Available Online through International Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605) www.ijpbs.com IJPBS |Volume 1| Issue 3 |JULY-SEPT |2011|364-371 THIOCOLCHICOSIDE AS MUSCLE RELAXANT: A REVIEW A.R Umarkar*, S.R Bavaskar & P.N.Yewale. Shree.Sureshdada Jain Institute of Pharmaceutical & Education and Research Jamner Dist: Jalgaon 424206 *Corresponding Author Email: [email protected] Review Article RECEIVED ON 29-08-2011 ACCEPTED ON 25-09-2011 ABSTRACT Thiocolchicoside, is a synthetic sulphur derivative of colchicoside, a naturally occurring glucosidecontained in the Colchicum autumnale plant Thiocolchicoside has a selective affinity for g-amino-butyric acid (GABA) receptors and acts on themuscular contracture by activating the GABA-nergicinhibitory pathways thereby acting as a potent mus-cle relaxant Thiocolchicoside (Muscoril, Myoril, Neoflax) is a muscle relaxant with anti-inflammatory and analgesic effects. It acts as a competitive GABAA receptor antagonist and also inhibits glycine receptors with similar potency and nicotinic acetylcholine receptors to a much lesser extent. It has powerful convulsant activity and should not be used in seizure- prone individuals. Mode of action includes modulation of chemokine and prostanoid production and inhibition of neutrophil and endothelial cell adhesion molecules by which it interferes with the initiation and amplification of the joint inflammation. THC is a muscle relaxant given by oral in the treatment of arthritis in a usual dose equivalent to 8 mg first day to 12-16mg /day KEYWORDS: Thiocolchicoside, convulsant activity Introduction Thiocolchicoside (THC) is used clinically for its C10H21NO7. THC is a muscle relaxant. Its mode muscle relaxant, anti-inflammatory, and of action includes modulation of chemokine analgesic properties, and it has been shown to and prostanoid production and inhibition of interact with g-amino butyric acid (GABA) type neutrophil and endothelial cell adhesion A receptors (GABAARs) and strychnine- molecules by which it interferes with the sensitive Glycine receptors in the rat central initiation and amplification of the joint nervous system. In contrast to a proposed inflammation1,2,3,4,5. agonistic action at these two types of inhibitory receptors, pharmacological evidence has Fig: [1] THC shown that, under certain conditions, THC H3C H3C S CH manifests convulsant activity in animals and O 3 humans. O O O OH Thiocolchicoside: O Chemically it is N-[3-(β-D-glucopyranosyloxy)- OH OH 1,2-dimethoxy-10(methylthio)-9-oxo-5,6,7,9- OH NH2 tetrahydrobenzo [a ] heptalen-7-yl] acetamide[1]. And has the empirical formula O CH3 364 Page International Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605) A.R Umarkar1*et al Int J Pharm Bio Sci www.ijpbs.com Available Online through www.ijpbs.com IJPBS |Volume 1| Issue 3 |JULY-SEPT |2011|364-371 Muscoril (Thiocolchicoside), a muscle relaxant SPBio_002478 agent with anti-inflammatory and analgesic BPBio1_000613 actions, also is used topically for the treatment C27H33NO10S of muscular spasms and for rheumatologic, EINECS 210-017-7 orthopedic, and traumatologic disorders. In Colchicoside, 10-thio- (8CI) this study, thiocolchicoside was formulated to AIDS131782 use as foam to avoid contact with the afflicted HMS1569L19 area during the spreading phase. To enhance NSC 147755 drug penetration, various enhancers were AIDS-131782 added to the base formulation.6,7,8. CID72067 9,10 BRN 0072205 SYNONYMS: NSC624673 Thiocolchicoside LS-9650 Tiocolchicosido SMR001233221 Thiocolchicosidum R. 271 Tiocolchicoside 4-17-00-03428 (Beilstein Handbook Reference) 10-Thiocolchicoside 2-10-Di(demethoxy)-2-glucosyloxy-10- Prestwick_875 methylthiocolchicine Tiocolchicoside [DCIT] BRD-A11605036-001-03-2 Colchicoside, 10-thio- 602-41-5 Prestwick0_000539 Acetamide, N-(3-(beta-D-glucopyranosyloxy)- Prestwick1_000539 5,6,7,9-tetrahydro-1,2-dimethoxy-10- Prestwick2_000539 (methylthio)-9-oxobenzo(a)heptalen-7-yl)-, (S)- Coltramyl N-(3-(Hexopyranosyloxy)-1,2-dimethoxy-10- Musco-ril (methylthio)-9-oxo-5,6,7,9- tetrahydrobenzo[a]heptalen-7-yl)acetamide Tiocolchicoside 8,9,11,12. Tiocolchicosido HISTORY: Thiocolchicosidum Thiocolchicoside is originated from Flower 10-Thiocolchicoside Seeds of Gloriosia superb. Prestwick_875 Colchicaceae. Tiocolchicoside [DCIT] Colchicoside, 10-thio- Gloriosa superba is the national flower of Prestwick0_000539 Zimbabwe (where it is a protected plant). It is Prestwick1_000539 also the state flower of Tamil Nadu state in Prestwick2_000539 India, and was the national flower of Tamil Thiocolchicosidum Eelam and as such was displayed during Tiocolchicosido Maaveerar Day. Thiocolchicoside [INN:DCF] BSPBio_000557 Thiocolchicoside is a natural derivated product MLS002153865 from colchicine & a semi-synthetic derivative of Thiocolchicine 2-glucoside analog colchicoside. 365 Page International Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605) A.R Umarkar1* et al Int J Pharm Bio Sci www.ijpbs.com Available Online through www.ijpbs.com IJPBS |Volume 1| Issue 3 |JULY-SEPT |2011|364-371 THIOCOLCHICOSIDE Description: Acid-insoluble ash : not more than 1 Percent Thiocolchicoside is a semi-synthetic sulfur derivative of colchicoside, a naturally occurring Alcohol-soluble extractive : not less than glucoside present in the plant Gloriosa superb 2.5 Percent flower seeds in the process of producing Colchicine. It is a pale yellow powder.13,14,15. Loss on drying : not less than 60 Percent Macroscopic characters:3,5,16. Volatile Oil : not less than Nature : Crystalline powder 0.1 Percent. Colour : Pale yellow to Pharmacological Study: Yellow. Thiocolchicoside binds to GABA-A and Odour : Characteristic strychnine sensitive glycine receptors. smell. Thiocolchicoside acting as a GABA-A receptor antagonist, its myorelaxant effects could be Taste : Unpleasant taste. exerted at the supra-spinal level, via complex Shape : Like that of colchicine with regulatory mechanisms, although a glycinergic extensive hydrogen mechanism of action cannot be excluded. The bonding determining the crystal structure. characteristics of the interaction of Thiocolchicoside with GABA-A receptors are Identity: qualitatively and quantitatively shared by its main circulating metabolite, the Purity : >95% glucuronidated Derivative. Thiocolchicoside is Strength : 4mg & 8mg rapidly absorbed after oral administration, and metabolized into 3 main metabolites. The two Foreign matter : not more main circulating forms were the than 2 Percent Thiocolchicoside aglycon and the glucuronidated derivative of Thiocolchicoside, Total ash : not more which is active. Thiocolchicoside is well 366 than 4 Percent Page International Journal of Pharmacy and Biological Sciences (eISSN: 2230-7605) A.R Umarkar1* et al Int J Pharm Bio Sci www.ijpbs.com Available Online through www.ijpbs.com IJPBS |Volume 1| Issue 3 |JULY-SEPT |2011|364-371 tolerated oral administration for periods of up phenolic compounds were assayed for their to 6 months.8,13,19. effect on the glucosyltransferase reaction.19 Synthesis Of Thiocolchicoside:20. (A) In a flask (C)Synthesis of colchicoside and at room temperature under inert atmosphere, thiocolchicoside:22 3-demethylthiocolchicine (201 mg, 0.5 mmol) and 2,3,4,6-tetra-O-acetyl-α, D-glycopyranosyl 01g of 3-demethylcolchicine was dissolved in fluoride (263 mg, 0.75 mmol) are suspended in water and dioxane mixture and added to three neck round bottom flask in basic medium of anhydrous CH3 CN (10 ml). The reaction mixture is added with 1,1,3,3- TEA under nitrogen atmosphere. Subsequently tetramethylguanidine (188 μl, 1,5 mmol). 06g of a- acetobromoglucose was dissolved in Following the addition of the base, the dioxane and added to reaction mixture. This reagents are dissolved and the solution is mass was kept agitated under the identical colored in red. Ether BF3 (502 pl, 8 mmol) is conditions over 24-48h. The temperature of added and the mixture becomes lighter in the reaction was maintained at 0±5oC. color.The reaction is continued with magnetic Monitoring of the progress of the reaction was done by TLC using the mobile phase as stirring and checked by TLC using a MeOH--CH2 mentioned earlier. Post reaction the mass was Cl2 1:9 system. After 20 minutes the starting washed with sodium bicarbonate solutions and product is completely transformed. A KHCO3 saturated solution is added and the phases are then with chloroform. The converted product partitioned; the aqueous phase is extracted was exchanged with methanolic chloroform. It with AcOEt (3×10 ml). The combined organic was then dried with Na2SO4 and concentrated under reduced pressure in rotary evaporator. phases are washed with a KHSO4 saturated solution and a NaCl saturated solution. The As a result the brownish syrupy mass was obtained. It was then dissolved in methanol mixture is dried over MgSO4, filtered and the solvent is evaporated off, to obtain a solid and deprotected, using 1% sodium hydroxide crude product (562 mg) which is dissolved in solution as an exothermic reaction. Finally the ethanol (4 ml). 1N NAOH (2 ml) is added, with product was recovered with 10% methanolic magnetic stirring. The progress of the reaction chloroform. Resulting mass was dried under reduced pressure and the off white is checked by TLC: (MeOH--CH2 Cl2 /1:9). The reaction is complete within 3 hours. colchicoside was thus recovered was 02g. On Thiocolchicoside (272 mg, 0.48 mmol) crystallization it yielded 1.5g of pure crystallizes directly from the reaction medium colchicoside of 99% assay. To