Showing posts with label New Drugs. Show all posts
Showing posts with label New Drugs. Show all posts

Thursday 4 February 2016

The Year In New Drugs ..........Speedier development and regulatory process contributed to a peak in product approvals in 2015

 09405-cover-graph

 
SURGE
New drug approvals have risen sharply in recent years. SOURCE: FDA

The Year In New Drugs

Speedier development and regulatory process contributed to a peak in product approvals in 2015
 
 
read at 
 Chemical & Engineering News
Volume 94 Issue 5 | pp. 12-17
Issue Date: February 1, 2016

http://cen.acs.org/articles/94/i5/Year-New-Drugs.html
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Saturday 26 October 2013

Aplastic Anemia




Aplastic anemia is a rare and potentially serious blood disorder in which the body's bone marrow doesn't make enough red blood cells, white blood cells, and platelets. In many people who have aplastic anemia, the cause is unknown but may be due to one of a number of causes (eg, toxins, cancer treatment, some medicines, infections, autoimmune disorders, pregnancy).  Treatments for aplastic anemia include blood transfusions, blood and marrow stem cell transplants, and medicines to stimulate bone marrow and to prevent infections. At present, there are no orphan drugs approved for aplastic anemia. For more information about aplastic anemia, visit http://www.nhlbi.nih.gov/health/health-topics/topics/aplastic/



Aplastic anemia is a syndrome of bone marrow failure characterized by peripheral pancytopenia and marrow hypoplasia, and mild macrocytosis is observed in association with stress erythropoiesis and an elevated fetal hemoglobin levels. Paul Ehrlich introduced the concept of aplastic anemia in 1888 when he studied the case of a pregnant woman who died of bone marrow failure. However, it was not until 1904 that Anatole Chauffard named this disorder aplastic anemia.
For excellent patient education resources, visit eMedicine‘s Blood and Lymphatic System Center. Also, see eMedicine’s patient education article Anemia.

Medication

The goals of pharmacotherapy in cases of aplastic anemia are to reduce morbidity, prevent complications, and eradicate malignancy.
Immunosuppressive Agents
The merits of additional immunosuppression versus the increased risk and cost should be considered. Data from a randomized prospective study indicated that an increased proportion of patients responded to the addition of CSA to ATG, but this did not translate into a long-term survival advantage.
For patients who cannot tolerate equine-based products, use of the commercially available rabbit-based ATG product (Thymoglobulin) may be considered. This product is currently approved in the United States and has been used for the treatment of aplastic anemia in Europe (although note the different dose schedule).

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease) for a variety of organs.
For children and adults, base the dosing on the ideal body weight. Frequent monitoring of drug levels is needed. To convert to the PO dose, use a IV-to-PO correction factor of 1:4. Dosage and duration of therapy may vary with different protocols.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions
Adult
1.5-2 mg/kg IV q12h, adjust to trough level of 500-800 ng/mL in mo 1 or so; then adjust to trough level of 200 ng/mL
Pediatric
Administer as in adults.

Methylprednisolone (Medrol, Solu-Medrol)

Steroids ameliorate the delayed effects of anaphylactoid reactions and may limit biphasic anaphylaxis. In severe serum sickness (mediated by immune complexes), parenteral steroids may reduce the inflammatory effects. Hence, used with ATG to decrease the adverse effects (eg, allergic reactions, serum sickness). Also an additional immunosuppressive. High doses or long duration may be needed if serum sickness occurs with ATG. The doses and duration may vary with different protocols.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions

Adult

5 mg/kg IV on days 1-8; then tapered by using PO 1 mg/kg on days 9-14; further tapering over days 15-29; stop after 1 mo except with evidence of serum sickness

Pediatric

Administer as in adults.

Lymphocyte immune globulin, equine (Atgam)

Inhibits cell-mediated immune response by altering T-cell function or eliminating antigen-reactive cells.There is little prospective randomized data to suggest a single schedule superior, but experience suggests that a short infusion is best tolerated.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions

Adult

100-200 mg/kg IV total dose over variable number of days based on different protocols

Pediatric

Administer as in adults.

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells. Monitor carefully; used only on an investigational basis.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions

Adult

45 mg/kg/d IV for 4 d

Pediatric

Administer as in adults

Lymphocyte immune globulin, rabbit (Thymoglobulin)

May modify T-cell function and possibly eliminate antigen-reactive T lymphocytes in peripheral blood. The dose and duration of therapy vary with the investigational protocols.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions

Adult

1.5 mg/kg IV qd for 7-14 d; up to 3.5 mg/kg for 5 d also used

Pediatric

Not established

Cytokines

Several preliminary studies have demonstrated that the addition of cytokines (eg, G-CSF, GM-CSF) may hasten the neutrophil recovery and that these agents may improve the response rate and survival, although long-term use may increase the risk of clonal evolution.

Sargramostim (Leukine, Prokine)

Recombinant human GM-CSF. Can activate mature granulocytes and macrophages. The dose and frequency of administration vary with the investigational protocol.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions
Adult
250 mcg/m2 IV/SC with twice weekly monitoring of CBC count
Pediatric
Not established; 5 mcg/kg/d SC used in some studies

Filgrastim (Neupogen)

G-CSF that activates and stimulates the production, maturation, migration, and cytotoxicity of neutrophils.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions
Adult
5 mcg/kg/d SC until ANC 5000/mm3
Pediatric
5-10 mcg/kg/d SC

Antineoplastic Agent, Antimetabolite (purine)

Antimetabolites are antineoplastic agent that inhibit cell growth and proliferation.

Fludarabine (Fludara)

Contains fludarabine phosphate, a fluorinated nucleotide analogue of the antiviral agent vidarabine, 9-b-D-arabinofuranosyladenine (ara-A) that enters the cell and is phosphorylated to form active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. Inhibits DNA polymerase, DNA primase, DNA ligase, and ribonucleotide reductase. This inhibits RNA function, RNA processing, and mRNA translation. Also activates apoptosis.
  • Dosing
  • Interactions
  • Contraindications
  • Precautions
Adult
30 mg/m2/dose for 4-6 d as IV infusion over 30 min-2 h
Pediatric
Administer as in adults
 The theoretical basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment.1,2,3 The distinction between acquired and inherited disease may present a clinical challenge, but more than 80% of cases are acquired. In acquired aplastic anemia, clinical and laboratory observations suggest that this is an autoimmune disease.
On morphologic evaluation, the bone marrow is devoid of hematopoietic elements, showing largely fat cells. Flow cytometry shows that the CD34 cell population, which contains the stem cells and the early committed progenitors, is substantially reduced.2,4 Data from in vitro colony-culture assays suggest profound functional loss of the hematopoietic progenitors, so much so that they are unresponsive even to high levels of hematopoietic growth factors.
Little evidence points to a defective microenvironment as a cause of aplastic anemia. In patients with severe aplastic anemia (SAA), stromal cells have normal function, including growth factor production. Adequate stromal function is implicit in the success of bone marrow transplantation (BMT) in aplastic anemia because the stromal elements are frequently of host origin.
The role of an immune dysfunction was suggested in 1970, when autologous recovery was documented in a patient with aplastic anemia in whom engrafting failed after BMT. Mathe proposed that the immunosuppressive regimen used for conditioning promoted the return of normal marrow function. Since then, numerous studies have shown that, in approximately 70% of patients with acquired aplastic anemia, immunosuppressive therapy improves marrow function.3,5,6,7,8  Immunity is genetically regulated (by immune response genes), and it is also influenced by environment (eg, nutrition, aging, previous exposure).9,10 Although the inciting antigens that breach immune tolerance with subsequent autoimmunity are unknown, human leukocyte antigen (HLA)-DR2 is overrepresented among European and United States patients with aplastic anemia, suggesting a role for antigen recognition, and its presence is predictive of a better response to cyclosporine.
Suppression of hematopoiesis is likely mediated by an expanded population of the following cytotoxic T lymphocytes (CTLs): CD8 and HLA-DR+, which are detectable in both the blood and bone marrow of patients with aplastic anemia. These cells produce inhibitory cytokines, such as gamma-interferon and tumor necrosis factor, which can suppress progenitor cell growth. Polymorphisms in these cytokine genes, associated with an increased immune response, are more prevalent in patients with aplastic anemia. These cytokines suppress hematopoiesis by affecting the mitotic cycle and cell killing by inducing Fas-mediated apoptosis. In addition, these cytokines induce nitric oxide synthase and nitric oxide production by marrow cells, which contributes to immune-mediated cytotoxicity and the elimination of hematopoietic cells.
Constitutive expression of Tbet, a transcriptional regulator that is critical to Th1 polarization, occurs in a majority of aplastic anemia patients.5 Perforin is a cytolytic protein expressed mainly in activated cytotoxic lymphocytes and natural-killer cells. Mutations in perforin gene are responsible for some cases of familial hemophagocytosis11 ; mutations in SAP, a gene encoding for a small modulator protein that inhibits undefined-interferon production, underlie X-linked lymphoproliferation, a fatal illness associated with an aberrant immune response to herpesviruses and aplastic anemia. Perforin and SAP protein levels are markedly diminished in a majority of acquired aplastic anemia cases.

Sunday 15 September 2013

LEVOCETRIZINE

File:Levocetirizine structure 2.svg
LEVOCETRIZINE
Levocetirizine (as levocetirizine dihydrochloride) is a third-generation non-sedative antihistamine, developed from the second-generation antihistamine cetirizine. Chemically, levocetirizine is the active enantiomer of cetirizine. It is the R-enantiomer of the cetirizine racemate. Levocetirizine works by blocking histamine receptors. It does not prevent the actual release of histamine from mast cells, but prevents it binding to its receptors. This in turn prevents the release of other allergy chemicals and increased blood supply to the area, and provides relief from the typical symptoms of hay fever.
The manufacturers claim it to be more effective with fewer side effects than the second-generation drugs; however, there have been no published studies supporting this assertion, although other studies have concluded it may be more effective.[1]

    History and formulations

    Levocetirizine was first launched in 2001 by Belgian pharmaceutical company UCB. It is sold under the brand name Xyzal/ˈzzæl/ in Australia, Czech Republic, Austria, Finland, France, Ireland, Netherlands, Portugal, Romania, Taiwan, Turkey, United States, South Africa and UK; Xuzal in Mexico; Xusal in Germany; and Xozal in Greece. In Hungary it is marketed by Richter Gedeon under the Zilola brand name.

    In India, levocetirizine is marketed by GlaxoSmithKline under the brand name Vozet and Xyzal. On May 25, 2007, theUnited States Food and Drug Administration approved Xyzal, where it is co-marketed by Sanofi-Aventis. Torrent Pharma launched UVNIL in rural market of India. It is also available as LEZYNCET 5 mg tablets through Unichem in India. In India, generic name of Lev-Cit 5 mg is manufactured by VIP Pharmaceuticals. Also marketed in India by Croslands (Ranbaxy Laboratories Ltd.) under the brand name Teczine. In Brazil it is marketed under the brand name 'Zyxem' by Farmalab. It is marketed in Egypt by BORG Pharma under the brand name 'Xaltec'Allear by western pharmaceuticals and levcet by marcryl.
    In Pakistan levocetirizine was first launched in liquid formulation by Novartis Consumer Health Division by the name of T-Day Syrup. It is available as 5 mg-strength tablets and a 0.5 mg/mL oral solution. In Pakistan levocetirizine is available in liquid formulation as well with the name of OCITRA and T-Day 2.5 mg/5 mL. In Bangladesh levocetirizine is available in 5 mg tablet & 2.5 mg/5 mL oral liquid formulation with the brand name of Alcet marketed by Healthcare Pharmaceuticals and Seasonix marketed by Incepta Pharmaceuticals. In Nepal levocetirizine is available in 5 mg tablet with brand name ofCurin manufactured by Beximco Pharma.[2]

    Side effectsl

    levocetirizine is called a non-sedating antihistamine as it does not enter the brain in significant amounts, and is therefore unlikely to cause drowsiness. However, some people may experience some slight sleepiness, headache, mouth dryness,lightheadedness, vision problems (mainly blurred vision), palpitations and fatigue.[3]

    Research

    latest research shows levocetirizine reduces asthma attacks by 70% in children.[4]

    Availability]

    The drug is currently available by prescription in the United States. Although the drug was only authorized by the FDA on 25 May 2007, it was already available in most European countries. Like many new drugs it entered the market at a higher price than currently available third and second generation antihistamines. In India, one form of the drug is available as Crohist MK tablets and syrup, a formulation of levocetirizine hydrochloride and montelukast. In India, Crohist MK is a Schedule 'H' drug and may only be prescribed by a registered medical practitioner. In Finland, the drug is sold over-the-counter.
    Different brands (ActavisGlenmarkUCB) Levocetirizine tablets and oral solution.


    1. ^ Grant, JA; Riethuisen, JM; Moulaert, B; DeVos, C; Gamalero, C.; Descalzi, D.; Folli, C.; Passalacqua, G. et al. (2002-02). "A double-blind, randomized, single-dose, crossover comparison of levocetirizine with ebastine, fexofenadine, loratadine, mizolastine, and placebo: suppression of histamine-induced wheal-and-flare response during 24 hours in healthy male subjects.". Ann Allergy Asthma Immunol 88 (2): 190–197. doi:10.1016/S1081-1206(10)61995-3PMID 11868924.
    2. ^ http://www.beximco-pharma.com/allergic-disorders/147-curin.html
    3. ^ XOZAL technical specifications booklet.
    4. ^ Pasquali, M; Baiardini, I; Rogkakou, A; Riccio, AM; Gamalero, C; Descalzi, D; Folli, C; Passalacqua, G et al. (2006-09)."Levocetirizine in persistent allergic rhinitis and asthma: effects on symptoms, quality of life and inflammatory parameters.".Clinical & Experimental Allergy 36 (9): 1161–7. doi:10.1111/j.1365-2222.2006.02548.xPMID 16961716.


    xyzal_structure.png
    Figure 1-The chemical structure of Xyzal

    BACKGROUND
    Cetirizine, chemically [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid is an antihistamine non-sedating type histamine H1-receptor antagonist, indicated for relief of symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis and related diseases.
    Figure US20110184174A1-20110728-C00003
    U.S. Pat. No. 4,525,358 and its equivalent EP 58146 disclose cetirizine and its pharmaceutically acceptable salts. The process for the synthesis of cetirizine comprises condensation of 1-[(4-chlorophenyl)-phenylmethyl]piperazine with 2-chloroethoxy acetamide to obtain 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy acetamide which on hydrolysis gives cetirizine.
    It was found later that the pharmacological activity resides primarily in (R)-isomer or (−) form known as levocetirizine. GB 2225321 describes a process for the preparation of the dextro and levorotatory isomers of cetirizine comprising hydrolysis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazynyl]-ethoxy acetonitrile.
    Figure US20110184174A1-20110728-C00004
    (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine is a very important intermediate in the synthesis of levocetirizine. U.S. Pat. No. 5,478,941 discloses a process for the synthesis of (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine involving hydrolyzing 1-[(4-chlorophenyl)-phenylmethyl]-4-(4-methylphenyl)sulfonyl piperazine with hydrobromic acid in the presence of 4-hydroxybenzoic acid.
    Figure US20110184174A1-20110728-C00005
    The alternative routes of synthesis of (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine disclosed in the prior art involve the use of bis chloro ethylamine which is carcinogenic in nature.
    Levocetirizine is a highly-potent non-sedating anti-allergic agent. Hence, there are continuous attempts to develop new processes for the synthesis of levocetirizine and its intermediates. The present invention describes a new process for the preparation of the key intermediate (−)-1-[(4-chlorophenyl)-phenylmethyl]piperazine.
    Levorotatory [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, also known by the generic name of levocetirizine, has proven useful as a therapeutic agent for the treatment of allergic disease.
    Levocetirizine and its salts including its dihydrochloride are known and are effective in the treatment of allergies, including but not limited to, chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like. Levocetirizine belongs to the second generation of H1 histamine receptor antagonists, which are believed to offer significant advantages over first generation compounds. Studies have shown that levocetirizine provides safe and effective symptomatic relief of seasonal allergies. Levocetirizine is used also for treating chronic idiopathic urticaria.
    GB 2,225,321 describes a process for the preparation of cetirizine in the levorotatory form, dextrorotatory form or a mixture thereof comprising the hydrolysis of enantiomerically pure [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetonitrile. Hydrolysis takes place in aqueous, alcoholic or aqueous-alcoholic medium by a base or by an acid; the acid thus obtained is converted to its dihydrochloride. Optically active starting material 1-[(4-chlorophenyl)phenylmethyl]piperazine is obtained by resolution of the corresponding racemic compound, preferably by conversion to its diastereoisomeric salt with tartaric acid. The yield of resolution is rather low, namely only 12.7%. The obtained optically active intermediate is further converted with chloroethoxyacetonitrile in 69% yield.
    EP 0 617 028 and EP 0 955 295 disclose a process for the preparation of optically active 1-[(4-chlorophenyl)phenylmethyl]piperazine and its conversion to cetirizine in the levorotatory form or dextrorotatory form or to derivative thereof. The process for the preparation is shown in the following scheme:
    Figure US08049011-20111101-C00001
    The drawback of the disclosed reaction is that it requires protection of N,N-bis(2-haloethyl)amine, and consequently deprotection of the intermediate obtained.
    Preparation of Cetirizine in its Levorotatory Form Proceeds in most known syntheses from enantiomerically pure 1-[(4-chlorophenyl)phenylmethyl]piperazine. Consequently it appears to be very desirable to provide new routes to prepare the enantiomers thereof with improved optical purity and good yields.
    Polymorphic form I of crystalline levorotatory dihydrochloride salt of cetirizine and amorphous form thereof are disclosed in WO 2004/050647 and WO 2004/065360. Crystalline form is prepared by crystallization from ketone-containing solvent, such as acetone, methyl ethyl ketone, dimethylketone, 2-pentanone and mixtures thereof. Amorphous form was prepared by solvent evaporation.
    There still exists a need for an efficient synthesis of levocetirizine, new intermediates used in the process, suitable for large-scale production.
    Synthesis of Xyzal:
    Figure 2 displays the synthesis of Cetirizine (Zyrtec). Levocetirizine, the R-enantiomer of cetirizine, is then formed from pyroglutamate salts in a synthesis that does not have attainable details.



    REAL_ceterizine_synthesis.png
    (Figure 2)

    The synthesis of Cetrizine begins by reducing molecule 33 with a catecholborane. This reaction yields molecule 34, which is then treated with tetraflouroboric acid and reacted with an amine, compound 35. In order to remove the chromium group, the compound is refluxed in pyridine and undergoes an acid hydrolysis. This results in a yield of cetrizine.



    Identification of all chirality centers:
    Stereogenic centers are carbon atoms that are bonded to 4 groups. Tetrahedral stereogenic centers are stereogenic centers that are not only bonded to 4 groups but are more importantly bonded to 4 different groups. If a molecule contains 1 tetrahedral stereogenic center it is said to be chiral (nonsuperimposable on its mirror image).If a given compound contains more than 1 stereogenic center it must be further analyzed to determine if it is chiral or achiral(superimosable on its mirror image). The carbon atom bonded to the phenyl groups was found to be a tetrahedral stereogenic center. Therefore,xyzal,which was found to contain only 1 tetrahedral stereogenic center is generally considered a chiral compound because it meets the requirements of chirality and does not have a plane of symmetry that superimposes one half of the molecule on the other and is not super imposable on its mirror image.

    Spectral data for Xyzal (IR and NMR):
    cetirizine_IR.png
    xyzal_nmr.png