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Available Online throughwww.ijpbs.comInternational Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605)IJPBS Volume 1 Issue 3 JULY-SEPT 2011 364-371THIOCOLCHICOSIDE AS MUSCLE RELAXANT: A REVIEWA.R Umarkar*, S.R Bavaskar & P.N.Yewale.Shree.Sureshdada Jain Institute of Pharmaceutical & Education and ResearchJamner Dist: Jalgaon 424206*Corresponding Author Email: arumarkar@gmail.comReview ArticleACCEPTED ON 25-09-2011RECEIVED ON 29-08-2011ABSTRACTThiocolchicoside, is a synthetic sulphur derivative of colchicoside, a naturally occurring glucosidecontained in theColchicum autumnale plant Thiocolchicoside has a selective affinity for g-amino-butyric acid (GABA) receptors and actson themuscular contracture by activating the GABA-nergicinhibitory pathways thereby acting as a potent mus-clerelaxant Thiocolchicoside (Muscoril, Myoril, Neoflax) is a muscle relaxant with anti-inflammatory and analgesic effects. Itacts as a competitive GABAA receptor antagonist and also inhibits glycine receptors with similar potency and nicotinicacetylcholine receptors to a much lesser extent. It has powerful convulsant activity and should not be used in seizureprone individuals. Mode of action includes modulation of chemokine and prostanoid production and inhibition ofneutrophil and endothelial cell adhesion molecules by which it interferes with the initiation and amplification of the jointinflammation. THC is a muscle relaxant given by oral in the treatment of arthritis in a usual dose equivalent to 8 mg firstday to 12-16mg /dayKEYWORDS: Thiocolchicoside, convulsant activityIntroductionThiocolchicoside (THC) is used clinically for itsmuscle relaxant, anti-inflammatory, andanalgesic properties, and it has been shown tointeract with g-amino butyric acid (GABA) typeA receptors (GABAARs) and strychninesensitive Glycine receptors in the rat centralnervous system. In contrast to a proposedagonistic action at these two types of inhibitoryreceptors, pharmacological evidence hasshown that, under certain conditions, THCmanifests convulsant activity in animals andhumans. .C10H21NO7. THC is a muscle relaxant. Its modeof action includes modulation of chemokineand prostanoid production and inhibition ofneutrophil and endothelial cell adhesionmolecules by which it interferes with theinitiation and amplification of the jointinflammation1,2,3,4,5.Fig: [1] de:Chemically it is yl]acetamide[1]. And has the empirical formulaH3COInternational Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605)A.R Umarkar1*et alInt J Pharm Bio Sciwww.ijpbs.com

Available Online throughwww.ijpbs.comIJPBS Volume 1 Issue 3 JULY-SEPT 2011 364-371Muscoril (Thiocolchicoside), a muscle relaxantagent with anti-inflammatory and analgesicactions, also is used topically for the treatmentof muscular spasms and for rheumatologic,orthopedic, and traumatologic disorders. Inthis study, thiocolchicoside was formulated touse as foam to avoid contact with the afflictedarea during the spreading phase. To enhancedrug penetration, various enhancers wereadded to the base sa superba is the national flower ofZimbabwe (where it is a protected plant). It isalso the state flower of Tamil Nadu state inIndia, and was the national flower of TamilEelam and as such was displayed duringMaaveerar Day.Thiocolchicoside is a natural derivated productfrom colchicine & a semi-synthetic derivative sidePrestwick 875Tiocolchicoside [DCIT]Colchicoside, 10-thioPrestwick0 000539Prestwick1 000539Prestwick2 sidoThiocolchicosidum10-ThiocolchicosidePrestwick 875Tiocolchicoside [DCIT]Colchicoside, 10-thioPrestwick0 000539Prestwick1 000539Prestwick2 side [INN:DCF]BSPBio 000557MLS002153865Thiocolchicine 2-glucoside analogSPBio 002478BPBio1 000613C27H33NO10SEINECS 210-017-7Colchicoside, 10-thio- (8CI)AIDS131782HMS1569L19NSC 147755AIDS-131782CID72067BRN 0072205NSC624673LS-9650SMR001233221R. 2714-17-00-03428 (Beilstein Handbook mide, -7-yl)-, )acetamideHISTORY:8,9,11,12.Thiocolchicoside is originated from FlowerSeeds of Gloriosia superb.International Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605)Int J Pharm Bio SciA.R Umarkar1* et alwww.ijpbs.com

Available Online throughwww.ijpbs.comIJPBS Volume 1 Issue 3 JULY-SEPT 2011 e is a semi-synthetic sulfurderivative of colchicoside, a naturally occurringglucoside present in the plant Gloriosa superbflower seeds in the process of producingColchicine. It is a pale yellow powder.13,14,15.Macroscopic characters:3,5,16.Nature: Crystalline powderColourYellow.: Pale yellow toOdoursmell.: CharacteristicTaste: Unpleasant taste.Shape: Like that of colchicine withextensivehydrogenbonding determining the crystal structure.Page366Identity:Purity: 95%Strength: 4mg & 8mgForeign matterthan 2 Percent:notmoreTotal ashthan 4 Percent:notmoreAcid-insoluble ashthan 1 Percent:Alcohol-soluble extractive2.5 Percentnotmore: not less thanLoss on drying60 Percent: not less thanVolatile Oil0.1 Percent.: not less thanPharmacological Study:Thiocolchicoside binds to GABA-A oside acting as a GABA-A receptorantagonist, its myorelaxant effects could beexerted at the supra-spinal level, via complexregulatory mechanisms, although a glycinergicmechanism of action cannot be excluded. Thecharacteristicsof theinteraction ofThiocolchicoside with GABA-A receptors arequalitatively and quantitatively shared by itsmaincirculatingmetabolite,theglucuronidated Derivative. Thiocolchicoside israpidly absorbed after oral administration, andmetabolized into 3 main metabolites. The conandtheglucuronidated derivative of Thiocolchicoside,which is active. Thiocolchicoside is wellInternational Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605)Int J Pharm Bio SciA.R Umarkar1* et alwww.ijpbs.com

Available Online throughPage367www.ijpbs.comIJPBS Volume 1 Issue 3 JULY-SEPT 2011 364-371tolerated oral administration for periods of upto 6 months.8,13,19.phenolic compounds were assayed for theireffect on the glucosyltransferase reaction.19Synthesis Of Thiocolchicoside:20. (A) In a flaskat room temperature under inert atmosphere,3-demethylthiocolchicine (201 mg, 0.5 mmol)and 2,3,4,6-tetra-O-acetyl-α, D-glycopyranosylfluoride (263 mg, 0.75 mmol) are suspended inanhydrous CH3 CN (10 ml). The ine (188 μl, 1,5 mmol).Following the addition of the base, thereagents are dissolved and the solution iscolored in red. Ether BF3 (502 pl, 8 mmol) isadded and the mixture becomes lighter incolor.The reaction is continued with magneticstirring and checked by TLC using a MeOH--CH2Cl2 1:9 system. After 20 minutes the startingproduct is completely transformed. A KHCO3saturated solution is added and the phases arepartitioned; the aqueous phase is extractedwith AcOEt (3 10 ml). The combined organicphases are washed with a KHSO4 saturatedsolution and a NaCl saturated solution. Themixture is dried over MgSO4, filtered and thesolvent is evaporated off, to obtain a solidcrude product (562 mg) which is dissolved inethanol (4 ml). 1N NAOH (2 ml) is added, withmagnetic stirring. The progress of the reactionis checked by TLC: (MeOH--CH2 Cl2 /1:9). Thereaction is complete within 3 hours.Thiocolchicoside (272 mg, 0.48 mmol)crystallizes directly from the reaction medium(97% uslysupplied3demethylthiocolchicine was converted into 3O-glucosyl thiocolchicine (thiocolchicoside) bya cell suspension culture of Centella asiatica.Around 30% of 3-demethylthiocolchicine (136μM) was glucosylated after an 11-dayincubation period. In vitro glucosylation by cellfree extracts demonstrated that hosphate-glucose (UDPG1c)as a highenergy glucose donor. Various endogenouscolchicosideand01g of 3-demethylcolchicine was dissolved inwater and dioxane mixture and added to threeneck round bottom flask in basic medium ofTEA under nitrogen atmosphere. Subsequently06g of a- acetobromoglucose was dissolved indioxane and added to reaction mixture. Thismass was kept agitated under the identicalconditions over 24-48h. The temperature ofthe reaction was maintained at 0 5oC.Monitoring of the progress of the reaction wasdone by TLC using the mobile phase asmentioned earlier. Post reaction the mass waswashed with sodium bicarbonate solutions andthen with chloroform. The converted productwas exchanged with methanolic chloroform. Itwas then dried with Na2SO4 and concentratedunder reduced pressure in rotary evaporator.As a result the brownish syrupy mass wasobtained. It was then dissolved in methanoland deprotected, using 1% sodium hydroxidesolution as an exothermic reaction. Finally theproduct was recovered with 10% methanolicchloroform. Resulting mass was dried underreduced pressure and the off whitecolchicoside was thus recovered was 02g. Oncrystallization it yielded 1.5g of purecolchicoside of 99% assay. To assess its purity itwas then taken as 01g, dissolved in 04g ofwater, and added to three necked roundbottom flask at 20 30oC. 0.5g of NaSCH3 wasadded over the period of 15-20 minutes.Reaction was monitored with the mobile phaseof CHCl3: AcOH: H2O (7:2:1). On completion ofthe reaction it was exchanged with 10%methanolic chloroform until the entire productwas recovered. The solution was dried in rotaryevaporator under reduced pressure to getsyrupy brownish residue. It was then made tosolubilise with methanol and kept in thefreezer for crystallization overnight. RecoveredInternational Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605)Int J Pharm Bio SciA.R Umarkar1* et alwww.ijpbs.com

Available Online throughwww.ijpbs.comIJPBS Volume 1 Issue 3 JULY-SEPT 2011 364-371crystallized product was 1.5g of fast yellowcolor. Its specification was as per USP. Figure 1and 2 may be referred as synthetic schemes.Adalgur (Thiocolchicoside andParacetamol)Teofarma, SpainAnalysis: The drug was analyzed by thepolarimeter for its SOR, purity by HPLC andconfirmation of the structure by 300 MHz1HNMR.AdeleksMustafa Nevzat, TurkeySide Effect of Thiocolchicoside: 23, 24, 25: Sideeffect of skeletal muscle relaxants may include:sedation, drowsiness, blurred or double vision,constipation or diarrhea, dizziness anddrowsiness, nervousness and confusion, drymouth, dyspepsia (chronic or recurrent pain inthe upper abdomen, upper abdominal fullness,and feeling full earlier than expected wheneating), fatigue, headache, heartburn, hiccupsand nausea, insomnia, stomach cramps,trembling, vomiting, and weakness; andpossible dependence following long-term use,Photosensitivity reactions.Therapuetic Uses:7,26MARKETED FORMULATIONS:27ColthiozidPharmy, FranceColtramylAventis, Peru; Roussel, Vietnam; SanofiAventis, France; Sanofi-Aventis, Malta;Sanofi-Aventis, Oman; Theraplix,Tunisia; Winthrop, TunisiaColtraxSanofi-Aventis, Brazil; Sanofi-Aventis,VenezuelaColvalValmor, VenezuelaDecontrilB&G, ItalyDynaxonWinthrop, TurkeyEusilenCofasa, VenezuelaHaliverVelka, GreeceLampralBiotech, VenezuelaMiorelDaiichi Sankyo, FranceMiotensDompé, ItalyMuscoflexBilim, Turkey; Epifarma, ItalyBrand NamesPage368Thiocolchicoside is a muscle-relaxant(skeletal)agent used for the treatment of orthopedic,traumatic and rheumatologic disorders.Antiinflammatory & Analgesic properties.Used incombination with glafenine and alpingography. In the treatment ofpainful muscle spasms. Muscle relaxantThiocolchicoside acts both in contractures ofcentral origin and in those of reflex type,rheumatic and traumatic. Spastic sequelae ofhemiparesis, Parkinson's disease and slectic syndrome. Acute and chroniclumbar and sciatic pain, cervico-brachialneuralgia, persistent torticollis, post-traumaticand post-operative pain.BiocolchidBiogalenic, VenezuelaInternational Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605)Int J Pharm Bio SciA.R Umarkar1* et alwww.ijpbs.com