In order to avoid difficulties in the formulation preparation, as described above, a vaccine formulation comprising one type of T-cell epitope peptides, methods for multiple types administered to the same patient is also contemplated. However, when administering plural kinds of vaccine preparation, it is necessary to vaccination of a plurality of locations of the body, burden on a patient is increased. Also peptide vaccine formulation, the DTH (Delayed Type Hypersensitivity) skin reactions are often caused called reaction after inoculation. Occurrence of skin reactions at a plurality of positions of the body, increases the discomfort of the patient. Therefore, in order to reduce the burden of patients in vaccination is preferably a vaccine formulation comprising a plurality of T-cell epitope peptide. Further, even when the plurality of kinds administering the vaccine formulation comprising a single type of epitope peptides, when manufacturing each peptide formulation is required the task of selecting an appropriate solvent for each peptide.</div>
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Patent Document 1: International Publication No. WO 2008/102557<br />Patent Document 2: International Publication No. 2004/031413 Patent<br />Patent Document 3: The European Patent Publication No. 2111867</div>
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PATENT</div>
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<a data-mce-href="https://www.google.com/patents/US8574586" href="https://www.google.com/patents/US8574586">https://www.google.com/patents/US8574586</a></div>
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PATENT</div>
<div class="addr" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
///////////Elpamotide, <i class="pull-left icon-bq icon-blackRed icon-Red">Phase III, </i>A neoangiogenesis antagonist, pancreatic cancer and biliary cancer, OTS-102, OncoTherapy Science Inc, <i id="yui_3_18_1_3_1462245037252_445">peptide</i></div>
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CC[C@H](C)<wbr></wbr>[C@@H](C(=O)<wbr></wbr>O)<wbr></wbr>NC(=O)<wbr></wbr>[C@H](CCCNC(=N)<wbr></wbr>N)<wbr></wbr>NC(=O)<wbr></wbr>[C@H](CC(=O)<wbr></wbr>N)<wbr></wbr>NC(=O)<wbr></wbr>CNC(=O)<wbr></wbr>[C@H](CC(=O)<wbr></wbr>O)<wbr></wbr>NC(=O)<wbr></wbr>[C@@H]1CCCN1C(=O)<wbr></wbr>[C@H](C(C)<wbr></wbr>C)<wbr></wbr>NC(=O)<wbr></wbr>[C@H](Cc2ccccc2)<wbr></wbr>NC(=O)<wbr></wbr>[C@H](CCCNC(=N)<wbr></wbr>N)<wbr></wbr>N</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-65217994828227595552016-04-26T10:17:00.002+05:302016-04-26T10:17:51.865+05:30Asfotase alfa<div dir="ltr" style="text-align: left;" trbidi="on">
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<img alt="" data-mce-src="http://www.strensiq.com/images/strensiq_logo_TM_new.png" src="http://www.strensiq.com/images/strensiq_logo_TM_new.png" style="height: auto; max-width: 100%;" /></div>
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<a data-mce-href="http://www.allfordrugs.com/wp-content/uploads/2016/04/STR1-16.jpg" href="http://www.allfordrugs.com/wp-content/uploads/2016/04/STR1-16.jpg" rel="attachment wp-att-5937"><img alt="STR1" class="alignnone size-full wp-image-5937" data-mce-src="http://www.allfordrugs.com/wp-content/uploads/2016/04/STR1-16.jpg" src="http://www.allfordrugs.com/wp-content/uploads/2016/04/STR1-16.jpg" height="198" style="height: auto; max-width: 100%;" width="265" /></a></div>
<pre class="sequence" style="font-family: Consolas, Monaco, monospace;">> Asfotase Alfa Sequence
LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL
HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS
RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL
SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK
SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI
QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA
DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA
HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC
APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV
KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD
DDDDDD</pre>
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Asfotase alfa</div>
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Indicated for the treatment of patients with perinatal/infantile and juvenile onset hypophosphatasia (HPP).</div>
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<span class="pull-left good-bq">(Strensiq<sup>®</sup>)</span><i class="pull-left icon-bq icon-blackRed">Approved</i></div>
A mineralized tissue targeted fusion protein used to treat hypophosphatasia.<br />
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<img alt="" data-mce-src="http://182.92.230.50:82/drug/images/PB0107-LOGO-01.png" src="http://182.92.230.50:82/drug/images/PB0107-LOGO-01.png" height="27" style="height: auto; max-width: 100%;" width="189" /></div>
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<span class="offset-r10 f-red">Research Code</span> <span class="f-red f_n">ALXN-1215; ENB-0040; sALP-FcD-10</span></div>
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<span class="f-red">CAS No.1174277-80-5</span></div>
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<tr><td class="weight-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">180000.0<br />
C<sub>7108</sub>H<sub>11008</sub>N<sub>1968</sub>O<sub>2206</sub>S<sub>56</sub></td></tr>
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<img alt="" data-mce-src="http://news.alexionpharma.com/sites/alxn.newshq.businesswire.com/themes/alxn_2016_newshq_theme/client_files/images/about-header.jpg" data-mce-style="line-height: 1.5;" src="http://news.alexionpharma.com/sites/alxn.newshq.businesswire.com/themes/alxn_2016_newshq_theme/client_files/images/about-header.jpg" style="height: auto; line-height: 1.5; max-width: 100%;" /></div>
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<table border="1" cellpadding="10" cellspacing="0" class="generalInfo gvTables" id="MainContent_PublicProductProfileControl_dvGeneralInformationMain" rules="all"><tbody>
<tr><td style="font-family: inherit; font-size: inherit;">Company</td><td style="font-family: inherit; font-size: inherit;">Alexion Pharmaceuticals Inc.</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Description</td><td style="font-family: inherit; font-size: inherit;">Fusion protein incorporating the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP; ALPL) and a bone-targeting peptide</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Molecular Target</td><td style="font-family: inherit; font-size: inherit;"></td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Mechanism of Action</td><td style="font-family: inherit; font-size: inherit;">Enzyme replacement therapy</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Therapeutic Modality</td><td style="font-family: inherit; font-size: inherit;">Biologic: Fusion protein</td></tr>
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<tr><td style="font-family: inherit; font-size: inherit;">Latest Stage of Development</td><td style="font-family: inherit; font-size: inherit;">Approved</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Standard Indication</td><td style="font-family: inherit; font-size: inherit;">Metabolic (unspecified)</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Indication Details</td><td style="font-family: inherit; font-size: inherit;">Treat hypophosphatasia (HPP); Treat hypophosphatasia (HPP) in children; Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age; Treat perinatal, infantile and juvenile-onset hypophosphatasia (HPP)</td></tr>
<tr><td style="font-family: inherit; font-size: inherit;">Regulatory Designation</td><td style="font-family: inherit; font-size: inherit;">U.S. - Breakthrough Therapy (Treat hypophosphatasia (HPP) in children);<br />
U.S. - Breakthrough Therapy (Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age);<br />
U.S. - Fast Track (Treat hypophosphatasia (HPP));<br />
U.S. - Orphan Drug (Treat hypophosphatasia (HPP));<br />
U.S. - Priority Review (Treat hypophosphatasia (HPP) in children);<br />
EU - Accelerated Assessment (Treat hypophosphatasia (HPP));<br />
EU - Accelerated Assessment (Treat hypophosphatasia (HPP) in children);<br />
EU - Orphan Drug (Treat hypophosphatasia (HPP));<br />
Japan - Orphan Drug (Treat hypophosphatasia (HPP));<br />
Australia - Orphan Drug (Treat hypophosphatasia (HPP)</td></tr>
</tbody></table>
</div>
Asfotase Alfa is a first-in-class bone-targeted enzyme replacement therapy designed to address the underlying cause of hypophosphatasia (<span class="caps">HPP</span>)—deficient alkaline phosphatase (<span class="caps">ALP</span>). Hypophosphatasia is almost always fatal when severe skeletal disease is obvious at birth. By replacing deficient <span class="caps">ALP</span>, treatment with Asfotase Alfa aims to improve the elevated enzyme substrate levels and improve the body’s ability to mineralize bone, thereby preventing serious skeletal and systemic patient morbidity and premature death. Asfotase alfa was first approved by Pharmaceuticals and Medicals Devices Agency of Japan (<span class="caps">PMDA</span>) on July 3, 2015, then approved by the European Medicine Agency (<span class="caps">EMA</span>) on August 28, 2015, and was approved by the U.S. Food and Drug Administration (<span class="caps">FDA</span>) on October 23, 2015. Asfotase Alfa is marketed under the brand name Strensiq® by Alexion Pharmaceuticals, Inc. The annual average price of Asfotase Alfa treatment is $285,000.<br />
Hypophosphatasia (HPP) is a rare inheritable disease that results from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Therapeutic options for treating the underlying pathophysiology of the disease have been lacking, with the mainstay of treatment being management of symptoms and supportive care. HPP is associated with significant morbidity and mortality in paediatric patients, with mortality rates as high as 100 % in perinatal-onset HPP and 50 % in infantile-onset HPP. Subcutaneous asfotase alfa (Strensiq(®)), a first-in-class bone-targeted human recombinant TNSALP replacement therapy, is approved in the EU for long-term therapy in patients with paediatric-onset HPP to treat bone manifestations of the disease. In noncomparative clinical trials in infants and children with paediatric-onset HPP, asfotase alfa rapidly improved radiographically-assessed rickets severity scores at 24 weeks (primary timepoint) as reflected in improvements in bone mineralization, with these benefits sustained after more than 3 years of treatment. Furthermore, patients typically experienced improvements in respiratory function, gross motor function, fine motor function, cognitive development, muscle strength (normalization) and ability to perform activities of daily living, and catch-up height-gain. In life-threatening perinatal and infantile HPP, asfotase alfa also improved overall survival. Asfotase alfa was generally well tolerated in clinical trials, with relatively few patients discontinuing treatment and most treatment-related adverse events being of mild to moderate intensity. Thus, subcutaneous asfotase alfa is a valuable emerging therapy for the treatment of bone manifestations in patients with paediatric-onset HPP.<br />
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FDA</div>
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October 23, 2015</div>
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Release</h2>
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Today, the U.S. Food and Drug Administration approved Strensiq (asfotase alfa) as the first approved treatment for perinatal, infantile and juvenile-onset hypophosphatasia (HPP).<br />
HPP is a rare, genetic, progressive, metabolic disease in which patients experience devastating effects on multiple systems of the body, leading to severe disability and life-threatening complications. It is characterized by defective bone mineralization that can lead to rickets and softening of the bones that result in skeletal abnormalities. It can also cause complications such as profound muscle weakness with loss of mobility, seizures, pain, respiratory failure and premature death. Severe forms of HPP affect an estimated one in 100,000 newborns, but milder cases, such as those that appear in childhood or adulthood, may occur more frequently.<br />
“For the first time, the HPP community will have access to an approved therapy for this rare disease,” said Amy G. Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research (CDER). “Strensiq’s approval is an example of how the Breakthrough Therapy Designation program can bring new and needed treatments to people with rare diseases.”<br />
Strensiq received a breakthrough therapy designation as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. The Breakthrough Therapy Designation program encourages the FDA to work collaboratively with sponsors, by providing timely advice and interactive communications, to help expedite the development and review of important new drugs for serious or life-threatening conditions. In addition to designation as a breakthrough therapy, the FDA granted Strensiq orphan drug designation because it treats a disease affecting fewer than 200,000 patients in the United States.<br />
Orphan drug designation provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Strensiq was also granted <a data-mce-href="http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm" href="http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm"><span data-mce-style="color: #0000ff;" style="color: blue;">priority review</span></a>, which is granted to drug applications that show a significant improvement in safety or effectiveness in the treatment of a serious condition. In addition, the manufacturer of Strensiq was granted a rare pediatric disease priority review voucher – a provision intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. Development of this drug was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.<br />
Strensiq is administered via injection three or six times per week. Strensiq works by replacing the enzyme (known as tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes.<br />
The safety and efficacy of Strensiq were established in 99 patients with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that patients with perinatal- and infantile-onset HPP treated with Strensiq had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated patients were alive at one year of age compared to 42 percent of control patients selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated patients compared to less than 50 percent for the natural history control patients.<br />
Patients with juvenile-onset HPP treated with Strensiq showed improvements in growth and bone health compared to control patients selected from a natural history database. All treated patients had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20 percent of control patients had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. Juvenile-onset patients also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. All treated patients demonstrated substantial healing of rickets on x-rays while some natural history control patients showed increasing signs of rickets over time.<br />
The most common side effects in patients treated with Strensiq include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.<br />
Strensiq is manufactured by Alexion Pharmaceuticals Inc., based in Cheshire, Connecticut.</div>
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<tr><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Patent Number</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pediatric Extension</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Approved</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Expires (estimated)</th><th style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"></th></tr>
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<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a class="wishart-link-out" data-mce-href="https://patents.google.com/patent/US7763712" href="https://patents.google.com/patent/US7763712" target="_blank">US7763712</a></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span class="label label-danger">No</span></td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2004-04-21</td><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2026-07-15</td></tr>
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STRENSIQ is a formulation of asfotase alfa, which is a soluble <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=16842" href="http://www.rxlist.com/script/main/art.asp?articlekey=16842" rel="dict">glycoprotein</a>composed of two identical <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=7766" href="http://www.rxlist.com/script/main/art.asp?articlekey=7766" rel="dict">polypeptide</a> chains. Each chain contains 726<a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=39555" href="http://www.rxlist.com/script/main/art.asp?articlekey=39555" rel="dict">amino acids</a> with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP), the human <a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=12077" href="http://www.rxlist.com/script/main/art.asp?articlekey=12077" rel="dict">immunoglobulin</a> G1 Fc domain and a deca-aspartate<a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=24643" href="http://www.rxlist.com/script/main/art.asp?articlekey=24643" rel="dict">peptide </a>used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds.</div>
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STRENSIQ is a tissue nonspecific alkaline phosphatase produced by<a data-mce-href="http://www.rxlist.com/script/main/art.asp?articlekey=5247" href="http://www.rxlist.com/script/main/art.asp?articlekey=5247" rel="dict">recombinant DNA technology</a> in a Chinese hamster ovary cell line. TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Asfotase alfa has a specific activity of 620 to 1250 units/mg. One activity unit is defined as the amount of asfotase alfa required to form 1 μmol of p-nitrophenol from pNPP per minute at 37°C.</div>
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STRENSIQ (asfotase alfa) is a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow, with few small translucent or white particles, aqueous solution for subcutaneous administration. STRENSIQ is supplied in glass single-use vials containing asfotase alfa; dibasic sodium phosphate, heptahydrate; monobasic sodium phosphate, monohydrate; and sodium chloride at a pH between 7.2 and 7.6. Table 5 describes the content of STRENSIQ vial presentations.</div>
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<b>Table 5: Content of STRENSIQ Vial Presentations</b></div>
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<tr><td class="EmphTd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">INGREDIENT</td><td class="EmphTd" colspan="4" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">QUANTITY PER VIAL</td></tr>
<tr><td class="EmphTd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="40%">ASFOTASE ALFA</td><td class="EmphTd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="15%">18 MG/0.45 ML</td><td class="EmphTd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="15%">28 MG/0.7 ML</td><td class="EmphTd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="15%">40 MG/ML</td><td class="EmphTd" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;" width="15%">80 MG/0.8 ML</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Dibasic sodium phosphate, heptahydrate</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2.48 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3.85 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5.5 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">4.4 mg</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Monobasic sodium phosphate, monohydrate</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.28 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.43 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.62 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">0.5 mg</td></tr>
<tr><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Sodium chloride</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">3.94 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">6.13 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">8.76 mg</td><td align="center" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">7.01 mg</td></tr>
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REFERENCES</div>
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<a data-mce-href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf" href="http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf">http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf</a></div>
<ol class="cite-this-references" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<li id="reference-A18408">Whyte MP: Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016 Apr;12(4):233-46. doi: 10.1038/nrendo.2016.14. Epub 2016 Feb 19. [<a class="wishart-link-out" data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/26893260" href="http://www.ncbi.nlm.nih.gov/pubmed/26893260" target="_blank">PubMed:26893260 </a>]</li>
<li id="reference-A18409">Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C: Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3. [<a class="wishart-link-out" data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/26529632" href="http://www.ncbi.nlm.nih.gov/pubmed/26529632" target="_blank">PubMed:26529632 </a>]</li>
<li id="reference-A18410">Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H: Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173. [<a class="wishart-link-out" data-mce-href="http://www.ncbi.nlm.nih.gov/pubmed/22397652" href="http://www.ncbi.nlm.nih.gov/pubmed/22397652" target="_blank">PubMed:22397652 </a>]</li>
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//////Asfotase alfa, Strensiq, treat hypophosphatasia, <span class="f-red f_n">ALXN-1215, ENB-0040, sALP-FcD-10, FDA 2015</span></div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-66248162101078785462016-04-25T11:57:00.002+05:302016-04-25T11:57:47.839+05:30Blinatumomab<div dir="ltr" style="text-align: left;" trbidi="on">
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Blinatumomab, AMG-103, MEDI-538, MT-103,</div>
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<span class="pull-left good-bq">(Blincyto<sup>®</sup>)</span> <i class="pull-left icon-bq icon-blackRed">Approved</i></div>
A bispecific CD19-directed CD3 T-cell engager used to treat philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).<br />
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Immunoglobulin, anti-(human CD19 (antigen)) (single-chain) fusion protein with immunoglobulin, anti-(human CD3 (antigen)) (clone 1 single-chain) (9CI)</div>
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Other Names</h3>
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1: PN: WO2005052004 SEQID: 1 claimed protein</h3>
cas 853426-35-4</div>
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<img alt="BLINCYTO (blinatumomab) for injection" data-mce-src="http://www.blincyto.com/static/images/base/header-logo.blincyto.290x97.png" src="http://www.blincyto.com/static/images/base/header-logo.blincyto.290x97.png" style="height: auto; max-width: 100%;" /><b>Blinatumomab</b> (trade name <b>Blincyto</b>, previously known as <b>AMG103</b>) is a <a data-mce-href="https://en.wikipedia.org/wiki/Biopharmaceutical" href="https://en.wikipedia.org/wiki/Biopharmaceutical" title="Biopharmaceutical">biopharmaceutical</a> drug used as a <a data-mce-href="https://en.wikipedia.org/wiki/Therapy#Lines_of_therapy" href="https://en.wikipedia.org/wiki/Therapy#Lines_of_therapy" title="Therapy">second-line treatment</a>for <a data-mce-href="https://en.wikipedia.org/wiki/Philadelphia_chromosome" href="https://en.wikipedia.org/wiki/Philadelphia_chromosome" title="Philadelphia chromosome">Philadelphia chromosome</a>-negative relapsed or refractory <a data-mce-href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" title="Acute lymphoblastic leukemia">acute lymphoblastic leukemia</a>. It belongs to a class of constructed<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Monoclonal_antibodies" href="https://en.wikipedia.org/wiki/Monoclonal_antibodies" title="Monoclonal antibodies">monoclonal antibodies</a>, <a data-mce-href="https://en.wikipedia.org/wiki/Bi-specific_T-cell_engager" href="https://en.wikipedia.org/wiki/Bi-specific_T-cell_engager" title="Bi-specific T-cell engager">bi-specific T-cell engagers</a> (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. Blinatumomab specifically targets the <a data-mce-href="https://en.wikipedia.org/wiki/CD19" href="https://en.wikipedia.org/wiki/CD19" title="CD19">CD19</a> <a data-mce-href="https://en.wikipedia.org/wiki/Antigen" href="https://en.wikipedia.org/wiki/Antigen" title="Antigen">antigen</a> present on <a data-mce-href="https://en.wikipedia.org/wiki/B_cell" href="https://en.wikipedia.org/wiki/B_cell" title="B cell">B cells</a>.<sup class="reference" id="cite_ref-usanname_1-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-usanname-1" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-usanname-1">[1]</a></sup> In December 2014 it was approved by the US <a data-mce-href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" href="https://en.wikipedia.org/wiki/Food_and_Drug_Administration" title="Food and Drug Administration">Food and Drug Administration</a> under the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/FDA_Accelerated_Approval" href="https://en.wikipedia.org/wiki/FDA_Accelerated_Approval" title="FDA Accelerated Approval">accelerated approval</a> program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval.<sup class="reference" id="cite_ref-Label_2-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Label-2" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Label-2">[2]</a></sup><sup class="reference" id="cite_ref-3"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-3" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-3">[3]</a></sup> When it launched, blinatumomab was priced at $178,000 per year in the United States; only about 1,000 people were eligible to take the drug, based on its label.<sup class="reference" id="cite_ref-Fierce_4-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Fierce-4" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Fierce-4">[4]</a></sup><br />
<img alt="" data-mce-src="http://d3md5dngttnvbj.cloudfront.net/content/bloodjournal/120/26/5094/F1.large.jpg?width=800&height=600&carousel=1" height="448" src="http://d3md5dngttnvbj.cloudfront.net/content/bloodjournal/120/26/5094/F1.large.jpg?width=800&height=600&carousel=1" style="height: auto; max-width: 100%;" width="640" /><br />
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<span class="mw-headline" id="Medical_use">Medical use</span></h2>
Blinatumomab is used as a <a data-mce-href="https://en.wikipedia.org/wiki/Therapy#Lines_of_therapy" href="https://en.wikipedia.org/wiki/Therapy#Lines_of_therapy" title="Therapy">second-line treatment</a> for <a data-mce-href="https://en.wikipedia.org/wiki/Philadelphia_chromosome" href="https://en.wikipedia.org/wiki/Philadelphia_chromosome" title="Philadelphia chromosome">Philadelphia chromosome</a>-negative relapsed or refractory Bcell precursor <a data-mce-href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" title="Acute lymphoblastic leukemia">acute lymphoblastic leukemia</a>.<sup class="reference" id="cite_ref-Label_2-1"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Label-2" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Label-2">[2]</a></sup><br />
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<span class="mw-headline" id="Mechanism_of_action">Mechanism of action</span></h2>
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<a class="image" data-mce-href="https://en.wikipedia.org/wiki/File:BiTE_antibody_en.svg" href="https://en.wikipedia.org/wiki/File:BiTE_antibody_en.svg"><img alt="" class="thumbimage" data-file-height="380" data-file-width="310" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/40/BiTE_antibody_en.svg/220px-BiTE_antibody_en.svg.png" height="270" src="https://upload.wikimedia.org/wikipedia/commons/thumb/4/40/BiTE_antibody_en.svg/220px-BiTE_antibody_en.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/4/40/BiTE_antibody_en.svg/330px-BiTE_antibody_en.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/4/40/BiTE_antibody_en.svg/440px-BiTE_antibody_en.svg.png 2x" style="height: auto; max-width: 100%;" width="220" /></a><br />
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Blinatumomab linking a <a data-mce-href="https://en.wikipedia.org/wiki/T_cell" href="https://en.wikipedia.org/wiki/T_cell" title="T cell">T cell</a> to a malignant B cell.</div>
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Blinatumomab enables a patient's <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/T_cells" href="https://en.wikipedia.org/wiki/T_cells" title="T cells">T cells</a> to recognize <a data-mce-href="https://en.wikipedia.org/wiki/Malignancy" href="https://en.wikipedia.org/wiki/Malignancy" title="Malignancy">malignant</a> B cells. A molecule of blinatumomab combines two binding sites: a<a data-mce-href="https://en.wikipedia.org/wiki/CD3_(immunology)" href="https://en.wikipedia.org/wiki/CD3_(immunology)" title="CD3 (immunology)">CD3</a> site for T cells and a <a data-mce-href="https://en.wikipedia.org/wiki/CD19" href="https://en.wikipedia.org/wiki/CD19" title="CD19">CD19</a> site for the target B cells. CD3 is part of the <a data-mce-href="https://en.wikipedia.org/wiki/T_cell_receptor" href="https://en.wikipedia.org/wiki/T_cell_receptor" title="T cell receptor">T cell receptor</a>. The drug works by linking these two cell types and <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/T_cell_activation#Activation" href="https://en.wikipedia.org/wiki/T_cell_activation#Activation" title="T cell activation">activating the T cell</a> to exert <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Cytotoxic" href="https://en.wikipedia.org/wiki/Cytotoxic" title="Cytotoxic">cytotoxic</a> activity on the target cell.<sup class="reference" id="cite_ref-5"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-5" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-5">[5]</a></sup> <a data-mce-href="https://en.wikipedia.org/wiki/CD3_(immunology)" href="https://en.wikipedia.org/wiki/CD3_(immunology)" title="CD3 (immunology)">CD3</a> and <a data-mce-href="https://en.wikipedia.org/wiki/CD19" href="https://en.wikipedia.org/wiki/CD19" title="CD19">CD19</a> are expressed in both pediatric and adult patients, making blinatumomab a potential therapeutic option for both pediatric and adult populations.<sup class="reference" id="cite_ref-amgen_2012_briefing_6-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-amgen_2012_briefing-6" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-amgen_2012_briefing-6">[6]</a></sup><br />
<img alt="" data-mce-src="https://extranet.fhcrc.org/EN/sections/spotlight/2014/01/crd_laszlo_fullimage2.jpg" height="435" src="https://extranet.fhcrc.org/EN/sections/spotlight/2014/01/crd_laszlo_fullimage2.jpg" style="height: auto; max-width: 100%;" width="640" /><br />
<img alt="" data-mce-src="http://media4.asco.org/144/8694/93809/93809_video_pvhr.jpg" height="480" src="http://media4.asco.org/144/8694/93809/93809_video_pvhr.jpg" style="height: auto; max-width: 100%;" width="640" /><br />
<h2>
<span class="mw-headline" id="History">History</span></h2>
The drug was developed by a German-American company <a class="new" data-mce-href="https://en.wikipedia.org/w/index.php?title=Micromet&action=edit&redlink=1" href="https://en.wikipedia.org/w/index.php?title=Micromet&action=edit&redlink=1" title="Micromet (page does not exist)">Micromet</a>, Inc. in cooperation with <a data-mce-href="https://en.wikipedia.org/wiki/Lonza_Group" href="https://en.wikipedia.org/wiki/Lonza_Group" title="Lonza Group">Lonza</a>; Micromet was later purchased by<a data-mce-href="https://en.wikipedia.org/wiki/Amgen" href="https://en.wikipedia.org/wiki/Amgen" title="Amgen">Amgen</a>, which has furthered the drug's clinical trials. In July 2014, the FDA granted breakthrough therapy status to blinatumomab for the treatment of <a data-mce-href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" title="Acute lymphoblastic leukemia">acute lymphoblastic leukemia</a> (ALL).<sup class="reference" id="cite_ref-amgenpr201407_7-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-amgenpr201407-7" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-amgenpr201407-7">[7]</a></sup> In October 2014, Amgen’s <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Biologics_License_Application" href="https://en.wikipedia.org/wiki/Biologics_License_Application" title="Biologics License Application">Biologics License Application</a> for blinatumomab was granted priority review designation by the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/FDA" href="https://en.wikipedia.org/wiki/FDA" title="FDA">FDA</a>, thus establishing a deadline of May 19, 2015 for completion of the FDA review process.<sup class="reference" id="cite_ref-amgenpr201410_8-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-amgenpr201410-8" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-amgenpr201410-8">[8]</a></sup><br />
On December 3, 2014, the drug was approved for use in the United States to treat <a data-mce-href="https://en.wikipedia.org/wiki/Philadelphia_chromosome" href="https://en.wikipedia.org/wiki/Philadelphia_chromosome" title="Philadelphia chromosome">Philadelphia chromosome</a>-negative relapsed or refractory <a data-mce-href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" href="https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukemia" title="Acute lymphoblastic leukemia">acute lymphoblastic leukemia</a> under the <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/FDA" href="https://en.wikipedia.org/wiki/FDA" title="FDA">FDA</a>'s <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/FDA_Accelerated_Approval" href="https://en.wikipedia.org/wiki/FDA_Accelerated_Approval" title="FDA Accelerated Approval">accelerated approval</a> program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval.<sup class="reference" id="cite_ref-Label_2-2"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Label-2" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Label-2">[2]</a></sup><sup class="reference" id="cite_ref-nature7530_9-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-nature7530-9" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-nature7530-9">[9]</a></sup><br />
<img alt="" data-mce-src="http://media4.asco.org/132/8148/81387/81387_video_pvhr.jpg" height="480" src="http://media4.asco.org/132/8148/81387/81387_video_pvhr.jpg" style="height: auto; max-width: 100%;" width="640" /><br />
<h2>
<span class="mw-headline" id="Cost">Cost</span></h2>
When blinatumomab was approved, Amgen announced that the price for the drug would be $178,000 per year, which made it the most expensive cancer drug on the market. Merck's <a data-mce-href="https://en.wikipedia.org/wiki/Pembrolizumab" href="https://en.wikipedia.org/wiki/Pembrolizumab" title="Pembrolizumab">pembrolizumab</a> was priced at $150,000 per year when it launched; unlike that drug and others, only about 1,000 people can be given the drug, based on its label.<sup class="reference" id="cite_ref-Fierce_4-1"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Fierce-4" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Fierce-4">[4]</a></sup><br />
Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan-Kettering Cancer Center, has calculated that according to "value-based pricing," assuming that the value of a year of life is $120,000 with a 15% "toxicity discount," the market price of blinaumomab should be $12,612 a month, compared to the market price of $64,260 a month. A representative of Amgen said, “The price of Blincyto reflects the significant clinical, economic and humanistic value of the product to patients and the health-care system. The price also reflects the complexity of developing, manufacturing and reliably supplying innovative biologic medicines.”<sup class="reference" id="cite_ref-Wall2015_10-0"><a data-mce-href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Wall2015-10" href="https://en.wikipedia.org/wiki/Blinatumomab#cite_note-Wall2015-10">[10]</a></sup></div>
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<img alt="" data-mce-src="http://media4.asco.org/156/10614/107803/107803_video_pvhr.jpg" height="359" src="http://media4.asco.org/156/10614/107803/107803_video_pvhr.jpg" style="height: auto; max-width: 100%;" width="640" /></div>
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<img alt="" data-mce-src="http://notiziario.comitatomarialetiziaverga.it/wp-content/uploads/2014/09/blinatumomab.jpg" height="358" src="http://notiziario.comitatomarialetiziaverga.it/wp-content/uploads/2014/09/blinatumomab.jpg" style="height: auto; max-width: 100%;" width="640" /></h2>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
</h2>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
Patent</h2>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
WO 2010052013</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.co.in/patents/WO2010052013A1?cl=en" href="http://www.google.co.in/patents/WO2010052013A1?cl=en">http://www.google.co.in/patents/WO2010052013A1?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
Examples:</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
1. CD19xCD3 bispecific single chain antibody</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
The generation, expression and cytotoxic activity of the CD19xCD3 bispecific single chain antibody has been described in WO 99/54440. The corresponding amino and nucleic acid sequences of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 1 and 2, respectively. The VH and VL regions of the CD3 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 7 to 10, respectively, whereas the VH and VL regions of the CD19 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs 3 to 6, respectively.</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.com.ar/patents/WO2010052014A1?cl=en" href="http://www.google.com.ar/patents/WO2010052014A1?cl=en">http://www.google.com.ar/patents/WO2010052014A1?cl=en</a></div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
WO 2015006749</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.com/patents/WO2015006749A2?cl=un" href="http://www.google.com/patents/WO2015006749A2?cl=un">http://www.google.com/patents/WO2015006749A2?cl=un</a></div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
PATENT</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
CN 104861067</div>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<a data-mce-href="http://www.google.com/patents/CN104861067A?cl=zh" href="http://www.google.com/patents/CN104861067A?cl=zh">http://www.google.com/patents/CN104861067A?cl=zh</a></div>
<table class="patent-data-table mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;"><tbody>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com.ar/patents/WO1998008875A1?cl=en" href="http://www.google.com.ar/patents/WO1998008875A1?cl=en">WO1998008875A1</a><span class="patent-tooltip-anchor" data-tooltip-text="Cited by examiner" data-tooltip="Cited by examiner"> *</span></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">18 Aug 1997</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">5 Mar 1998</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Viva Diagnostika Diagnostische Produkte Gmbh</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Novel combination preparations and their use in immunodiagnosis and immunotherapy</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com.ar/patents/WO1999054440A1?cl=en" href="http://www.google.com.ar/patents/WO1999054440A1?cl=en">WO1999054440A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Apr 1999</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">28 Oct 1999</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Micromet Gesellschaft Für Biomedizinische Forschung Mbh</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">CD19xCD3 SPECIFIC POLYPEPTIDES AND USES THEREOF</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com.ar/patents/WO2004106381A1?cl=en" href="http://www.google.com.ar/patents/WO2004106381A1?cl=en">WO2004106381A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">26 May 2004</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">9 Dec 2004</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Micromet Ag</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Pharmaceutical compositions comprising bispecific anti-cd3, anti-cd19 antibody constructs for the treatment of b-cell related disorders</td></tr>
<tr><td class="patent-data-table-td citation-patent" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="http://www.google.com.ar/patents/WO2007068354A1?cl=en" href="http://www.google.com.ar/patents/WO2007068354A1?cl=en">WO2007068354A1</a></td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">29 Nov 2006</td><td class="patent-data-table-td patent-date-value" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">21 Jun 2007</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Micromet Ag</td><td class="patent-data-table-td " style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Means and methods for the treatment of tumorous diseases</td></tr>
</tbody></table>
<h2 style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif;">
<span class="mw-headline" id="References">References</span></h2>
<div class="reflist columns references-column-width" style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
<ol class="references">
<li id="cite_note-usanname-1"> <span class="reference-text"><cite class="citation web"><a class="external text" data-mce-href="http://www.ama-assn.org/resources/doc/usan/x-pub/blinatumomab.pdf" href="http://www.ama-assn.org/resources/doc/usan/x-pub/blinatumomab.pdf" rel="nofollow">"blinatumomab"</a> (PDF). <i>United States Adopted Names Council » <a data-mce-href="https://en.wikipedia.org/wiki/United_States_Adopted_Name" href="https://en.wikipedia.org/wiki/United_States_Adopted_Name" title="United States Adopted Name">Adopted Names</a></i>.<a data-mce-href="https://en.wikipedia.org/wiki/American_Medical_Association" href="https://en.wikipedia.org/wiki/American_Medical_Association" title="American Medical Association">American Medical Association</a>. 2008. N08/16.</cite>(<a data-mce-href="https://en.wikipedia.org/wiki/Wikipedia:Verifiability#Access_to_sources" href="https://en.wikipedia.org/wiki/Wikipedia:Verifiability#Access_to_sources" title="Wikipedia:Verifiability">registration required</a>)</span></li>
<li id="cite_note-Label-2"> <span class="reference-text"><a class="external text" data-mce-href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125557lbl.pdf" href="http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125557lbl.pdf" rel="nofollow">Blinatumomab label</a> Updated 12/2014</span></li>
<li id="cite_note-3"> <span class="reference-text">Food and Drug Administration December 3, 2014 <a class="external text" data-mce-href="http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm425597.htm" href="http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm425597.htm" rel="nofollow">FDA Press release: Blinatumomab</a></span></li>
<li id="cite_note-Fierce-4"> <span class="reference-text">Tracy Staton for FiercePharmaMarketing. December 18, 2014 <a class="external text" data-mce-href="http://www.fiercepharmamarketing.com/story/amgen-slaps-record-breaking-178k-price-rare-leukemia-drug-blincyto/2014-12-18" href="http://www.fiercepharmamarketing.com/story/amgen-slaps-record-breaking-178k-price-rare-leukemia-drug-blincyto/2014-12-18" rel="nofollow">Amgen slaps record-breaking $178K price on rare leukemia drug Blincyto</a></span></li>
<li id="cite_note-5"> <span class="reference-text"><cite class="citation journal">Mølhøj, M; Crommer, S; Brischwein, K; Rau, D; Sriskandarajah, M; Hoffmann, P; Kufer, P; Hofmeister, R; Baeuerle, PA (March 2007). "CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis".<i><a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/Mol._Immunol." href="https://en.wikipedia.org/wiki/Mol._Immunol." title="Mol. Immunol.">Molecular Immunology</a></i> <b>44</b> (8): 1935–43. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1016%2Fj.molimm.2006.09.032" href="https://dx.doi.org/10.1016%2Fj.molimm.2006.09.032" rel="nofollow">10.1016/j.molimm.2006.09.032</a>.<a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/PubMed_Identifier" href="https://en.wikipedia.org/wiki/PubMed_Identifier" title="PubMed Identifier">PMID</a> <a class="external text" data-mce-href="https://www.ncbi.nlm.nih.gov/pubmed/17083975" href="https://www.ncbi.nlm.nih.gov/pubmed/17083975" rel="nofollow">17083975</a>.</cite><a data-mce-href="https://en.wikipedia.org/wiki/Closed_access" href="https://en.wikipedia.org/wiki/Closed_access" title="Closed access"><img alt="Closed access" data-file-height="1000" data-file-width="640" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c1/Closed_Access_logo_alternative.svg/8px-Closed_Access_logo_alternative.svg.png" height="13" src="https://upload.wikimedia.org/wikipedia/commons/thumb/c/c1/Closed_Access_logo_alternative.svg/8px-Closed_Access_logo_alternative.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/c/c1/Closed_Access_logo_alternative.svg/12px-Closed_Access_logo_alternative.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/c/c1/Closed_Access_logo_alternative.svg/16px-Closed_Access_logo_alternative.svg.png 2x" style="height: auto; max-width: 100%;" width="8" /></a></span></li>
<li id="cite_note-amgen_2012_briefing-6"> <span class="reference-text"><cite class="citation report"><a data-mce-href="https://en.wikipedia.org/wiki/Amgen" href="https://en.wikipedia.org/wiki/Amgen" title="Amgen">Amgen</a> (30 October 2012). <a class="external text" data-mce-href="http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM330210.pdf" href="http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM330210.pdf" rel="nofollow">Background Information for the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee Meeting 04 December 2012</a> (PDF) (PDF). <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/USFDA" href="https://en.wikipedia.org/wiki/USFDA" title="USFDA">Food and Drug Administration</a>. Blinatumomab (AMG 103).</cite></span></li>
<li id="cite_note-amgenpr201407-7"> <span class="reference-text"><cite class="citation pressrelease"><a class="external text" data-mce-href="http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1944069" href="http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1944069" rel="nofollow">"Amgen Receives FDA Breakthrough Therapy Designation For Investigational BiTE® Antibody Blinatumomab In Acute Lymphoblastic Leukemia"</a> (Press release). <a data-mce-href="https://en.wikipedia.org/wiki/Amgen" href="https://en.wikipedia.org/wiki/Amgen" title="Amgen">Amgen</a>. 1 July 2014.</cite></span></li>
<li id="cite_note-amgenpr201410-8"> <span class="reference-text"><cite class="citation pressrelease"><a class="external text" data-mce-href="http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1975963" href="http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1975963" rel="nofollow">"Amgen's BiTE® Immunotherapy Blinatumomab Receives FDA Priority Review Designation In Acute Lymphoblastic Leukemia"</a> (Press release). <a data-mce-href="https://en.wikipedia.org/wiki/Amgen" href="https://en.wikipedia.org/wiki/Amgen" title="Amgen">Amgen</a>. 9 October 2014.</cite></span></li>
<li id="cite_note-nature7530-9"><span class="reference-text"><cite class="citation journal">"Business: Antibody advance". Seven Days. <i>Nature</i> (paper) <b>516</b> (7530): 149. 11 December 2014. <a data-mce-href="https://en.wikipedia.org/wiki/Digital_object_identifier" href="https://en.wikipedia.org/wiki/Digital_object_identifier" title="Digital object identifier">doi</a>:<a class="external text" data-mce-href="https://dx.doi.org/10.1038%2F516148a" href="https://dx.doi.org/10.1038%2F516148a" rel="nofollow">10.1038/516148a</a>.</cite><a data-mce-href="https://en.wikipedia.org/wiki/Open_access" href="https://en.wikipedia.org/wiki/Open_access" title="open access publication - free to read"><img alt="open access publication - free to read" data-file-height="1000" data-file-width="640" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/77/Open_Access_logo_PLoS_transparent.svg/8px-Open_Access_logo_PLoS_transparent.svg.png" height="13" src="https://upload.wikimedia.org/wikipedia/commons/thumb/7/77/Open_Access_logo_PLoS_transparent.svg/8px-Open_Access_logo_PLoS_transparent.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/7/77/Open_Access_logo_PLoS_transparent.svg/12px-Open_Access_logo_PLoS_transparent.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/7/77/Open_Access_logo_PLoS_transparent.svg/16px-Open_Access_logo_PLoS_transparent.svg.png 2x" style="height: auto; max-width: 100%;" width="8" /></a></span></li>
<li id="cite_note-Wall2015-10"> <span class="reference-text"><cite class="citation news">Peter Loftus (June 18, 2015). <a class="external text" data-mce-href="http://www.wsj.com/articles/how-much-should-cancer-drugs-cost-1434640914" href="http://www.wsj.com/articles/how-much-should-cancer-drugs-cost-1434640914" rel="nofollow">"How Much Should Cancer Drugs Cost? Memorial Sloan Kettering doctors create pricing calculator that weighs factors such as side effects, extra years of life"</a>. The Wall Street Journal<span class="reference-accessdate">. Retrieved <span class="nowrap">22 June</span> 2015</span>.</cite></span></li>
</ol>
</div>
<table class="infobox mce-item-table" style="border: 1px dashed rgb(187, 187, 187); color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;"><caption style="border: 1px dashed rgb(187, 187, 187);"><span title="International nonproprietary name (INN): Blinatumomab">Blinatumomab</span></caption><tbody>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Monoclonal_antibody" href="https://en.wikipedia.org/wiki/Monoclonal_antibody" title="Monoclonal antibody">Monoclonal antibody</a></th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/File:Engineered_monoclonal_antibodies.svg" href="https://en.wikipedia.org/wiki/File:Engineered_monoclonal_antibodies.svg" title="File:Engineered monoclonal antibodies.svg">Type</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Bi-specific_T-cell_engager" href="https://en.wikipedia.org/wiki/Bi-specific_T-cell_engager" title="Bi-specific T-cell engager">Bi-specific T-cell engager</a></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Monoclonal_antibody#Production" href="https://en.wikipedia.org/wiki/Monoclonal_antibody#Production" title="Monoclonal antibody">Source</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Mouse" href="https://en.wikipedia.org/wiki/Mouse" title="Mouse">Mouse</a></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Antigen" href="https://en.wikipedia.org/wiki/Antigen" title="Antigen">Target</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CD19" href="https://en.wikipedia.org/wiki/CD19" title="CD19">CD19</a>, <a data-mce-href="https://en.wikipedia.org/wiki/CD3_(immunology)" href="https://en.wikipedia.org/wiki/CD3_(immunology)" title="CD3 (immunology)">CD3</a></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Clinical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" href="https://en.wikipedia.org/wiki/Drug_nomenclature#Trade_names" title="Drug nomenclature">Trade names</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Blincyto</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category" href="https://en.wikipedia.org/wiki/Pregnancy_category" title="Pregnancy category">Pregnancy<br />category</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" href="https://en.wikipedia.org/wiki/Pregnancy_category#United_States" title="Pregnancy category">C</a> (Risk not ruled out)</li>
</ul>
</div>
</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Route_of_administration" href="https://en.wikipedia.org/wiki/Route_of_administration" title="Route of administration">Routes of<br />administration</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">intravenous</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Legal status</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" href="https://en.wikipedia.org/wiki/Regulation_of_therapeutic_goods" title="Regulation of therapeutic goods">Legal status</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><div class="plainlist">
<ul>
<li><small><abbr title="United States">US</abbr>:</small> <a data-mce-href="https://en.wikipedia.org/wiki/Prescription_drug" href="https://en.wikipedia.org/wiki/Prescription_drug" title="Prescription drug">℞-only</a></li>
</ul>
</div>
</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Pharmacokinetics" href="https://en.wikipedia.org/wiki/Pharmacokinetics" title="Pharmacokinetics">Pharmacokinetic</a> data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Bioavailability" href="https://en.wikipedia.org/wiki/Bioavailability" title="Bioavailability">Bioavailability</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">100% (IV)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Drug_metabolism" href="https://en.wikipedia.org/wiki/Drug_metabolism" title="Drug metabolism">Metabolism</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">degradation into small peptides and amino acids</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Biological_half-life" href="https://en.wikipedia.org/wiki/Biological_half-life" title="Biological half-life">Biological half-life</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">2.11 hours</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Excretion" href="https://en.wikipedia.org/wiki/Excretion" title="Excretion">Excretion</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">urine (negligible)</td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Identifiers</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/CAS_Registry_Number" href="https://en.wikipedia.org/wiki/CAS_Registry_Number" title="CAS Registry Number">CAS Number</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="www.commonchemistry.org"><a class="external text" data-mce-href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=853426-35-4" href="http://www.commonchemistry.org/ChemicalDetail.aspx?ref=853426-35-4" rel="nofollow">853426-35-4</a></span><sup> <img alt="" data-file-height="600" data-file-width="525" data-mce-src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" height="8" src="https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/7px-X_mark.svg.png" srcset="//upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/11px-X_mark.svg.png 1.5x, //upload.wikimedia.org/wikipedia/commons/thumb/a/a2/X_mark.svg/14px-X_mark.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" href="https://en.wikipedia.org/wiki/Anatomical_Therapeutic_Chemical_Classification_System" title="Anatomical Therapeutic Chemical Classification System">ATC code</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ATC_code_L01" href="https://en.wikipedia.org/wiki/ATC_code_L01" title="ATC code L01">L01XC19</a> (<span title="www.whocc.no"><a class="external text" data-mce-href="http://www.whocc.no/atc_ddd_index/?code=L01XC19" href="http://www.whocc.no/atc_ddd_index/?code=L01XC19" rel="nofollow">WHO</a></span>)</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/ChemSpider" href="https://en.wikipedia.org/wiki/ChemSpider" title="ChemSpider">ChemSpider</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">none</td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" href="https://en.wikipedia.org/wiki/Unique_Ingredient_Identifier" title="Unique Ingredient Identifier">UNII</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="fdasis.nlm.nih.gov"><a class="external text" data-mce-href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=4FR53SIF3A" href="http://fdasis.nlm.nih.gov/srs/srsdirect.jsp?regno=4FR53SIF3A" rel="nofollow">4FR53SIF3A</a></span><sup> <img alt="Yes" data-file-height="600" data-file-width="600" data-mce-src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" height="7" src="https://upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/7px-Yes_check.svg.png" srcset="//upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/11px-Yes_check.svg.png 1.5x, //upload.wikimedia.org/wikipedia/en/thumb/f/fb/Yes_check.svg/14px-Yes_check.svg.png 2x" style="height: auto; max-width: 100%;" width="7" /></sup></td></tr>
<tr><th colspan="2" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">Chemical data</th></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Chemical_formula" href="https://en.wikipedia.org/wiki/Chemical_formula" title="Chemical formula">Formula</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><span title="Carbon">C</span><sub>2367</sub><span title="Hydrogen">H</span><sub>3577</sub><span title="Nitrogen">N</span><sub>649</sub><span title="Oxygen">O</span><sub>772</sub><span title="Sulfur">S</span><sub>19</sub></td></tr>
<tr><th scope="row" style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;"><a data-mce-href="https://en.wikipedia.org/wiki/Molar_mass" href="https://en.wikipedia.org/wiki/Molar_mass" title="Molar mass">Molar mass</a></th><td style="border: 1px dashed rgb(187, 187, 187); font-family: inherit; font-size: inherit;">54.1 <a class="mw-redirect" data-mce-href="https://en.wikipedia.org/wiki/KDa" href="https://en.wikipedia.org/wiki/KDa" title="KDa">kDa</a></td></tr>
</tbody></table>
<div style="color: #333333; font-family: Georgia, 'Times New Roman', 'Bitstream Charter', Times, serif; font-size: 16px; line-height: 24px;">
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0tag:blogger.com,1999:blog-569892385714118127.post-81609369742991890592016-03-18T10:23:00.002+05:302016-03-18T10:23:45.264+05:30Trioxacarcin A<div dir="ltr" style="text-align: left;" trbidi="on">
<div style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
<img alt="" src="http://www.nature.com/nchem/journal/v5/n10/images/nchem.1746-compI.gif" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /><img alt="" src="http://www.chemspider.com/ImagesHandler.ashx?id=25059616&w=250&h=250" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
<div style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
Trioxacarcin A, DC-45A</div>
<div style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin-bottom: 1.5em; outline: 0px; padding: 0px;">
CAS No. <b id="on_casno" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a href="http://www.molbase.com/en/81552-36-5-moldata-1643643.html" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">81552-36-</a>5</b></div>
<ul class="struct-props" style="background-color: white; border: 0px; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin: 0.5em 0px 1.5em 1.5em; outline: 0px; padding: 0px 0px 0px 20px;">
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span class="prop_title" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Molecular Formula</span><span id="ctl00_ctl00_ContentSection_ContentPlaceHolder1_RecordViewDetails_rptDetailsView_ctl00_prop_MF" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">42</span>H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">52</span>O<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">20</span></span></li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><span class="prop_title" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Average mass</span>876.850 Da</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><div class="syn" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">
<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">17′-[(4-C-Acetyl-2,<wbr></wbr>6-dideoxyhexopyrano<wbr></wbr>syl)oxy]-19′-(dimet<wbr></wbr>hoxymethyl)-10′,13′<wbr></wbr>-dihydroxy-6′-metho<wbr></wbr>xy-3′-methyl-11′-ox<wbr></wbr>ospiro[oxirane-2,18<wbr></wbr>‘-[16,20,22]trioxah<wbr></wbr>exacyclo[17.2.1.0<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">2,15</span><wbr></wbr>.0<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">5,14</span><wbr></wbr>.0<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">7,12</span><wbr></wbr>.0<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">17,21</span><wbr></wbr> ]docosa[2<wbr></wbr>(15),3,5(14),6,12]p<wbr></wbr>entaen]-8′-yl 4-O-a<wbr></wbr>cetyl-2,6-dideoxy-3<wbr></wbr>-C-methylhexopyrano<wbr></wbr>side</strong></div>
<div class="syn" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">
(1S,2R,3aS,4S,8S,10S,13aS)-13a-(4-C-Acetyl-2,6-dideoxy-alpha-L-xylo-hexopyranosyloxy)-2-(dimethoxymethyl)-10,12-dihydroxy-7-methoxy-5-methyl-11-oxo-4,8,9,10,11,13a-hexahydro-3aH-spiro[2,4-epoxyfuro[3,2-b]naphtho[2,3-h]-1-benzopyran-1,2′-oxiran]-8-yl 4-O-acetyl-2,6-dideoxy-3-C-methyl-alpha-L-xylo-hexopyranoside</div>
</li>
<li style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Kyowa Hakko Kirin INNOVATOR</li>
</ul>
<h1 style="background-color: white; border: 0px; color: #333333; font-family: Arial, Helvetica, sans-serif; font-size: 27.8400001525879px; font-weight: normal; line-height: 1.1em; margin: 0.5em 0px; outline: 0px; padding: 0px;">
Trioxacarcin B</h1>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><img alt="" src="https://encrypted-tbn3.gstatic.com/images?q=tbn:ANd9GcR1Ta7q0vi-RNLszOjhBfk2fIzB8L-ziqGVs9JKsVgMwxS1MtLpbQ" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></strong></div>
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Trioxacarcin B; Antibiotic DC 45B1; DC-45-B1; Trioxacarcin A, 14,17-deepoxy-14,17-dihydroxy-; AC1MJ5N1; 81534-36-3;</div>
<table class="top-summary-items" style="background-color: white; border-collapse: collapse; border: 0px; color: black; font-family: Arial, Helvetica, sans-serif; font-size: 13.9200000762939px; line-height: 22.2719993591309px; margin: 0px; outline: 0px; padding: 0px; width: 893px;"><tbody style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">
<tr style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><th style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 6px;">Molecular Formula:</th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 6px;"><a href="https://pubchem.ncbi.nlm.nih.gov/search/#collection=compounds&query_type=mf&query=C42H54O21&sort=mw&sort_dir=asc" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;" title="Find all compounds with formula C42H54O21">C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span><span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">5</span><span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>O<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span><span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">1</span></a></td></tr>
<tr style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><th style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 6px;">Molecular Weight:</th><td style="border-bottom-color: rgb(204, 204, 204); border-bottom-style: dotted; border-width: 0px 0px 1px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 6px;">894.86556 g/mol</td></tr>
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Trioxacarcin C</h1>
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(CAS NO.81781-28-4):C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">42</span>H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">54</span>O<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">20</span><br />Molecular Weight: 878.8662 g/mol<br />Structure of Trioxacarcin C :<br /><img alt="" src="http://www.lookchem.com/UserFilesUpload/15(26).png" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="276" /></div>
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The trioxacarcins are polyoxygenated, structurally complex natural products that potently inhibit the growth of cultured human cancer cells</div>
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Natural products that bind and often covalently modify duplex DNA figure prominently in chemotherapy for human cancers. The trioxacarcins are a new class of DNA- modifying natural products with antiproliferative effects. The trioxacarcins were first described in 1981 by Tomita and coworkers (Tomita et al. , J. Antibiotics, 34( 12): 1520- 1524, 1981 ; Tamaoki et al., J. Antibiotics 34( 12): 1525- 1530, 1981 ; Fujimoto et al. , J. Antibiotics 36(9): 1216- 1221 , 1983). Trioxacarcin A, B, and C were isolated by Tomita and coworkers from the culture broth of Streptomyces bottropensis DO-45 and shown to possess anti-tumor activity in murine models as well as gram-positive antibiotic activity. Subsequent work led to the discovery of other members of this family. Trioxacarcin A is a powerful anticancer agent with subnanmolar IC70 values against lung (LXFL 529L, H-460), mammary (MCF-7), and CNS (SF-268) cancer cell lines. The trioxacarcins have also been shown to have antimicrobial activity {e.g., anti-bacterial and anti-malarial activity) (see, e.g. , Maskey et al., J. Antibiotics (2004) 57:771 -779).</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000002_0001.png" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="Figure imgf000002_0001" class="patent-full-image" id="imgf000002_0001" src="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000002_0001.png" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="292" /></a></div>
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trioxacarcin A</div>
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An X-ray crystal structure of trioxacarcin A bound to N-7 of a guanidylate residue in a duplex DNA oligonucleotide substrate has provided compelling evidence for a proposed pathyway of DNA modification that proceeds by duplex intercalation and alkylation (Pfoh et al, Nucleic Acids Research 36( 10):3508-3514, 2008).</div>
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All trioxacarcins appear to be derivatives of the aglycone, which is itself a bacterial isolate referred to in the patent literature as DC-45-A2. U.S. Patent 4,459,291 , issued July 10, 1984, describes the preparation of DC-45-A<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span> by fermentation. DC-45-A2 is the algycone of trioxacarcins A, B, and C and is prepared by the acid hydrolysis of the fermentation products trioxacarcins A and C or the direct isolation from the fermentation broth of Streptomyces bottropensis.</div>
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Based on the biological activity of the trioxacarcins, a fully synthetic route to these compounds would be useful in exploring the biological and chemical activity of known trioxacarcin compounds and intermediates thereto, as well as aid in the development of new trioxacarcin compounds with improved biological and/or chemical properties.</div>
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PAPER</div>
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<strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Component-Based Syntheses of Trioxacarcin A, DC-45-A1, and Structural Analogs</strong><strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">T. Magauer</strong>, D. Smaltz, A. G. Myers, <em style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">Nat. Chem. </em><strong style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">2013</strong>, <em style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">5</em>, 886–893. (<a href="http://www.nature.com/nchem/journal/vaop/ncurrent/full/nchem.1746.html" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Link)</a></div>
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<a href="http://www.nature.com/nchem/journal/v5/n10/full/nchem.1746.html" style="border: 0px; color: #227ad1; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Component-based syntheses of <span class="highlight-entity-missing" style="border: 0px; font-size: 25.4736003875732px; margin: 0px; outline: 0px; padding: 0px;">trioxacarcin A</span>, DC-45-A1 and structural analogues</a></h2>
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<li class="vcard" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="name" href="http://www.nature.com/nchem/journal/v5/n10/fig_tab/nchem.1746_F4.html#auth-1" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Thomas Magauer</a><span class="comma" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">,</span></li>
<li class="vcard no-comma" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;"><a class="name" href="http://www.nature.com/nchem/journal/v5/n10/fig_tab/nchem.1746_F4.html#auth-2" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Daniel J. Smaltz</a></li>
<li class="vcard last-author c1 no-comma" style="border: 0px; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px;">& <a class="name" href="http://www.nature.com/nchem/journal/v5/n10/fig_tab/nchem.1746_F4.html#auth-3" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">Andrew G. Myers</a></li>
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<dl class="citation" style="border: 0px; font-size: 13.9200000762939px; margin: 0px 1.5em; outline: 0px; padding: 0px;"><dd class="journal-title" style="border: 0px; font-size: 13.9200000762939px; margin: 0px 0px 1em 1.5em; outline: 0px; padding: 0px;">Nature Chemistry5,886–893(2013)</dd><dd class="doi" style="border: 0px; font-size: 13.9200000762939px; margin: 0px 0px 1em 1.5em; outline: 0px; padding: 0px;">doi:10.1038/nchem.1746</dd></dl>
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AN 11-STEP SYNTHESIS OF <span class="highlight-entity-missing" style="border: 0px; font-size: 16.1471996307373px; margin: 0px; outline: 0px; padding: 0px;">TRIOXACARCIN A</span> WAS ACHIEVED BY THE CONVERGENT ASSEMBLY OF FIVE MODULAR COMPONENTS OF SIMILAR STRUCTURAL COMPLEXITY, EACH DENOTED WITH A COLOURED CIRCLE. THIS STRATEGY PROVIDES A GENERAL ROUTE TO ANALOGUES WITH DEEP-SEATED STRUCTURAL VARIATIONS. MOM, METHOXYMETHYL;<span class="highlight-entity-missing" style="border: 0px; font-size: 16.1471996307373px; margin: 0px; outline: 0px; padding: 0px;">BRBCAT</span>, <span class="highlight-entity-missing" style="border: 0px; font-size: 16.1471996307373px; margin: 0px; outline: 0px; padding: 0px;"><i style="border: 0px; font-size: 16.1471996307373px; margin: 0px; outline: 0px; padding: 0px;">B</i>-BROMOCATECHOLBORANE</span>.</div>
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PAPER</div>
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<img alt="A schematic shows a trioxacarcin C molecule, whose structure was revealed for the first time through a new process developed by the Rice lab of synthetic organic chemist K.C. Nicolaou. Trioxacarcins are found in bacteria but synthetic versions are needed to study them for their potential as medications. Trioxacarcins have anti-cancer properties. Source: Nicolaou Group/Rice University " class="caption-processed" src="http://www.dddmag.com/sites/dddmag.com/files/ddd1603_rice-anticancer.jpg" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" /></div>
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A schematic shows a trioxacarcin C molecule, whose structure was revealed for the first time through a new process developed by the Rice lab of synthetic organic chemist K.C. Nicolaou. Trioxacarcins are found in bacteria but synthetic versions are needed to study them for their potential as medications. Trioxacarcins have anti-cancer properties. Source: Nicolaou Group/Rice University</div>
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A team led by Rice University synthetic organic chemist K.C. Nicolaou has developed a new process for the synthesis of a series of potent anti-cancer agents originally found in bacteria.</div>
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The Nicolaou lab finds ways to replicate rare, naturally occurring compounds in larger amounts so they can be studied by biologists and clinicians as potential new medications. It also seeks to fine-tune the molecular structures of these compounds through analog design and synthesis to improve their disease-fighting properties and lessen their side effects.</div>
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Such is the case with their synthesis of trioxacarcins, reported this month in the Journal of the American Chemical Society.</div>
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PAPER</div>
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PATENT</div>
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<a href="http://www.google.com/patents/EP2550285A1?cl=en" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">http://www.google.com/patents/EP2550285A1?cl=en</a></div>
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(S)-9-Hvdrox v- 10-methoxy-5-(4-methoxybenzylox v)- 1 -(methoxymethox y)-3- methyl-8-oxo-5,6.7.8-tetrahvdroanthracene-2-carbaldehvde. Potassium osmate dihydrate (29 mg, 0.079 mmol, 0.05 equiv) was added to an ice -cooled mixture of (S,£)-9-hydroxy- 10- methoxy-4-(4-methoxybenzyloxy)-8-(methoxymethoxy)-6-methyl-7-(prop- l -enyl)-3,4- dihydroanthracen-l -one (780 mg, 1.58 mmol, 1 equiv), 2,6-lutidine (369 μί, 3.17 mmol, 2.0 equiv), and sodium periodate ( 1.36 g, 6.33 mmol, 4.0 equiv) in a mixture of tetrahydrofuran (20 mL) and water ( 10 mL). After 10 min, the cooling bath was removed and the reaction flask was allowed to warm to 23 °C. After 1.5 h, the reaction mixture was partitioned between water ( 100 mL) and ethyl acetate (150 mL). The layers were separated. The organic layer was washed with aqueous sodium chloride solution (50 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (20% ethyl acetate- hexanes) to provide 498 mg of the product, (5)-9-hydroxy- 10-methoxy-5-(4- methoxybenzyloxy)- l -(methoxymethoxy)-3-methyl-8-oxo-5,6,7,8-tetrahydroanthracene-2- carbaldehyde, as an orange foam (65%). Ή NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>): 15.17 (s, 1 H), 10.74 (s, 1 H), 7.66 (s, 1 H), 7.27 (d, 2H, 7 = 8.5 Hz), 6.86 (d, 2H, 7 = 8.6 Hz), 5.30-5.18 (m, 3H), 4.63 (d, 1H,7= 11.1 Hz), 4.52 (d, 1H,7 = 12.0 Hz), 3.86 (s, 3H), 3.79 (s, 3H), 3.62 (s, 3H), 3.22 (m, 1H), 2.75 (s, 3H), 2.63 (m, 1H), 2.54 (m, 1H), 2.08 (m, 1H). <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">I3</span>C NMR (125 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>): 204.9, 193.2, 163.2, 161.7, 159.2, 144.4, 141.7, 137.0, 130.1, 129.4, 120.7, 117.9, 113.8, 110.0, 102.8, 70.4, 67.2, 62.9, 58.3, 55.2, 32.3, 26.3, 22.2. FTIR, cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">-1</span> (thin film): 2936 (m), 2907 (m), 1684 (s), 1611 (s), 1377 (s), 1246 (s). HRMS (ESI): Calcd for</div>
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(C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">27</span>H2808+K)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span>: 519.1416; Found 519.1368. TLC (20% ethyl acetate-hexanes): R,= 0.17 (CAM).</div>
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86% yield</div>
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[00457] (S)-l,9-Dihvdroxy-10-methoxy-5-(4-methoxybenzyloxy)-3-methyl-8-oxo-5,6,7,8- tetrahydroanthracene-2-carbaldehyde. A solution of B-bromocatecholborane (418 mg, 2.10 mmol, 2.0 equiv) in dichloromethane (15 mL) was added to a solution of (S)-9-hydroxy-10- methoxy-5-(4-methoxybenzyloxy)-l-(methoxymethoxy)-3-methyl-8-oxo-5,6,7,8- tetrahydroanthracene-2-carbaldehyde (490 mg, 1.05 mmol, 1 equiv) in dichloromethane (15 mL) at -78 °C. After 50 min, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (25 mL) and dichloromethane (100 mL). The cooling bath was removed, and the partially frozen mixture was allowed to warm to 23 °C. The biphasic mixture was diluted with 0.2 M aqueous sodium hydroxide solution (100 mL). The layers were separated. The aqueous layer was extracted with dichloromethane (100 mL). The organic layers were combined. The combined solution was washed sequentially with 0.1 M aqueous hydrochloric acid solution (100 mL), water (2 x 100 mL), then saturated aqueous sodium chloride solution (100 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to provide 380 mg of the product, (S)-\ ,9- dihydroxy-10-methoxy-5-(4-methoxybenzyloxy)-3-methyl-8-oxo-5,6,7,8- tetrahydroanthracene-2-carbaldehyde, as a yellow foam (86%). Ή NMR (500 MHz, CDCI3):</div>
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15.89 (brs, 1H), 12.81 (br s, 1H), 10.51 (s, 1H), 7.27-7.26 (m, 3H), 6.86 (d, 2H, J = 9.2 Hz), 5.14 (app s, 1H),4.62 (d, \H,J= 11.0 Hz), 4.51 (d, 1H,7= 11.0 Hz), 3.85 (s, 3H), 3.80 (s, 3H), 3.21 (m, 1H), 2.73 (s, 3H), 2.62 (m, 1H), 2.54 (m, 1H), 2.07 (m, 1H). <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">I3</span>C NMR (125 MHz, CDCI3): 204.4, 192.7, 166.6, 164.3, 159.3, 144.4, 142.7, 137.9, 130.4, 130.2, 129.4, 114.9, 114.2, 113.9, 113.8, 109.4, 70.4, 67.1,62.8, 55.3, 31.8, 26.5. FTIR, cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">-1</span> (thin film): 3316 (brw), 2938 (m), 1678 (m), 1610 (s), 1514 (m), 1393 (m), 1246 (s). HRMS (ESI): Calcd for (C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">25</span>H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">24</span>0<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">7</span>+Na)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span>459.1414; Found 459.1354. TLC (50% ethyl acetate-hexanes): R = 0.30 (CAM).</div>
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[00458] (5)-2,2-Di-/erf-butyl-7-methoxy-8-(4-methoxybenzyloxy)-5-methyl- 1 1 -oxo- 8,9, 10, 1 1 -tetrahydroanthra[9, 1 -de \ 1 ,3,21dioxasiline-4-carbaldehyde. Όι<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">‘</span>-tert- butyldichlorosilane (342 μL·, 1.62 mmol, 1.8 equiv) was added to a solution of (5)-l ,9- dihydroxy- 10-methoxy-5-(4-methoxybenzyloxy)-3-methyl-8-oxo-5,6,7,8- tetrahydroanthracene-2-carbaldehyde (380 mg, 0.90 mmol, 1 equiv), hydroxybenzotriazole (60.8 mg, 0.45 mmol, 0.50 equiv) and diisopropylethylamine (786 μί, 4.50 mmol, 5.0 equiv) in dimethylformamide (30 mL). The reaction flask was heated in an oil bath at 55 °C. After 2 h, the reaction flask was allowed to cool to 23 °C. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (150 mL). The layers were separated. The organic layer was washed sequentially with water (2 x 100 mL) then saturated aqueous sodium chloride solution (100 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (10% ethyl acetate- hexanes) to provide 285 mg of the product, (S)-2,2-di-/<?ri-butyl-7-methoxy-8-(4- methoxybenzyloxy)-5-methyl- 1 1 -oxo-8,9, 10, 1 1 -tetrahydroanthra[9, 1 -de] [ 1 ,3,2]dioxasiline-4- carbaldehyde, as a yellow foam (56%). The enantiomeric compound (/?)-2,2-di-½ri-butyl-7- methoxy-8-(4-methoxybenzyloxy)-5-methyl- l 1 -oxo-8,9, 10, 1 1 -tetrahydroanthra[9, 1 – i/e][ l ,3,2]dioxasiline-4-carbaldehyde has been prepared using the same route by utilizing R- (4-methoxybenzyloxy)cyclohex-2-enone as starting material. Ή NMR (500 MHz, CDCI3): 10.84 (s, 1 H), 7.37 (s, 1 H), 7.25 (d, 2H, J = 8.8 Hz), 6.85 (d, 2H, = 8.7 Hz), 5.20 (app s, 1 H), 4.62 (d, 1 H, 7 = 10.0 Hz), 4.51 (d, 1H, J = 1 1.4 Hz), 3.88 (s, 3H), 3.78 (s, 3H), 3.03 (m, 1H), 2.73 (s, 3H), 2.57-2.53 (m, 2H), 2.07 (m, 1H), 1.16 (s, 9H), 1.14 (s, 9H). <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">13</span>C NMR (125 MHz, CDCl<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>): 195.6, 190.9, 160.5, 159.2, 150.4, 145.7, 140.4, 134.0, 133.9, 130.3, 129.4, 1 19.5, 1 16.6, 1 15.8, 1 15.3, 1 13.8, 70.4, 67.8, 62.9, 55.2, 34.0, 26.0, 26.0, 22.5, 21.3, 21.1. FTIR, cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">“1</span> (thin film): 2936 (m), 2862 (m), 1682 (s), 1607 (s), 1371 (s), 1244 (s) 1057 (s). HRMS (ESI): Calcd for (C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>3H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>o0<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">7</span>Si+H)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 577.2616; Found 577.2584. TLC (10% ethyl acetate-hexanes): R/ = 0.19 (CAM). Alternative Routes to (4S,6S)-6-(½rt-Butyldimethylsilyloxy)-4-(4-methoxybenzyloxy) cyclohex-2-enone.</div>
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Alternative Route 1.</div>
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[00459] (25,45,55)-2,4-Bis(ferf-butyldimethylsilyloxy)-5-hvdroxycvclohexanone. Dess- Martin periodinane (6.1 1 g, 14.4 mmol, 1.1 equiv) was added to a solution of diol (5.00 g, 13.3 mmol, 1 equiv) in tetrahydrofuran (120 mL) at 23 °C (Lim, S. M.; Hill, N.; Myers, A. G. J. Am. Chem. Soc. 2009, 131, 5763-5765). After 40 min, the reaction mixture was diluted with ether (300 mL). The diluted solution was filtered through a short plug of silica gel (-5 cm) and eluted with ether (300 mL). The filtrate was concentrated. The bulk of the product was transformed as outlined in the following paragraph, without purification. Independently,</div>
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s</div>
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an analytically pure sample of the product was obtained by flash-column chromatography (20% ethyl acetate-hexanes) and was characterized by Ή NMR, <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">l 3</span>C NMR, IR, and HRMS. TLC: (17% ethyl acetate-hexanes) R = 0.14 (CAM); Ή NMR (500 MHz, CDCI3) δ: 4.41 (dd, 1 H, 7 = 9.8, 5.5 Hz), 4.05 (m, l H), 4.00 (m, 1H), 2.81 (ddd, 1 H, 7 = 14.0, 3.7, 0.9 Hz), 2.52 (ddd, 1 H, 7 = 14.0, 5.3, 0.9 Hz), 2.29 (br s, 1 H), 2.18 (m, 1H), 1.98 (m, 1 H), 0.91 (s, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.1 1 (s, 3H), 0.09 (s, 3H), 0.04 (s, 3H); <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">l 3</span>C NMR (125 MHz, CDCI3) δ: 207.9, 73.9, 73.3, 70.5, 43.3, 39.0, 25.7, 25.6, 18.3, 17.9, -4.7, -4.8, -4.9, -5.4; FTIR (neat), cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">“</span>‘ : 3356 (br), 2954 (m), 2930 (m), 2857 (m), 1723 (m), 1472 (m). 1253 (s), 1 162 (m), 1 105 (s), 1090 (s), 1059 (s), 908 (s), 834 (s), 776 (s), 731 (s); HRMS (ESI): Calcd for (C|<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">8</span>H380<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>Si2+H)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 375. 2381 , found 375.2381.</div>
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[00460] (4 ,6 )-4.6-Bis(fcr/-butyldimethylsilyloxy)cvclohex-2-enone. Trifluoroacetic anhydride (6.06 mL, 43.6 mmol, 3.3 equiv) was added to an ice-cooled solution of the alcohol ( 1 equiv, see paragraph above) and triethylamine ( 18.2 mL, 131 mmol, 9.9 equiv) in dichloromethane (250 mL) at 0 °C. After 20 min, the cooling bath was removed and the reaction flask was allowed to warm to 23 °C. After 18 h, the reaction flask was cooled in an ice bath at 0 °C, and the product solution was diluted with water ( 100 mL). The cooling bath was removed and the reaction flask was allowed to warm to 23 °C. The layers were separated. The aqueous layer was extracted with dichloromethane (2 x 200 mL). The organic layers were combined. The combined solution was washed with saturated aqueous sodium chloride solution ( 100 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash- column chromatography (6% ethyl acetate-hexanes) to provide 3.02 g of the product, (4S,65)-4,6-bis(/eri-butyldimethylsilyloxy)cyclohex-2-enone, as a colorless oil (64% over two steps). TLC: (20% ethyl acetate-hexanes) R = 0.56 (CAM); Ή NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 6.76 (dd, 1 Η, / = 10.1 , 3.6 Hz), 5.88 (d, 1 H, 7 = 10.1 Hz), 4.66 (ddd, 1 H, 7 = 5.6, 4.1 , 3.6 Hz), 4.40 (dd, 1 H, 7 = 8.1 , 3.7 Hz), 2.26 (ddd, 1 H, / = 13.3, 8.0, 4.1 Hz), 2.1 1 (ddd, 1 H, J = 13.2, 5.6, 3.8 Hz), 0.91 (s, 9H), 0.89 (s, 9H), 0.12 (s, 3H), 0. 1 1 (s, 3H), 0. 10 (s, 3H), 0.10 (s, 3H); <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">13</span>C NMR ( 125 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 197.5, 150.3, 127.0, 71 .0, 64.8, 41.6, 25.7, 25.7, 18.3, 18.1 , -4.7, -4.8, -4.8, -5.4; FTIR (neat), cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">-1</span> : 3038 (w), 2955 (m), 2930 (m), 1705 (m), 1472 (m), 1254 (m), 1084 (m), 835 (s), 777 (s), 675 (s); HRMS (ESI): Calcd for (C,8H360<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>Si2+Na)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 379. 2095, found 379. 2080.</div>
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[00461] (4S,6S)-6-(/er/-Butyldimethylsilyloxy)-4-hydroxycvclohex-2-enone. Tetra- j- butylammonium fluoride ( 1 .0 M solution in tetrahydrofuran, 8.00 mL, 8.00 mmol, 1 .0 equiv) was added to an ice-cooled solution of the enone (2.85 g, 8.00 mmol, 1 equiv) and acetic acid (485 ί, 8.00 mmol, 1 .0 equiv) in tetrahydrofuran (80 mL) at 0 °C. After 2 h, the cooling bath was removed and the reaction flask was allowed to warm to 23 °C. After 22 h, the reaction mixture was partitioned between water ( 100 mL) and ethyl acetate (300 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 300 mL). The organic layers were combined. The combined solution was washed sequentially with saturated aqueous sodium bicarbonate solution ( 100 mL) then saturated aqueous sodium chloride solution ( 100 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash- column chromatography (25% ethyl acetate-hexanes) to provide 760 mg of the product, (4S,6S)-6-(ferNbutyldimethylsilyloxy)-4-hydroxycyclohex-2-enone, as a white solid (39%). TLC: (20% ethyl acetate-hexanes) R/ = 0.20 (CAM); Ή NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 6.87 (dd, 1 Η, 7 = 10.2, 3.2 Hz), 5.95 (dd, 1H, J = 10.3, 0.9 Hz), 4.73 (m, 1 H), 4.35 (dd, 1 H, 7 = 7.6, 3.7 Hz), 2.39 (m, 1 H), 2. 13 (ddd, 1 H, J = 13.3, 6.2, 3.4 Hz), 1.83 (d, 1 H, J = 6.2), 0.89 (s, 9H), 0.10 (s, 3H), 0. 10 (s, 3H); <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">13</span>C NMR ( 125 MHz, CDCb) δ: 197.3, 150.0, 127.5, 70.9, 64.2, 41 .0, 25.7, 18.2, -4.8, -5.4; FTIR (neat), cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">“1</span> : 2956 (w), 293 1 (w), 2858 (w), 1694 (m); HRMS (ESI): Calcd for (C |<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>H220<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>Si+H)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 243.141 1 , found 243. 1412.</div>
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82″:.</div>
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[00462] (45.6S)-6-(fgrf-Butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)cvclohex-2- enone. Triphenylmethyl tetrafluoroborate ( 16 mg, 50 μπιοΐ, 0.050 equiv) was added to a solution of 4-methoxybenzyl-2,2,2-trichloroacetimidate (445 μΙ_, 2.5 mmol, 2.5 equiv) and alcohol (242 mg, 1 .0 mmol, 1 equiv) in ether ( 10 mL) at 23 °C. After 4 h, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution ( 15 mL) and ethyl acetate (50 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined. The combined solution was washed with water (2 x 20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (5% ethyl acetate-hexanes initially, grading to 10% ethyl acetate-hexanes) to provide 297 mg of the product, (4S,6S)-6-(im-butyldimethylsilyloxy)-4-(4- methoxybenzyloxy)cyclohex-2-enone, as a colorless oil (82%).</div>
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Alternative Route 2.</div>
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[00463] (5)-?erf-Butyl(4-(4-methoxybenzyloxy)cvclohexa- 1.5-dienyloxy)dimethylsilane. rerr-Butyldimethylsilyl trifluoromethanesulfonate (202 iL, 0.94 mmol, 2.0 equiv) was added to an ice-cooled solution of triethylamine (262 μί, 1.88 mmol, 4.0 equiv) and enone ( 109 mg, 0.47 mmol, 1 equiv) in dichloromethane (5.0 mL). After 30 min, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution ( 10 mL), water (30 mL), and dichloromethane (40 mL). The layers were separated. The organic layer was washed sequentially with saturated aqueous ammonium chloride solution (20 mL) then saturated aqueous sodium chloride solution (20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography with triethylamine-treated silica gel (5% ethyl acetate-hexanes), to provide 130 mg of the product, (5)-ierr-butyl(4-(4- methoxybenzyloxy)cyclohexa- l ,5-dienyloxy)dimethylsilane, as a colorless oil (80%). Ή</div>
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NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>): 7.27 (d, 2H, J = 8.7 Hz), 6.88 (d, 2H, J = 8.6 Hz), 5.96 (dd, 1 H, J = 9.9, 3.5 Hz), 5.87 (d, 1 H, 7 = 9.6 Hz), 4.94 (m, l H), 4.46 (s, 2H), 4.14 (m, 1 H), 3.81 (s, 3H), 2.49 (m, 2H), 0.93 (s, 9H), 0. 16 (s, 3H), 0.15 (s, 3H). <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">, 3</span>C NMR ( 125 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>): 159.1 , 147.5, 130.9, 129.2, 128.6, 128.1 , 1 13.8, 101.4, 70.2, 69.0, 55.3, 28.5, 25.7, 18.0, ^1.5, -4.5. FTIR, cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">-1</span> (thin film): 2957 (m), 2931 (m), 2859 (m), 1655 (w), 1613 (w), 1515 (s), 1248 (s), 1229 (s), 1037 (m), 910 (s). HRMS (ESI): Calcd for (C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>oH3o0<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>Si+H)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 347.2037; Found 347.1912. TLC (20% ethyl acetate-hexanes): R = 0.74 (CAM).</div>
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OP B OPMB DM 00 ,,Α,,</div>
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c Ύ’<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">“</span> -ietone ii ·η- ) ‘”OH</div>
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OTBS 82 <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">Q</span></div>
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[00464] (4S,6S)-6-Hvdroxy-4-(4-methoxybenzyloxy)cvclohex-2-enone. A solution of dimethyldioxirane (0.06 M solution in acetone, 2.89 mL, 0.17 mmol, 1.2 equiv) was added to an ice-cooled solution of (S)-ieri-butyl(4-(4-methoxybenzyloxy)cyclohexa- l ,5- dienyloxy)dimethylsilane (50 mg, 0.14 mmol, 1 equiv). After 10 min, the reaction mixture was partitioned between dichloromethane ( 15 mL) and 0.5 M aqueous hydrochloric acid ( 10 mL). The layers were separated. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution ( 10 mL) then water ( 10 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography to provide 30 mg of the product, (4S,6S)-6-hydroxy-4-(4-methoxybenzyloxy)cyclohex-2-enone, as a colorless oil (82%). Ή NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>): 7.28 (d, 2H, J = 8.2 Hz), 6.89 (m, 3H), 6.09 (d, 1 H, J = 10.1 Hz), 4.64 (m, 2H), 4.53 (d, 1 H, 7 = 1 1 .4 Hz), 4.24 (m, 1 H), 3.81 (s, 3H), 3.39 (d, 1 H, 7 = 1.4 Hz), 2.67 (m, 1 H), 1 .95 (ddd, 1 H, 7 = 12.8, 12.8, 3.6 Hz). <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">I 3</span>C NMR ( 125 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>): 200.4, 159.5, 146.6, 129.7, 129.4, 127.8, 1 14.0, 71.6, 69.8, 68.9, 55.3, 35.1 . FTIR, cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">-1</span> (thin film): 3474 (br), 2934 (m), 2864 (m), 1692 (s), 1613 (m), 1512 (s), 1246 (s), 1059 (s), 1032 (s). HRMS (ESI): Calcd for (C,<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">l6</span>O<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>+Na)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 271.0941 ; Found 271.0834. TLC (50% ethyl acetate-hexanes): R/ = 0.57 (CAM).</div>
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[00465] (45,65)-6-(½rt-Butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)cvclohex-2- enone. rerr-Butyldimethychlorosilane (26 mg, 0.18 mmol, 1.5 equiv) was added to an ice- cooled solution of (45,65)-6-hydroxy-4-(4-methoxybenzyloxy)cyclohex-2-enone (29 mg, 0.12 mmol, 1 equiv) and imidazole (24 mg, 0.35 mmol, 3 equiv) in dimethylformamide (0.5 mL). After 45 min, the reaction mixture was partitioned between water (15 mL), saturated aqueous sodium chloride solution (15 mL), and ethyl acetate (20 mL). The layers were separated. The organic layer was washed with water (2 x 20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography to provide 29 mg of the product, (4S,6S)-6-(rm-butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)cyclohex-2- enone, as a colorless oil (87%).</div>
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Glycosylation experiments</div>
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[00466] Glycosylation experiments demonstrate that the chemical process developed allows for the preparation of synthetic, glycosylated trioxacarcins. Specifically, the C4 or CI 3 hydroxyl group may be selectively glycosylated with a glycosyl donor (for example, a glycosyl acetate) and an activating agent (for example, TMSOTf), which enables preparation of a wide array of trioxacarcin analogues.</div>
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Selective Glycosylation of the C4 Hydroxyl Group</div>
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[00467] 2,3-Dichloro-5,6-dicyanobenzoquinone ( 19.9 mg, 88 μιτιοΐ, 1.1 equiv) was added to a vigorously stirring, biphasic solution of differentially protected trioxacarcin precursor (60 mg, 80 μιτιοΐ, 1 equiv) in dichloromethane ( 1.1 mL) and pH 7 phosphate buffer (220 μί) at 23 °C. The reaction flask was covered with aluminum foil to exclude light. Over the course of 3 h, the reaction mixture was observed to change from myrtle green to lemon yellow. The product solution was partitioned between water (5 mL) and dichloromethane (50 mL). The layers were separated. The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by preparatory HPLC (Agilent Prep-C 18 column, 10 μιτι, 30 x 150 mm, UV detection at 270 nm, gradient elution with 40→90% acetonitrile in water, flow rate: 15 mL/min) to provide 33 mg of the product as a yellow-green powder (65%).</div>
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[00468] Trimethylsilyl triflate ( 10% in dichloromethane, 28.3 μί, 16 μπιοΐ, 0.3 equiv) was added to a suspension of deprotected trioxacarcin precursor (33 mg, 52 μπιοΐ, 1 equiv), 1 -0- acetyltrioxacarcinose A ( 14.1 mg, 57 μιτιοΐ, 1.1 equiv), and powdered 4- A molecular sieves (-50 mg) in dichloromethane (1 .0 mL) at -78 °C. After 5 min, the mixture was diluted with dichloromethane containing 10% triethylamine and 10% methanol (3 mL). The reaction flask was allowed to warm to 23 °C. The mixture was filtered and partitioned between</div>
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dichloromethane (40 mL) and saturated aqueous sodium chloride solution (5 mL). The layers were separated. The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by preparatory HPLC (Agilent Prep-C 18 column, 10 μπι, 30 x 150 mm, UV detection at 270 nm, gradient elution with 40→90% acetonitrile in water, flow rate: 15 mL/min) to provide 20 mg of the product as a yellow-green powder (47%). TLC: (5% methanol-dichloromethane) R = 0.40 (CAM); Ή NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 7.47 (s, 1H), 5.38 (d, 1H, J = 3.6 Hz), 5.35 (app s, 1 H), 5.26 ppm (d, 1 H, 7 = 4.0 Hz), 4.84 (d, 1 H, J = 4.0 Hz), 4.78 (dd, 1 H, 7 = 12.3, 5.2 Hz), 4.75 (s, 1H), 4.71 (s, 1 H), 4.52 (q, 1H, J = 6.6 Hz), 3.86 (s, 1 H), 3.83 (s, 3H), 3.62 (s, 3H), 3.47 (s, 3H), 3.15 (d, l H, y = 5.3 Hz), 3.05 (d, 1 H, 7 = 5.3 Hz), 2.60 (s, 3H), 2.58 (m, 1H), 2.35 (m, 1 H), 2.14 (s, 3H), 1.96 (dd, 1 H, 7 = 14.6, 4.1 Hz), 1.62 (d, 1 H, 7 = 14.6 Hz), 1.26 (s, 1 H), 1.23 (d, 3H, J = 6.6 Hz), 1.08 (s, 3H), 0.95 (s, 9H), 0.24 (s, 3H), 0.16 (s, 3H); ‘<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">3</span>C NMR ( 125 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) 6: 202.8, 170.5, 163.2, 151.8, 144.4, 142.4, 135.2, 126.6, 1 16.8, 1 15.2, 1 15.1 , 108.3, 104.0, 100.3, 98.6, 98.3, 74.6, 73.4, 69.8, 69.5, 69.5, 68.9, 69.5, 69.5, 68.9, 68.4, 62.9, 62.7, 57.2, 56.8, 50.7, 38.8, 36.8, 26.0, 25.9, 21.1 , 20.6, 18.6, 17.0, -4.2, -5.3; FTIR (neat), cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">“</span>‘ : 2953 (w), 2934 (w), 2857 (w), 1749 (w), 1622 (m), 1570 (w), 1447 (w), 1391 (m), 1321 (w), 1294 (w), 1229 (m), 1 159 (m), 1 121 (s), 1084 (s), 1071 (m), 1020 (m), 995 (s), 943 (s), 868 (m), 837 (m), 779 (m); HRMS (ESI): Calcd for (C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>oH<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">54</span>0i<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">6</span>Si+Na)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 841.3073, found</div>
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841.3064.</div>
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Glycosylation of a Cycloaddition Coupling Partner</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000155_0001.png" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="Figure imgf000155_0001" class="patent-full-image" id="imgf000155_0001" src="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000155_0001.png" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="392" /></a></div>
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[00469] 2,3-Dichloro-5,6-dicyanobenzoquinone ( 14.3 mg, 63 μπιοΐ, 1.2 equiv) was added to a vigorously stirring, biphasic solution of differentially protected aldehyde (37 mg, 52 μιτιοΐ, 1 equiv) in dichloromethane (870 μί) and water (175 μί) at 23 °C. The reaction flask was covered with aluminum foil to exclude light. Over the course of 2 h, the reaction mixture was observed to change from myrtle green to lemon yellow. The product solution was partitioned between water (5 mL) and dichloromethane (40 mL). The layers were separated. The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash-column chromatography (5% ethyl acetate-hexanes initially, grading to 10% ethyl acetate-hexanes) to provide 28 mg of the product as a yellow powder (91 %). TLC: (20% ethyl acetate-hexanes) R/ = 0.37 (CAM); Ή NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 10.83 (s, 1H), 7.30 (s, 1 H), 5.45 (m, 1H), 4.68 (dd, 1H, / = 10.3, 4.2 Hz), 3.97 (s, 3H), 3.31 (brs, 1H), 2.72 (s, 3H), 2.51-2.45 (m, 1H), 2.41-2.37 (m, 1H), 1.15 (s, 9H), 1 , 13 (s, 9H), 0.88 (s, 9H), 0.15 (s, 3H), 0.1 1 (s, 3H); <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">l 3</span>C NMR (125 MHz, CDCI3) δ: 194.6, 191 , 160.5, 150.2, 146, 140.8, 135.8, 134, 1 19.6, 1 16.2, 1 15.4, 1 14.7, 72.7, 63.7, 62.4, 38.8, 29.9, 62.4, 38.8, 63.7, 62.4, 38.8, 63.7, 62.4, 38.8, 29.9, 26.2, 26.1 , 26, 22.7, 21.4; FTIR (neat), cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">“1</span> : 3470 (br, w), 2934 (w), 2888 (w), 1684 (s), 1607 (s), 1560 (w), 1472 (m), 1445 (w), 1392 (m), 1373 (s), 1242 (s), 1 153 (s), 1 1 19 (w), 1074 (m), 1044 (s), 1013 (s), 982 (w), 934 (m), 907 (w), 870 (m), 827 (s), 795 (s), 779 (s), 733 (s), 664 (s); HRMS (ESI): Calcd for (C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>iH<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">46</span>0<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">7</span>Si<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>+H)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 587.2855, found 587.2867.</div>
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[00470] Trimethylsilyl triflate (10% in dichloromethane, 25.9 μί, 14 μπιοΐ, 0.3 equiv) was added to a suspension of deprotected aldehyde (28 mg, 48 μηιοΐ, 1 equiv), 1-0- acetyltrioxacarcinose A (12.9 mg, 52 μπιοΐ, 1.1 equiv), and powdered 4-A molecular sieves (-50 mg) in dichloromethane ( 1.0 mL) at -78 °C. After 5 min, the mixture was diluted with dichloromethane containing 10% triethylamine and 10% methanol (3 mL). The reaction flask was allowed to warm to 23 °C. The mixture was filtered and partitioned between dichloromethane (40 mL) and saturated aqueous sodium chloride solution (5 mL). The layers were separated. The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by preparatory HPLC (Agilent Prep-C 18 column, 10 μπι, 30 x 150 mm, UV detection at 270 nm, gradient elution with 80→98% acetonitrile in water, flow rate: 15 mL/min) to provide 15 mg of the product as a yellow powder (41 %). TLC: (20% ethyl acetate-hexanes) R/ = 0.29 (CAM); Ή NMR (500 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 10.83 (s, 1 H), 7.32 (s, 1 H), 5.43 (d, 1 H, J = 3.9 Hz), 5.32 (m, 1H), 4.74 (s, 1 H), 4.67 (dd, 1 H, J = 12.3, 5.0 Hz), 4.54 (q, 1H, J = 6.6 Hz), 3.91 (s, 1H), 3.88 (s, 3H), 2.72 (s, 3H), 2.59 (ddd, 1 H, J = 13.8, 5.0, 3.2 Hz), 2.34 (m, 1H), 2.14 (s, 3H), 1.97 (dd, 1H, J = 14.2, 4.2 Hz), 1.71 (d, 1 Η, / = 14.6 Hz), 1.22 (d, 3H, J = 6.3 Hz), 1.15 (s, 9H), 1.15 (s, 9H), 1.08 (s, 3H), 0.93 (s, 9H), 0.23 (s, 3H), 0.13 (s, 3H); <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">13</span>C NMR (125 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 193.9, 191.0, 170.5, 146.4, 140.9, 134.0, 132.4, 1 19.8, 1 16.8, 1 15.8, 1 15.0, 1 10.8, 99.6, 74.6, 71.5, 70.4, 68.9, 62.9, 62.7, 39.1 , 36.9, 26.2, 26.1 , 26.1 , 25.9, 24.1 , 22.7, 21.5, 21.3, 21.1 , 18.7, 16.9, -4.1 , -5.3; FTIR (neat), cm<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">-1</span> : 3524 (br, w), 2934 (m), 2861 (m), 1749 (m), 1686 (s), 1607 (s), 1560 (m), 1474 (m), 1447 (m), 1424 (w), 1375 (s), 1233 (s), 1 159 (s), 1 1 17 (m), 1080 (m), 1049 (s), 1015 (s), 997 (s), 937 (m), 883 (m), 872 (m), 827 (s), 797 (m), 781 (m), 737 (w), 677 (w), 667 (m); HRMS (ESI): Calcd for (C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">40</span>H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">60</span>O, ,Si<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>+H)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span>773.3747, found 773.3741.</div>
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General Glycosylation Procedure of the C13 Hydroxyl Group</div>
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[00471] Crushed 4-A molecular sieves (-570 mg / 1 mmol sugar donor) was added to a stirring solution of the sugar acceptor (1 equiv.) and the sugar donor (30.0 equiv.) in dichloromethane ( 1.6 mL / 1 mmol sugar donor) and diethylether (0.228 mL / 1 mmol sugar donor) at 23 °C. The bright yellow mixture was stirred for 90 min at 23 °C and finally cooled to -78 °C. TMSOTf (10.0 equiv.) was added over the course of 10 min at -78 °C. After 4 h, a second portion of TMSOTf (5.0 equiv.) was added at -78 °C and stirring was continued for 1 h. The last portion of TMSOTf (5 equiv.) was added. After 1 h, triethylamine (20 equiv.) was added and the reaction the product mixture was filtered through a short column of silica gel deactivated with triethylamine (30% ethyl acetate-hexanes initially, grading to 50% ethyl acetate-hexanes). H NMR analysis of the residue showed minor sugar donor remainings and that the sugar acceptor had been glycosylated. The residue was purified by preparatory HPLC (Agilent Prep-C 18 column, 10 μπι, 30 x 150 mm, UV detection at 270 nm, gradient elution with 40→100% acetonitrile in water, flow rate: 15 mL/min) to provide the glycosylation product as a bright yellow oil</div>
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Three Specific Compounds Prepared by the General Glycosylation Procedure for the CI 3 Hydroxyl Group:</div>
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<a href="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000157_0001.png" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="Figure imgf000157_0001" class="patent-full-image" id="imgf000157_0001" src="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000157_0001.png" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="176" /></a></div>
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[00472] 10% yield; TLC: (50% ethyl acetate-hexane) R = 0.58 (UV, CAM); Ή NMR (600 MHz, CDC1<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>) δ: 7.43 (s, 1 H), 5.84 (t, J = 3.6 Hz, 1 H), 5.29 (d, J = 4.2 Hz, 1 H), 5.19 (d, J = 4.2 Hz, 1 H), 5.01 (q, J = 6.6 Hz, 1 H), 4.75 (t, J = 3.6 Hz, 1 H), 4.73 (s, 1 H), 3.88 (s, OH), 3.77 (s, 3H), 3.63 (s, 3H), 3.47 (s, 3H), 3.03 (app q, J = 5.4 Hz, 2H), 2.84 (d, J = 6.0 Hz, 1 H), 2.77 (d, J = 6.0 Hz, 1 H), 2.72 (t, J = 6.6 Hz, 2H), 2.58 (s, 3H), 2.36 (s, 3H), 2.33 (t, J = 3.0 Hz, 2H), 2.23 (s, 3H), 2.1 1 -2.06 (m, 2H), 1.08 (d, J = 6.0 Hz, 3H). <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">‘</span></div>
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<a href="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000157_0002.png" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;"><img alt="Figure imgf000157_0002" class="patent-full-image" id="imgf000157_0002" src="http://patentimages.storage.googleapis.com/WO2011119549A1/imgf000157_0002.png" style="border: none; font-size: 13.9200000762939px; margin: 0px; max-width: 100%; outline: 0px; padding: 0px;" width="200" /></a></div>
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[00473] 81 % yield, TLC: (50% ethyl acetate-hexane) R = 0.30 (UV, CAM); Ή NMR (600 MHz, CDCI3) δ: 7.46 (s, 1 H), 7.28 (d, J = 9 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2 H), 5.83 (dd, J = 3.6, 1.8 Hz, 1 H), 5.30 (d, J = 4.2 Hz, 1 H), 5.19 (d, J = 4.2 Hz, 1 H), 5.19 (m, 1 H), 5.00 (q, J = 6.0 Hz, 1 H), 4.96 (dd, J = 12.0, 4.8 Hz, 1 H), 4.75 (t, J = 3.6 Hz, 1 H), 4.74 (s, l H), 4.70 (d, y = 10.8 Hz, 1 H), 4.59 (d, J = 10.8 Hz, 1 H), 3.86 (s, OH), 3.83 (s, 3H), 3.80 (s, 3H), 3.63 (s, 3H), 3.47 (s, 3H), 2.81 (d, J = 6.0 Hz, 1 H), 2.73-2.68 (m, 1 H), 2.70 (d, J = 6.0 Hz, 1 H), 2.59 (s, 3H), 2.35 (s, 3H), 2.33-2.28 (m, 2H), 2.22 (s, 3H), 2.19- 2.1 3 (m, 1 H), 1 .08 (d, J = 6.0 Hz, 3H), 0.97 (s, 9H), 0.25 (s, 3H), 0.17 (s, 3H); HRMS (ESI): Calcd for (C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">4</span>9H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">62</span>0<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">18</span>Si+H)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 967.3778, found 967.3795; HRMS (ESI): Calcd for (C ¾<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span>0,<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">8</span>Si+Na)<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">+</span> 989.3598, found 989.3585.</div>
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[00474] Compound Detected by ESI Mass Spectrometry: Calculated Mass for</div>
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[C52H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">7</span>| N<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span>02i Si-Hr<span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">l</span> = 1 100.4277, Measured Mass = 1 100.4253.</div>
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PATENT</div>
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US 4511560</div>
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<a href="https://www.google.com/patents/US4511560" style="border: 0px; color: #227ad1; font-size: 13.9200000762939px; margin: 0px; outline: 0px; padding: 0px; text-decoration: none;">https://www.google.com/patents/US4511560</a></div>
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The physico-chemical characteristics of DC-45-A and DC-4-5-B<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span> according to this invention are as follows:</div>
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(1) DC-45-A</div>
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(1) Elemental analysis: H:5.74%, C:55.11%</div>
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(2) Molecular weight: 877</div>
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(3) Molecular formula: C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">42</span> H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">52</span> O<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">20</span></div>
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(4) Melting point: 180° C.±3° C. (decomposed)</div>
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(5) Ultraviolet absorption spectrum: As shown in FIG. 1 (in 50% methanol)</div>
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(6) Infrared absorption spectrum: As shown in FIG. 2 (KBr tablet method)</div>
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(7) Specific rotation: [α]<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">D</span> <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">25</span> =-15.3° (c=1.0, ethanol)</div>
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(8) PMR spectrum (in CDC]<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span> ; ppm): 1.07 (3H,s); 1.10 (3H, d, J=6.8); 1.24 (3H,d, J=6.5); many peaks between 1.40-2.30; 2.14 (3H,s); 2.49 (3H,s); 2.63 (3H,s); many peaks between 2.30-2.80; 2.91 (1H,d, J=5.6); 3.00 (1H,d, J=5.6); 3.49 (3H,s); 3.63 (3H,s); 3.85 (3H, s); many peaks between 3.60-4.00; 4.18 (1H,s); 4.55 (1H,q, J=6.8); many peaks between 4.70-4.90; 5.03 (1H, q, J=6.5); 5.25 (1H,d, J=4.0); 5.39 (1H, d, J=4.0); 5.87 (1H, m); 7.52 (1H,s); 14.1 (1H,s)</div>
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(9) CMR spectrum (in CDCl<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span> ; ppm): 210.9; 203.8; 170.3; 162.1; 152.5; 145.2; 142.3; 135.3; 126.7; 117.0; 114.2; 108.3; 105.3; 99.7; 97.2; 93.7; 85.1; 79.0; 74.6; 71.1; 69.6; 69.3; 68.8; 67.9; 66.3; 64.0; 62.8; 57.3; 55.9; 36.5; 32.2; 28.0; 25.7; 20.9; 20.2; 17.0; 14.7</div>
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(10) Solubility: Soluble in methanol, ethanol, water and chloroform; slightly soluble in acetone and ethyl acetate, and insoluble in ether and n-hexane</div>
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(2) DC-45-B<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">2</span></div>
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(1) Elemental analysis: H: 6.03%, C: 54.34%</div>
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(2) Molecular weight: 879</div>
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(3) Molecular formula: C<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">42</span> H<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">54</span> O<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">20</span></div>
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(4) Melting point: 181°-182° C. (decomposed)</div>
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(5) Ultraviolet absorption spectrum: As shown in FIG. 5 (in 95% ethanol)</div>
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(6) Infrared absorption spectrum: As shown in FIG. 6 (KBr tablet method)</div>
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(7) Specific rotation: [α]<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">D</span> <span style="border: 0px; bottom: 1ex; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; vertical-align: baseline;">25</span> =-10° (c=0.2, ethanol)</div>
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(8) PMR spectrum (in CDCl<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span> ; ppm): 1.07 (3H,s); many peaks between 1.07-1.5; many peaks between 1.50-2.80; 2.14 (3H,s); 2.61 (3H, broad s); 2.86 (1H, d, J=5.7); 2.96 (1H, d, J=5.7); 3.46 (3H,s); 3.63 (3H, s); 3.84 (3H, s); many peaks between 3.65-4.20; many peaks between 4.40-5.00; many peaks between 5.10-5.50; 5.80 (1H, broad s); 7.49 (1H, d, J=1.0); 14.1 (1H, s)</div>
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(9) CMR spectrum (in CDCl<span style="border: 0px; font-size: 0.7em; height: 0px; line-height: 1; margin: 0px; outline: 0px; padding: 0px; position: relative; top: 0.5ex; vertical-align: baseline;">3</span> ; ppm): 202.8; 170.2; 163.1; 151.8; 144.8; 142.9; 135.4; 126.5; 116.8; 114.9; 107.3; 104.6; 101.5; 99.6; 98.0; 94.4; 74.4; 72.5; 71.4; 70.4; 69.1; 68.8; 68.3; 67.9; 67.5; 66.4; 62.9; 62.7; 56.8; 56.5; 48.0; 36.7; 32.3; 25.7; 20.8; 20.3; 18.2; 16.9; 15.5</div>
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(10) Solubility: Soluble in methanol, ethanol, acetone, ethyl acetate and chloroform; slightly soluble in benzene, ether and water; and insoluble in n-hexane.</div>
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CC1C(C(CC(O1)OC2CC(C(=O)C3=C(C4=C5C(=C(C=C4C(=C23)OC)C)C6C7C(O5)(C8(CO8)C(O6)(O7)C(OC)OC)OC9CC(C(C(O9)C)(C(=O)C)O)O)O)O)(C)O)OC(=O)C</div>
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DRUG PATENTS INTERNATIONALhttp://www.blogger.com/profile/12652768774396889936noreply@blogger.com0