Rupatadine

Rupatadine

Rupatadine

CAS 158876-82-5,

8-Chloro-11-(1-((5-methylpyridin-3-yl)methyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine,

8-chloro-11-(1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin

UNII-2AE8M83G3E, UR 12592

Molecular Formula: C26H26ClN3

Molecular Weight: 415.95774 g/mol

Percent Composition: C 75.07%, H 6.30%, Cl 8.52%, N 10.10%

Properties: Creamy solid, mp 58-61°.

Melting point: mp 58-61°

Platelet activating factor receptor antagonist; Histamine H1 receptor antagonist

Allergic rhinitis; Urticaria

J. Uriach & Cia. S.A.

Uriach developed and launched rupatadine for treating of allergic rhinitis and urticaria. Family members of the product case EP577957, have SPC protection in the EU until 2016.

As of January 2015, Newport Premium™ reports that Cadila Pharmaceuticals is producing or capable of producing commercial quantities of rupatadine fumarate and holds an active USDMF since September 2012.

Rupatadine is a second generation antihistamine and PAF antagonist used to treat allergies. It was discovered and developed by J. Uriach y Cia, S. A.[1] and is marketed under several trade names such as Rupafin, Alergoliber, Rinialer, Pafinur, Rupax and Ralif.

Therapeutic indications approved

Rupatadine fumarate has been approved for the treatment of allergic rhinitis and chronic urticaria in adults and children over 12 years. The defined daily dose (DDD) is 10 mg orally.

Derivative Type: Fumarate

CAS Registry Number: 182349-12-8

Trademarks: Rupafin (Uriach)

Molecular Formula: C26H26ClN3.C4H4O4

Molecular Weight: 532.03

Percent Composition: C 67.73%, H 5.68%, Cl 6.66%, N 7.90%, O 12.03%

Derivative Type: Trihydrochloride

CAS Registry Number: 156611-76-6

Molecular Formula: C26H26ClN3.3HCl

Molecular Weight: 525.34

Percent Composition: C 59.44%, H 5.56%, Cl 26.99%, N 8.00%

Properties: Crystals from ethyl acetate + ether, mp 213-217°.

Melting point: mp 213-217°.

Therap-Cat: Antihistaminic.

Keywords: Antihistaminic; Tricyclics; Other Tricyclics; Platelet Activating Factor Antagonist.

Available form

Rupatadine is available as round, light salmon coloured tablets containing 10 mg of rupatadine (as fumarate) to be administered orally, once a day.

Side effects

Rupatadine is a non-sedating antihistamine. However, as in other non sedating second-generation antihistamines, the most common side effects in controlled clinical studies weresomnolence, headaches and fatigue.

Mechanism of action

Rupatadine is a second generation, non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist activity. It further blocks the receptors of the platelet-activating factor (PAF) according to in vitro and in vivo studies.[2]

Rupatadine possesses anti-allergic properties such as the inhibition of the degranulation ofmast cells induced by immunological and non-immunological stimuli, and inhibition of the release of cytokines, particularly of the TNF in human mast cells and monocytes.[3]

Pharmacokinetics

Rupatadine has several active metabolites such as desloratadine, 3-hydroxydesloratadine, 6-hydroxydesloratadine and 5-hydroxydesloratadine.

History

Rupatadine discovery, pre-clinical and clinical development was performed by J. Uriach y Cia, S. A., a Spanish pharmaceutical company. It was launched in 2003 in Spain by J. Uriach y Cia, S. A., with the brand name of Rupafin. The registration of the product is approved in 23 countries from the EU, 8 Central American countries, Brazil, Argentina, Chile, Turkey and 14 African countries.

Efficacy in humans

The efficacy of rupatadine as treatment for allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) has been investigated in adults and adolescents (aged over 12 years) in several controlled studies, showing a rapid onset of action and a good safety profile even in prolonged treatment periods of a year.[3][4][5]

• Rupatadine (I) is an authorized antihistaminic agent and has IUPAC name 8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, CAS number 158876-82-5 for the free base and the following chemical formula:

  
• Rupatadine is currently marketed in 10 mg (rupatadine) tablets as rupatadine fumarate (CAS 182349-12-8 for the fumarate salt) for the treatment of allergic rhinitis and urticaria in adults and teenagers.
• Rupatadine free base was first disclosed in EP0577957 .
• Spanish patent application ES2087818 discloses the monofumarate salt of rupatadine (i.e. rupatadine fumarate) and aqueous liquid pharmaceutical compositions of rupatadine fumarate. In particular, this document discloses a syrup containing rupatadine fumarate at 4 g/L, sucrose, a flavouring agent, a sweetening agent and water; and a solution for injection which contains rupatadine fumarate at 20 g/L, benzyl alcohol, propyleneglycol and water.
• EP0577957 discloses some liquid pharmaceutical compositions of rupatadine free base; compound 4 in EP0577957 is rupatadine free base. The formulations disclosed therein are identical to those disclosed in ES2087818 but rupatadine free base is used instead of rupatadine fumarate.
• Despite the aqueous liquid pharmaceutical compositions disclosed in EP0577957and ES2087818 , the inventors have found that the solubility in water of rupatadine fumarate is 2.9 g/L (see Reference example 1) and therefore these prior art formulations may have stability problems due to supersaturation of rupatadine free base or rupatadine fumarate and would not be suitable for use as a medicament.
• CN101669901 and CN101669926 disclose liquid formulations of rupatadine free base using cyclodextrins to dissolve rupatadine.
• CN101669901 is directed to liquid formulations of rupatadine free base for ophthalmic delivery comprising rupatadine, a solvent and a cyclodextrin.
• CN10169926 is directed to liquid formulations of rupatadine free base for nasal delivery comprising rupatadine, a solvent and a cyclodextrin. It is stated that rupatadine has low solubility in water (1.39 mg/mL to 0.82 mg/mL at pH 3.0 to 7.0, table 9 in CN10169926 ) and the problem of its low solubility is solved using cyclodextrins (tables 10-12 of CN10169926 ) in order to obtain liquid formulations.

The reaction of 2-cyano-3-methylpyridine (I) with H2SO4 in t-BuOH gives the N-tert-butylamide (II), which is treated with two equivalents of BuLi and the corresponding dianion alkylated with 3-chlorobenzyl chloride to afford amide (III). The treatment of (III) with POCl3 gives nitrile (IV) which is cyclized to ketone (V) by subsequent treatment with CF3SO3H and aqueous HCl. Reaction of ketone (V) with the Grignard derivative prepared from chloride (VI) affords alcohol (VII) which is finally dehydrated by H2SO4 to give UR-12592 (1), as shown in Scheme 20491401a. The key intermediate (VI) is synthesized through the condensation of 5-methylnicotinic acid (VIII) with 4-hydroxypiperidine by means of DCC in DMF to give amide (IX), followed by reduction with POCl3 and NaBH4 to give the amino alcohol (X) which is treated with SOCl2. Scheme 20491402a. Description White crystals, m.p. 196-8 癈. References 1. Carceller, E., Jim閚ez, P.J., Salas, J. (J. Uriach & Cia SA). Process for the preparation of 8-chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4 -piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. ES 9602107.

The key intermediate (VI) is synthesized through the condensation of 5-methylnicotinic acid (VIII) with 4-hydroxypiperidine by means of DCC in DMF to give amide (IX), followed by reduction with POCl3 and NaBH4 to give the amino alcohol (X), which is treated with SOCl2.

………………………….

EXAMPLE 4

•  http://www.google.com/patents/EP0577957A1?cl=en

8-chloro-11-(1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin

• To a solution of 1.7 mL (15 mmol) of 3,5-lutidine in 100 mL of CCl₄ was added 2.6 g (15 mmol) of NBS and the mixture was stirred at reflux under an argon atmosphere for 2 h. Then, the mixture was allowed to cool, the solid obtained was filtered off and to the filtrate was added 2.4 g (7.5 mmol) of the compound obtained in preparation 1 and 20 mg of 4-(dimethylamino)pyridine. The resulting mixture was stirred at room temperature for 18 h and 1.68 mL of triethylamine was added. It was diluted with 100 mL of dichloromethane and washed with 0.5N NaHCO₃ solution and with water. The organic phase was dried over sodium sulfate and the solvent was removed, to give 5.7 g of a residue that was chromatographed on silica gel (chloroform : methanol : ammonia, 60 : 2 : 0.2). 1.3 g of the title compound of the example was obtained as a white solid (yield: 40%).
  mp: 58-61°C;
  IR (KBr) ν: 3419, 3014, 1635, 1576, 1472 cm⁻¹;
  ¹H RMN (80 MHz, CDCl₃) δ (TMS): 8.39 (m, 3H, ar), 7.48 (m, 1H, ar), 7.37 (m, 1H, ar), 7.12 (m, 4H, ar), 3.45 (s, 2H, CH₂N), 3.36 (m, 2H), 3.1-2.1 (m, 13H). ¹³C RMN (20.15 MHz, CDCl₃) δ (TMS): 157.20 (C), 148.93 (CH), 147.46 (CH), 146.48 (CH), 139.50 (C), 138.56 (C), 137.06 (CH), 133.3 (C), 132.54 (C), 130.67 (CH), 128.80 (CH), 125.85 (CH), 121.92 (CH), 59.84 (CH₂), 54.63 (CH₂), 31.70 (CH₂), 31.32 (CH₂), 30.80 (CH₂), 30.56 (CH₂), 18.14 (CH₃).

………………………….

WO2006114676

http://www.google.com/patents/WO2006114676A2?cl=en

Scheme-1

Example 1

Preparation of3-bromomethyl-5-methylpyridine hydrochloride: A mixture of carbon tetrachloride (4000ml), azobisisobutyronitrile (45.96gm, 0.279mol), 3,5-lutidine (150gm, 1.399mol) and N-bromosuccinamide (299.4gm, 1.682mol) is refluxed for 2 hours. The reaction mixture is cooled to room temperature and solid is filtered. HCl gas is passed to the filtrate and solid obtained is separated and filtered. Yield is 196gm Yield is 67.66%. Example 2

Preparation of Rupatadine :

A mixture of desloratadine (5.0gm, 0.016mol), methylene chloride (15ml), tetrabutylammonium bromide (0.575gm, 0.0018mol) and sodium hydroxide solution (2.5gm, 0.064mol in 8ml water) is cooled to 0 to 50C. 3-bromomethyl-5- methylpyridine hydrochloride (7.18gm, 0.032mol) in methylene chloride (35ml) is added to above mixture. The reaction mixture is stirred at 0 to 50C for 1 hour and at room temperature for 12 hours. Layers are separated and organic layer is washed with dilute HCl solution and water. Methylene chloride is distilled. Yield = 9.5g %Yield =

67.66%.

Example 3

Preparation of “Rupatadine fumarate:

A solution of fumaric acid (3.3gm) in methanol (46ml) is added to solution of

Rupatadine (4.5gm) in ethyl acetate (30ml) at room temperature. The reaction mass is cooled to -5 to O0C for 4 hours. Rupatadine fumarate is separated filtered and Washed with ethylacetate. Yield = 5.5 gm.

…………………………..

NEW PATENT

EP-02824103…An improved process for the preparation of rupatadine fumarate, Cadila Pharmaceuticals Ltd

Process for the preparing rupatadine intermediate (particularly 5-methylpyridine-3-methanol) comprises reduction of 5-methyl nicotinic acid alkyl ester using alkali metal borohydride is claimed. For a prior filing see WO2006114676, claiming the process for preparation of rupatadine fumarate.

……………………………………

J. Med. Chem., 1994, 37 (17), pp 2697–2703

DOI: 10.1021/jm00043a009

http://pubs.acs.org/doi/abs/10.1021/jm00043a009

References

1. Patents: EP 577957, US 5407941, US 5476856
2. Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Queralt, M.; Puigdemont, A.; García-Rafanell, J.; Forn, J. (1997). “Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF)”. The Journal of Pharmacology and Experimental Therapeutics 280 (1): 114–121. PMID 8996188. edit
3. Picado, C. S. (2006). “Rupatadine: Pharmacological profile and its use in the treatment of allergic disorders”. Expert Opinion on Pharmacotherapy 7 (14): 1989–2001. doi:10.1517/14656566.7.14.1989. PMID 17020424. edit
4. Keam, S. J.; Plosker, G. L. (2007). “Rupatadine: A review of its use in the management of allergic disorders”. Drugs 67 (3): 457–474. doi:10.2165/00003495-200767030-00008. PMID 17335300. edit
5. Mullol, J.; Bousquet, J.; Bachert, C.; Canonica, W. G.; Gimenez-Arnau, A.; Kowalski, M. L.; Martí-Guadaño, E.; Maurer, M.; Picado, C.; Scadding, G.; Van Cauwenberge, P. (2008). “Rupatadine in allergic rhinitis and chronic urticaria”. Allergy 63: 5–28.doi:10.1111/j.1398-9995.2008.01640.x. PMID 18339040. edit

Literature References: Dual antagonist of histamine H1 and platelet-activating factor receptors. Prepn: E. Carceller et al., ES 2042421; eidem, US 5407941 (1993, 1995 both to Uriach);

eidem,J. Med. Chem. 37, 2697 (1994).

Mechanism of action: M. Merlos et al., J. Pharmacol. Exp. Ther. 280, 114 (1997).

Clinical trial in seasonal allergic rhinitis: F. Saint-Martin et al., J. Invest. Allergol. Clin. Immunol. 14, 34 (2004);

and comparison with ebastine: E. M. Guadaño et al., Allergy 59, 766 (2004).

Review of pharmacology and clinical development: N. Y. Van Den Anker-Rakhmanina, Curr. Opin. Anti-Inflam. Immunomod. Invest. Drugs 2, 127-132 (2000).

1 TO 8 OF 8
PATENT	SUBMITTED	GRANTED
8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine [US5407941]	1995-04-18
Treatment of PAF and histamine-mediated diseases with 8-chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine [US5476856]	1995-12-19
Process for the synthesis of n-(5-methylnicotinoyl)-4 hydroxypiperidine, a key intermediate of rupatadine [US6803468]	2004-03-04	2004-10-12
$g(b)2-ADRENERGIC RECEPTOR AGONISTS [EP1003540]	2000-05-31
$g(b)2-ADRENERGIC RECEPTOR AGONISTS $g(b)2-ADRENERGIC RECEPTOR AGONISTS [EP1019360]	2000-07-19
8-Chloro-11-[1-[(5-methyl-3-pyridyl)methyl]-4-piperidyliden]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine. [EP0577957]	1994-01-12	1995-07-12
NOVEL CRYSTALLINE FORM OF RUPATADINE FREE BASE [US2009197907]	2009-08-06
METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS [WO9966944]	1999-12-29

RUPATADINE

SYSTEMATIC (IUPAC) NAME
8-Chloro-6,11-dihydro-11-[1-[(5-methyl-3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine fumarate
CLINICAL DATA
TRADE NAMES	Rupafin, Alergoliber, Rinialer, Pafinur, Rupax, Ralif
AHFS/DRUGS.COM	International Drug Names
LEGAL STATUS	Prescription drug
ROUTES	Oral
PHARMACOKINETIC DATA
PROTEIN BINDING	98–99%
METABOLISM	Hepatic, CYP-mediated
HALF-LIFE	5.9 hours
EXCRETION	34.6% urine, 60.9% faeces
IDENTIFIERS
CAS NUMBER	158876-82-5  (free base) 182349-12-8 (fumarate)
ATC CODE	R06AX28
PUBCHEM	CID 133017
CHEMSPIDER	117388
UNII	2AE8M83G3E
CHEMBL	CHEMBL91397
CHEMICAL DATA
FORMULA	C26H26ClN3
MOLECULAR MASS	415.958 g/mol

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Novartis obtains European approval for Cosentyx to treat psoriasis

Novartis obtains European approval for Cosentyx to treat psoriasis

Novartis obtains European approval for Cosentyx to treat psoriasis
Swiss drug-maker Novartis has received approval from the European Commission (EC) for its Cosentyx (secukinumab, formerly known as AIN457) to treat moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy.SEE

http://www.pharmaceutical-technology.com/news/newsnovartis-obtains-european-approval-for-cosentyx-to-treat-psoriasis-4492415?WT.mc_id=DN_News

PSORIAIS

secukinumab

Secukinumab is a human monoclonal antibody designed for the treatments of uveitis,rheumatoid arthritis, ankylosing spondylitis, and psoriasis. It targets member A from thecytokine family of interleukin 17.[1][2] At present, Novartis Pharma AG, the drug’s developer, plans to market it under the trade name “Cosentyx.” [3] It is highly specific to the human immunoglobulin G1k (IgG1k) subclass.[2]

In July 2014 secukinumab established superiority to placebo and to etanercept for the treatment of chronic plaque psoriasis in Phase III clinical trials.[4] In October 2014, the FDA Dermatologic and Ophthalmic Drugs Advisory Committee unanimously voted to recommend the drug for FDA approval, although this vote in and of itself does not constitute an approval. However, the FDA typically follows recommendations from these committees.[5] In October 2014, Novartis announced that the drug had achieved a primary clinical endpoint in two phase III clinical trials for ankylosing spondylitis.[6] As of 28 October, the relevant FDA committee had not yet responded to these results. In early November 2014, Novartis also released the results of a Phase 3 study on Psoriatic Arthritis that yielded very promising results.[7]

Although the drug was originally intended to treat rheumatoid arthritis, phase II clinical trials for this condition yielded disappointing results.[8] Similarly, while patients in a phase II clinical trial for [psoriatic arthritis] did show improvement over placebo, the improvement did not meet adequate endpoints and Novartis is considering whether to do more research for this condition.[9] Novartis has said that it is targeting approval and release in early 2015 for plaque psoriasis and ankyloding spondylitis indications.

It is also in a phase II clinical trial for Multiple Sclerosis [10] as it has exhibited efficacy in treating experimental autoimmune encephalomyelitis (EAE), an animal model of MS.

CAS registry numbers

• 875356-43-7 (heavy chain)
• 875356-44-8 (light chain)

References

1. “Statement On A Nonproprietary Name Adopted By The USAN Council: Secukinumab”. American Medical Association.
2.  Hueber, W.; Patel, D. D.; Dryja, T.; Wright, A. M.; Koroleva, I.; Bruin, G.; Antoni, C.; Draelos, Z.; Gold, M. H.; Psoriasis Study, P.; Durez, P. P.; Tak, J. J.; Gomez-Reino, C. S.; Rheumatoid Arthritis Study, R. Y.; Foster, C. M.; Kim, N. S.; Samson, D. S.; Falk, D.; Chu, Q. D.; Callanan, K.; Nguyen, A.; Uveitis Study, F.; Rose, K.; Haider, A.; Di Padova, F. (2010). “Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis”. Science Translational Medicine 2 (52): 52ra72.doi:10.1126/scitranslmed.3001107. PMID 20926833. edit
3.  http://www.medscape.com/viewarticle/835331
4.  Langley RG, Elewski BE, Mark Lebwohl M, et al., for the ERASURE and FIXTURE Study Groups (July 24, 2014). “Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials”. N Engl J Med 371: 326–338. doi:10.1056/NEJMoa1314258.
5.  committees.http://www.familypracticenews.com/index.php?id=2934&type=98&tx_ttnews=306073[dead link]
6. http://inpublic.globenewswire.com/2014/10/23/Novartis+AIN457+secukinumab+meets+primary+endpoint+in+two+Phase+III+studies+in+ankylosing+spondylitis+a+debilitating+joint+condition+of+the+spine+HUG1864939.html
7.  http://www.medpagetoday.com/MeetingCoverage/ACR/48743
8.  http://www.medscape.com/viewarticle/806510_6
9.  http://www.ncbi.nlm.nih.gov/pubmed/23361084
10. http://clinicaltrials.gov/show/NCT01874340

SECUKINUMAB 

MONOCLONAL ANTIBODY
TYPE	Whole antibody
SOURCE	Human
TARGET	IL17A
CLINICAL DATA
LEGAL STATUS	Investigational
IDENTIFIERS
CAS NUMBER
ATC CODE	L04AC10
DRUGBANK	DB09029
SYNONYMS	AIN457
CHEMICAL DATA
FORMULA	C6584H10134N1754O2042S44
MOLECULAR MASS	147.94 kDa

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Logistics of process R&D: transforming laboratory methods to manufacturing scale

Logistics of process R&D: transforming laboratory methods to manufacturing scale

The manufacture of a | omeprazole (racemic product; top), and esomeprazole (the (S)-enantiomer; bottom), including b | a flow chart of the process for the …

Nature Reviews Drug Discovery 2, 654-664 (August 2003) | doi:10.1038/nrd1154

• • SEARCH PUBMED FOR

• • Hans-Jürgen Federsel

Logistics of process R&D: transforming laboratory methods to manufacturing scale

Hans-Jürgen Federsel

In the past, process R&D — which is responsible for producing candidate drugs in the required quantity and of the requisite quality — has had a low profile, and many people outside the field remain unaware of the challenges involved. However, in recent years, the increasing pressure to achieve shorter times to market, the demand for considerable quantities of candidate drugs early in development, and the higher structural complexity — and therefore greater cost — of the target compounds, have increased awareness of the importance of process R&D. Here, I discuss the role of process R&D, using a range of real-life examples, with the aim of facilitating integration with other parts of the drug discovery pipeline.

Federsel HJ

Process R&D, AstraZeneca, SE-151 85 Södertälje, Sweden. Hans-Jurgen.Federsel@astrazeneca.com

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Ayurveda………..Medicinal Benefits of Liquorice (Mulethi) (मुलेठी, 甘草, شیرین بیان)

Ayurveda………..Medicinal Benefits of Liquorice (Mulethi) (मुलेठी, 甘草, شیرین بیان)

Licorice or Mulethi is a medicinal herb which is used in various Ayurvedic medicines. Its underground stems and roots are used for medicinal purpose. It has antioxidant, antimicrobial, anti-inflammatory and hepatoprotective properties.
Mulethi is useful in cough, sore throat, bronchitis, sexual weakness, skin problems, jaundice, hoarseness, vata dosha, ulcers etc. It has demulcent and expectorant properties.

read…………MY OLD ARTICLE

Liquorice, or licorice, (/ˈlɪk(ə)rɪʃ/ lik-(ə-)rish or /ˈlɪk(ə)rɪs/ lik-(ə-)ris)[2] is the root ofGlycyrrhiza glabra from which a sweet flavour can be extracted. The liquorice plant is alegume native to southern Europe, India, and parts of Asia. It is not botanically related toanise, star anise, or fennel, which are sources of similar flavouring compounds. The word liquorice / licorice is derived (via the Old French licoresse) from the Greek γλυκύρριζα (glukurrhiza), meaning “sweet root”,[3] from γλυκύς (glukus), “sweet”[4] + ῥίζα (rhiza), “root”,[5][6] the name provided by Dioscorides.[7] It has been traditionally known and used as medicine in Ayurveda for rejuvenation.[8] It is called asadhimadhuram (அதிமதுரம்) in Tamil, irattimadhuram in Malayalam, yastimadhu (यस्टिमधु) in Sanskrit, mulethi (मुलेठी) in Hindi, andjethimadh (જેઠીમધ) in Gujarati language.[9]

Licorice (Glycyrrhiza glabra), locally known as mulethi, has been revered for centuries as a medicinal herb in Ayurveda. Besides possessing numerous medicinal properties, it is also a popular flavoring herb as it is 50 times sweeter than sugar, due to the presence of a compound called glycyrrhizin.

Through research, the anti-oxidant, anti-inflammatory, anti-microbial, analgesic (pain-relieving) and expectorant properties of this is sweet, moist herb have been established worldwide. It is also diuretic, rejuvenating and mildly laxative in nature. These properties have helped Licorice find a place in both Eastern and Western medicine for treating an array of ailments, ranging from cold and cough to arthritis, respiratory, digestive and liver problems.

The Sanskrit name for licorice is Yashtimadhu, which literally means “sweet root”. It is sweet, cool and heavy to digest. The Rasa (taste) of this herb is madhura (sweet), which makes it beneficial for vata and pitta doshas, while it’s Virya (action) is sheetal (cooling), which generally increases kapha when consumed in large doses over long term.

The medicinal property of mulethi is mainly because of the presence of powerful phytochemicals namely flavonoids, chalcones, saponins and xenoestrogens. Glycyrrhizin (salts of glycyrrhizic acid) is a popular saponin found in roots of mulethi that is responsible for the characteristic sweet taste (50 times more sweet than sugar) flavor. Liquiritin, licoflavonol, liquiritigenin, etc are the common chalcones that provide the distinct yellowish color to mulethi; while, the aroma of its root is mainly because of anethole. Here are the ten health benefits of mulethi:

Information

Latin name: Glycyrrhiza glabra
Sanskrit: Madhuyashti
Hindi: Mulhatti, Jethimadh, Mithilakdi
English: Sweetwood, Liquorice, Licorice
Bengali: Jashtimadhu
Gujrati: Jethi Madh
Marathi: Jeshtamadhu
Kannada: Jeshthamadhu
Malayalam: Itarttimadhuram, Erattimadhuram
Tamil: Atimadhuram
Telugu: Atimadhuramu

Anti-microbial activity – Roots of mulethi are very effective in protecting against virus, bacteria and fungi due to the presence of Glycyrrhizin that blocks the microbial growth. The root extract possesses the power to control malaria (as per preliminary research), influenza and also helps in the treatment of herpes resulting in virus suppression and severity of sores.

Anti-inflammatory activity – Liquorice has powerful anti-inflammatory and anti-allergic activity and can be used to treat chronic inflammation like rheumatic problems & arthritis, skin diseases and autoimmune diseases. It is also used for preventing any inflammatory conditions related to eye and also to treat conjunctivitis with the help of glycyrrhizin activity that counteracts negative effects caused by cortisol.

Improves immunity – Root extracts of mulethi aids in increasing the production of lymphocytes and macrophage thereby improving your defense mechanism & preventing microbial attack. It also helps in minimizing immune related allergic reactions and autoimmune complications.

Memory improvement – Roots of licorice exert supportive effect on the adrenal gland and thus indirectly aid in stimulating the brain. It not only decreases the effects of amnesia & improves learning but its antioxidant property (mulethi contains flavonoids) renders a shielding effect on the brain cells.

Anti-ulcer activity – The potent antioxidant and anti-inflamatory properties of licorice makes it the best natural medicinal aid to treat ulcers of stomach, intestine and mouth. The compound carbenoxolone synthesized from glycyrrhizin plays key role in healing mouth and gastric ulcers along with reducing gastric secretions and promoting development of intestinal mucus lining.

Liver protection – Licorice is one of the most common traditional remedy used to treat jaundice. Its antioxidant property is the key for preventing your liver from the action of free radicals and toxic materials. This herb is also reported to exhibit protection against diclofenac induced toxicity and also, in inhibiting damage of liver.

Digestive aid – Roots of licorice are also used to deal with stomach and digestion problems with the help of glycyrrhizin and its compound, carbenoxolone. It is one of the ancient home remedies for relieving constipation, acidity, heartburn, stomach discomfort, inflammation of digestive system and gastro esophageal acid reflux. As a mild laxative, it plays an effective role in bowel movements and also for treatment of allergic cough in addition to maintaining normal pH levels.

Hormonal regulation – The phytoestrogenic compounds present in mulethi roots exert valuable action against women hormonal imbalance problems, menopause symptoms like hot flashes & exhaustion, mood swings, etc. It is also found to help in cortisol production and relieving premenstrual issues like nausea and menstrual cramps. Licorice powder acts as the traditional medicine for nursing mothers to regulate body hormones and aid in milk secretion.

Heart healthy effects – Research studies have proved that licorice roots help in controlling cholesterol levels by increasing the body’s flow of bile and also reducing high blood cholesterol levels. The anti-oxidant property of licorice acts in increasing the blood capillary health, reducing inflammation, prevents blood vessel damage and block development of arterial plaque.

Other effects – Licorice roots work wonders in treatment of depression, diabetes and respiratory tract infection like sore throat (hoarseness of voice), cold and cough, etc in addition to rendering effective skin benefits, oral hygiene and weight loss. It is found to act as a cancer cure remedy, a potent aphrodisiac and a powerful analgesic agent.

Description

It is a herbaceous perennial, growing to 1 m in height, with pinnate leaves about 7–15 cm (3–6 in) long, with 9–17 leaflets. The flowers are 0.8–1.2 cm (1/3 to 1/2 in) long, purple to pale whitish blue, produced in a loose inflorescence. The fruit is an oblong pod, 2–3 cm (1 in) long, containing several seeds.[10] The roots are stoloniferous.[11]

Chemistry

The scent of liquorice root comes from a complex and variable combination of compounds, of which anethole is up to 3% of total volatiles. Much of the sweetness in liquorice comes from glycyrrhizin, which has a sweet taste, 30–50 times the sweetness of sugar. The sweetness is very different from sugar, being less instant, tart, and lasting longer.

The isoflavene glabrene and the isoflavane glabridin, found in the roots of liquorice, arephytoestrogens.[12][13]

Cultivation and uses

Liquorice, which grows best in well-drained soils in deep valleys with full sun, is harvested in the autumn two to three years after planting.[10] Countries producing liquorice include Iran, Afghanistan, the People’s Republic of China, Pakistan, Iraq, Azerbaijan, Uzbekistan, Turkmenistan, and Turkey.[14]

The world’s leading manufacturer of liquorice products is M&F Worldwide, which manufactures more than 70% of the worldwide liquorice flavours sold to end users.[15]

Safe dosage

Licorice is available in various forms – root, powder and extracts. Licorice root can be chewed directly while licorice tea (prepared by boiling licorice root in water) is also extremely beneficial as a home remedy.

Daily intake of 5-6 grams of licorice powder is considered safe while 250-500 mg of concentrated extracts can be taken thrice a day. Unsupervised use in high doses is not recommended for long term. People with hypertension or heart disease, pregnant women and breastfeeding mothers should avoid using licorice without prior consulation with an Ayurveda doctor.

plant

Medicine

The compound glycyrrhizin (or glycyrrhizic acid), found in liquorice, has been proposed as being useful for liver protection in tuberculosis therapy, but evidence does not support this use, which may in fact be harmful.[24] Glycyrrhizin has also demonstrated antiviral, antimicrobial, anti-inflammatory, hepatoprotective, and blood pressure-increasing effects in vitro and in vivo, as is supported by the finding that intravenous glycyrrhizin (as if it is given orally very little of the original drug makes it into circulation) slows the progression of viral and autoimmune hepatitis.[25][26] Liquorice has also demonstrated promising activity in one clinical trial, when applied topically, against atopic dermatitis.[27] Additionally, liquorice has also proven itself effective in treating hyperlipidaemia (a high amount of fats in the blood).[28]Liquorice has also demonstrated efficacy in treating inflammation-induced skinhyperpigmentation.[29][30] Liquorice may also be useful in preventing neurodegenerative disorders and dental caries.[31][32][33]

The antiulcer, laxative, antidiabetic, anti-inflammatory, immunomodulatory, antitumour andexpectorant properties of liquorice have been investigated.[34]

Folk medicine

In traditional Chinese medicine, liquorice (मुलेठी, 甘草, شیرین بیان) is believed to “harmonize” the ingredients in a formula and to carry the formula to the 12 “regular meridians”.[35]

References

1.  “Glycyrrhiza glabra information from NPGS/GRIN”. http://www.ars-grin.gov. Retrieved6 March 2008.
2.  licorice. Merriam-Webster’s Medical Dictionary, © 2007 Merriam-Webster, Inc.
3.  γλυκύρριζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
4.  γλυκύς, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus
5. Jump up^ ῥίζα, Henry George Liddell, Robert Scott, A Greek-English Lexicon, on Perseus<
6. Jump up^ liquorice, on Oxford Dictionaries
7. Jump up^ google books Maud Grieve, Manya Marshall – A modern herbal: the medicinal, culinary, cosmetic and economic properties, cultivation and folk-lore of herbs, grasses, fungi, shrubs, & trees with all their modern scientific uses, Volume 2 Dover Publications, 1982 & Pharmacist’s Guide to Medicinal Herbs Arthur M. Presser Smart Publications, 1 Apr 2001 2012-05-19
8. Jump up^ Balakrishna, Acharya (2006). Ayurveda: Its Principles & Philosophies. New Delhi, India: Divya prakashan. p. 206. ISBN 8189235567.
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10. ^ Jump up to:a b Huxley, A., ed. (1992). New RHS Dictionary of Gardening. ISBN 0-333-47494-5
11. Jump up^ Brown, D., ed. (1995). “The RHS encyclopedia of herbs and their uses”.ISBN 1-4053-0059-0
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14. ^ Jump up to:a b c M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2010.
15. Jump up^ M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2001.
16. Jump up^ Erik Assadourian, Cigarette Production Drops, Vital Signs 2005, at 70.
17. Jump up^ M & F Worldwide Corp., Annual Report on Form 10-K for the Year Ended December 31, 2005.
18. ^ Jump up to:a b c Marvin K. Cook, The Use of Licorice and Other Flavoring Material in Tobacco (Apr. 10, 1975).
19. Jump up^ Boeken v. Phillip Morris Inc., 127 Cal. App. 4th 1640, 1673, 26 Cal. Rptr. 3d 638, 664 (2005).
20. Jump up^ [1] the online Dutch food composition database]
21. Jump up^ “Right good food from the Ridings”. AboutFood.com. 25 October 2007.
22. Jump up^ “Where Liquorice Roots Go Deep”. Northern Echo. Retrieved 9 December2008.
23. Jump up^ http://science.howstuffworks.com/life/botany/licorice-info.htm
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25. Jump up^ Chien, CF; Wu, YT; Tsai, TH (January 2011). “Biological analysis of herbal medicines used for the treatment of liver diseases.”. Biomedical Chromatography 25(1-2): 21–38.doi:10.1002/bmc.1568. PMID 21204110.
26. Jump up^ Yasui, S; Fujiwara, K; Tawada, A; Fukuda, Y; Nakano, M; Yokosuka, O (December 2011). “Efficacy of intravenous glycyrrhizin in the early stage of acute onset autoimmune hepatitis.”.Digestive Diseases and Sciences 56 (12): 3638–47.doi:10.1007/s10620-011-1789-5. PMID 21681505.
27. Jump up^ Reuter, J; Merfort, I; Schempp, CM (2010). “Botanicals in dermatology: an evidence-based review.”. American Journal of Clinical Dermatology 11 (4): 247–67.doi:10.2165/11533220-000000000-00000. PMID 20509719.
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29. Jump up^ Callender, VD; St Surin-Lord, S; Davis, EC; Maclin, M (April 2011). “Postinflammatory hyperpigmentation: etiologic and therapeutic considerations.”.American Journal of Clinical Dermatology12 (2): 87–99. doi:10.2165/11536930-000000000-00000. PMID 21348540.
30. Jump up^ Leyden, JJ; Shergill, B; Micali, G; Downie, J; Wallo, W (October 2011). “Natural options for the management of hyperpigmentation.”. Journal of the European Academy of Dermatology and Venereology 25 (10): 1140–5. doi:10.1111/j.1468-3083.2011.04130.x. PMID 21623927.
31. Jump up^ Kannappan, R; Gupta, SC; Kim, JH; Reuter, S; Aggarwal, BB (October 2011). “Neuroprotection by spice-derived nutraceuticals: you are what you eat!”(PDF). Molecular Neurobiology 44(2): 142–59. doi:10.1007/s12035-011-8168-2.PMC 3183139. PMID 21360003.
32. Jump up^ Gazzani, G; Daglia, M; Papetti, A (April 2012). “Food components with anticaries activity.”. Current Opinion in Biotechnology 23 (2): 153–9.doi:10.1016/j.copbio.2011.09.003.PMID 22030309.
33. Jump up^ Messier, C; Epifano, F; Genovese, S; Grenier, D (January 2012). “Licorice and its potential beneficial effects in common oro-dental diseases.”. Oral Diseases 18(1): 32–9.doi:10.1111/j.1601-0825.2011.01842.x. PMID 21851508.
34. Jump up^ Shibata, S (October 2000). “A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice.”. Yakugaku Zasshi 120 (10): 849–62.PMID 11082698.
35. Jump up^ Bensky, Dan; et al. (2004). Chinese Herbal Medicine: Materia Medica, Third Edition. Eastland Press. ISBN 0-939616-42-4.
36. Jump up^ Olukoga, A; Donaldson, D (June 2000). “Liquorice and its health implications.”. The Journal of the Royal Society for the Promotion of Health 120 (2): 83–9.doi:10.1177/146642400012000203. PMID 10944880.
37. Jump up^ Armanini, D; Fiore, C; Mattarello, MJ; Bielenberg, J; Palermo, M (September 2002). “History of the endocrine effects of licorice.”. Experimental and Clinical Endocrinology & diabetes 110 (6): 257–61. doi:10.1055/s-2002-34587.PMID 12373628.
38. Jump up^ Omar, Hesham R; Komarova,, Irina; El-Ghonemi,, Mohamed; Ahmed, Fathy; Rashad, Rania; Abdelmalak, Hany D; Yerramadha, Muralidhar Reddy; Ali, Yaseen; Camporesi, Enrico M. “How much is too much? in Licorice abuse: time to send a warning message from Therapeutic Advances in Endocrinology and Metabolism”. http://www.ncbi.nlm.nih.gov. SAGE Publications. Retrieved 13 January2015.

38 Toxicology Center[2]

External links

Glycyrrhiza glabra (licorice), Kew plant profile

• Licorice, Medline, National Institutes of Health
• What’s That Stuff?: Licorice, Chemical & Engineering News

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