INTRODUCTION:

Chemically it is N-[3-(β-D-glucopyranosyloxy)- 1,2-dimethoxy-10(methylthio)-9-oxo-5,6,7,9- tetrahydrobenzo [a] heptalen-7-yl] acetamide. Thiocolchicoside is semi synthetic derivative of colchicoside and natural derivative of colchisine. Colchicoside and colchisine both are extracted from seeds of Gloriosa superba (Liliaceae)^1-2. Thiocolchicoside is a muscle relaxant agent launched since 1959. Its good clinical efficacy has been demonstrated in several clinical trials. The tuberous roots of Gloriosa superba can be used potentially to cure snakebites, skin diseases and ulcers, or to treat inflammation. Its seeds are helpful in relieving rheumatic as well as muscle pains.

Thiocolchicoside (THC) is used widely for its wide spectrum activities such as muscle relaxant, anti-inflammatory, and analgesic, and it has ability to interact with g-amino butyric acid (GABA) type A receptors (GABAARs) and strychnine-sensitive Glycinergic

receptors in the rat central nervous system, and has the empirical formula C₁₀H₂₁N³Thiocolchicoside is a potent antagonist of the GABA-A receptor as well as inhibits the activity of the strychnine-sensitive glycine receptor^4-5.

Table 1: Chemical Taxonomy

Description:	This compound belongs to the class of organic compounds known as phenolic glycosides. These are organic compounds containing a phenolic structure attached to a glycosyl moiety. Some examples of phenolic structures include lignans, and flavonoids. Among the sugar units found in natural glycosides are D-glucose, L-Fructose, and L rhamnose.
Kingdom:	Organic compounds
Super Class:	Organic oxygen compounds
Class:	Organooxygen compounds
Sub Class:	Carbohydrates and carbohydrate conjugates
Direct Parent:	Phenolic glycosides
Alternative Parents:	Hexoses/O-glycosyl compounds/Tropones/ Anisoles/Alkyl arylethers/Alkylarylthioethers/ Oxanes/Acetamides/ Secondary carboxylic acid amides/Secondary alcohols.
Substituents:	Acetal/Acetamide/Alcohol/Alkylarylthioether/ Anisole/Aromatic heteropolycyclic compound/ Aryl thioether/Benzenoid/Carbonyl group Carboxamide group.
Molecular Framework:	Aromatic heteropolycyclic compounds

Figure 1: Structure of Thiocolchicoside¹

Figure 2: Muscle Spasm Cycle⁶

Mechanism of Action:

Thiocolchicoside shows a selective affinity for the inhibition of glycinergic receptors and gamma aminobutyric acid receptors² for the moderation of its myorelaxant effectit is having an agonistic action at the spinal-strychnine-sensitive receptors. However, experimental and clinical evidence strongly suggest a proconvulsant action for thiocolchicoside. Interaction with glycine receptors does not elucidate the convulsant action of the molecule. According to a study, the possibility of preferential interaction of thiocolchicoside with cortical subtype of gamma-aminobutyric acid type-A (GABA) has been suggested. An antagonist-binding siteappeared to be low-affinity recognition site. This explains the proconvulsant effect of thiocolchicoside. This is in contrast to earlier studies that suggested a GABA mimetic effect which would explain its muscle relaxant property⁷. GABA-B receptors are heavily unaffected by thiocolchicosideand do not take part into its muscle relaxation action⁸. Hence, the exact mechanism for muscle relaxation is yet to be known, although from available evidence, inhibition of glycine receptors is a possible mechanism².

Pharmacokinetics:

In oral administration of thiocolchicoside, peak plasma concentration is achieved after 50 min. whereas in intramuscular administration, peak plasma concentration is achieved after 30 min⁹. During absorption and during the first-pass effect through the liverthiocolchicoside is rapidly converted to 3-desmethylthiocolchicine (possibly partially in the acidic stomach juices)¹⁰. The apparent volume of distribution of thiocolchicoside is estimated to be 42.7L after the I.M. administration of the drug. The pharmacokinetics also includes the protein binding in which, according to equilibrium dialysis and centrifugation studies it has shown that the binding of thiocolchicoside and its derivative to the human serum, purified human protein was 38.9⁰C and 12.8⁰C±5.3% with the albumin. Thiocolchicoside metabolizes into three main metabolites and it is mainly metabolizes in intestine with the help of 3-o-glucoronodemethylcholin. Alsoit has the half life of 7.7 hrs¹¹. The elimination of thiocolchicoside remains unchanged after three metabolites found either in the feces and urine⁹.When thiocolchicoside were administered to patients in combination or mixed at the time of administration does not show any type of mixture and also does not show any type of changes in the chemical structure and also for the action¹².

Extraction of Thiocolchicoside:

The thiocolchicoside is a natural glycoside of superba gloriosa andsemi synthetic derivative of colchicine. The extraction of thiocolchicosideis carried out from the seeds of plant Gloriosa superba. With the help of HPLC method, it is found that maximum amount of colchicine is present in the seeds of gloriosa superba. For extraction, 25ml of petroleum ether is used for 0.5gm of powdered plant extract. Extraction is carried out twicely with petroleum ether, and during this, frequent shaking should be applied for 1 hr and finally filtration is done. The solid precipitates were dried by the air and then extraction with the help of 10ml of dichloromethane at room temperature for 30min with continuous shaking. Then 10% solution of ammonia (0.5ml) was combined to the mixture with strong shaking for 10 min; the mixture was not disturbed for 30 min and then filtered. The precipitate was washed twice with 10ml of dichloromethane and then added with the filtrate. The organic phase was evaporated to dryness and then dissolved in 1ml of 70% ethanol to yield the test sample¹³.

Synthesis of Thiocolchicoside:

Take acetonitrile in a flask. Suspend 3-demethylthiocolchicine, D-glycopyranosyl fluoride and 2,3,4,6-tetra-O-acetyl-α into acetonitrile, at room temperature and inert atmosphere. The reaction mixture is added with 1,1,3,3-tetramethylguanidine. After dissolving the reagents the solution becomes red in color. Then Boron trifluoride etherate is added. The mixture becomes light in color due to addition of Boron trifluoride etherate. With the continuous magnetic stirring the reaction is being checked with the help of TLC method. After 20 minutes the starting product is transformed. Then the saturated solution of potassium bicarbonate is added and the phases are equally separated; the aqueous phase is extracted with AcOEt. The mixture is dried and filtered over MgSO4 and the solvent is evaporated, to obtain a crude product which is dissolved in ethanol. Then NaOH is added with the continuous magnetic stirring. The progress of the reaction is checked with the help of TLC. The reaction took 3 hrs. to complete. Thiocolchicoside crystallizes directly from the reaction medium, and 97% of yield of thiocolchicoside is obtained. Thiocolchicoside level in Gloriosa superba could be enhanced by using suspension culture method. Suspension culture of Gloriosa superbacould be used for biosynthesis of high content levels of thiocolchicoside. The method may be used for commercial supply of thiocolchicoside in future for therapeutic purposes¹⁴.

Figure 3: Synthesis of Thiocolchicoside

Adverse Effect of Thiocolchicoside:

Adverse effects of thiocolchicoside includes Dizziness and Drowsiness, Blurred or Double vision, Nervousness and Confusion, Dry mouth, Dyspepsia (chronic or recurrent pain in the upper abdomen, upper abdominal fullness, and feeling full earlier than expected when eating), Fatigue, Headache, Stomach cramps, Trembling, Vomiting, and Weakness and Photosensitivity reactions. Constipation or Diarrhea.TCC induces seizures in humans and animals by down-regulating the function of the main inhibitory systems in the brain and spinal cord. In some cases liver hepatotoxicity may has been observed. The drug thiocolchicoside can cause immediate hypersensitivity reactions^15-17

Toxicity of Thiocolchicoside:

Thiocolchicoside can cause male infertility and chromosomal aneuploidy and it should be contraindicated during all stages of pregnancy, puberty and lactation. There is risk of causing cancer from thiocolchicoside. In 2013, The European Medical Association (EMA) instructed that the use of thiocolchicoside-containing medicines should be restricted by mouth or injection across the European Union (EU). For adults and adolescents which are 16 years older, it is now recommended that these drugs are only used as an adjunct treatment for severe muscle pain contraction resulting from spinal injuries. Although the dosage forms of thiocolchicoside administered by mouth or injection should be in the limit. On the basis of the experimental evidence the drug thiocolchicoside having the tendency to damage the dividing cells, which results in aneuploidy. From the recommendations the oral dose of thiocolchicoside should be maximized only up to 8 mg every 12hrs and the treatment should not be more than 7 consecutive days. When it is administered intramuscularly (IM) the dose should not be more than 4 mg every 12Hrs. and the treatment should not be more than the 5 days. An investigation was carried out in surplus of above mentioned toxicity for the hepatotoxic potential of the drug. After the administration of thiocolchicoside as an oral dose of 8mg/day, it was observed that there is an increase in serum ALT and AST levels. After discontinuing therapy of the drug from two weeks the liver enzymes decreased the serum levels in the normal range. Therefore in clinical practice thiocolchicoside should be considered as a rare hepatotoxic agent¹⁸.

Therapeutic Uses:

Thiocolchicoside is known as skeletal muscle-relaxing agent. It is used in the treatment of traumatic, rheumatologicorthopedic disorders. There is a combination of glafenine and meprobamate used to tranquilize patients undergoing hysterosalpingography having an anti-inflammatory and Analgesic properties. In the treatment of painful muscle spasms i.e Thiocolchicoside is the muscle relaxant works in both of the contractures of central origin and those of reflex types which are rheumatic and traumatic. Thiocolchicoside also finds is use during treatment of parkinson's disease and drug induced parkinsonism, the neurodyslectic syndrome, cervico-brachial neuralgia, acute and chronic torticollis, Spastic hemiplegia, post-traumatic and post-operative pain, etc.The main and the most commonly encountered problem regarding muscle relaxant use in general clinical practice was observed to be sedation, but thiocolchicoside were observed to produce no sedation in the patient on their treatment ongoing with it. Paravertebral muscles pasmisa very common ﬁnding in acute LBP cases and may aggravate the pain felt by the patient by creating a vicious cycle of pain—spasm—pain, A common treatment approach to acute LBP includes the use of thiocolchicoside with combination of analgesics, NSAIDs and muscle relaxants are much effective. Alsothiocolchicoside exhibits anticancer effects through downregulation of NF-kB pathway^19-20. The drug thiocolchicoside is effective in the treatment of acute low back pain.

Various Dosage Forms of Thiocolchicoside:

1. Ointment:

According to the studies conducted by Ketencia et.al. We observed that sixty-five patients with acute myofascial pain syndrome were recruited. The patients were divided by them into three groups. First group of patients received Thiocolchicoside ointment onto the trigger points, the second group of patients received 8 mg thiocolchicoside intramuscular injection to the trigger points, and the third group of patients received both treatments. Treatment continues for the next 5 consecutive days. On first day, third day and fifth day, pain severity assessments with visual analogue scale (VAS) along with algometric and genometric measurements were repeated. After this experimental method they have finalized some results showing pain severity measured with VAS significantly improved after the first day in the mono-therapy groups of patients and after the third day in all groups of patients. While significant improvement was observed in all three groups of patients in right lateral flexion measurements, and further no significant changes was observed in the combined treatment group in left lateral flexion measurements. After reviewing this successful trail of experiment and final result we concluded that thiocolchicoside can be used in the treatment of myofascial pain syndrome. The ointment form of thiocolchicoside may be considered as safe and effective dosage form for the patients who cannot receive injenctions and other dosage forms²¹.

2. Transdermal Film of Thiocolchicoside:

Federica Bigucci et al stated that the aim of this study was to develop the chitosan/hyaluronan transdermal films to increase thiocolchicoside bioavailability. This methodology offers the likelihood to evade the principal pass digestion and simultaneously can give an anticipated and broadened length of action. This examination obviously affirmed that the choice of an appropriate polymeric weight proportion and fitting preparative conditions permits the regulation of film practical properties, recommending that these plans could be utilized as a novel mechanical stage for transdermal medication conveyance,and there outcomes affirmed the significance of chitosan/hyaluronan polyelectrolyte buildings as new materials to foster adaptable dose structures ready to permit negligible dose and recurrence, and portrayed by insignificant effect on way of life, and simple and easy administration²².

3. Tablet:

A randomized, double-blinded clinical trial study was conducted including patients having acute low back pain (LBP) with muscle spasm. Effects of oral thiocolchicoside (TCC), Tizanidine (TZ) and placebo on psychomotor performances was analyzed by a visual analogue scale (VAS) of tiredness, drowsiness, dizziness and alertness. Psychometric tests after 2 and 5–7 days of treatment. In further efficacy assessment study both thiocolchicoside and Tizanidine were showing better effect than placebo in improving pain at rest and decreased paracetamol consumption. Among all groups, significant differences were observed in favour of TCC compared to TZ in VAS. 97 patients (50 women and 47 men) were recruited. Of the 97 patients enrolled, 38 (39.1%) received TCC, 32(32.9%) TZ and 27(28%) placebos. Among all the groups, there were no consequential differences with respect to their gender, height, age, weight, physical examination, clinical findings and laboratory parameters including psychomotor performance of patients evaluated by VAS and psychometric tests, showing that the treatment groups are comparable and well matched. But in another case of scenario or the study it was found that oral solution of TCC was found to be more effective and potent than the orally given tablets, later on as the expected parenteral formulations of TCC proved to be more effective as it has the most absorption and also the highest biovaibility²³ Buccal or sublingual administration is a useful alternative to the oral route, avoiding pre-systemic metabolism²⁴.

4. Thiocolchicoside Foams:

Two thiocolchicoside topical formulations were evaluated in this study. During study, the formulations were applied with the frequency and duration compatible according clinical practices .The innovative thiocolchicoside foam formulation utilized in the study, contained 0.25% of thiocolchicoside in addition to the following excipients: polysorbate 80(4%), propylene glycol (4%), alcohol (ethanol; 20%), propylene glycol diperlargonate (1%), benzyl alcohol (1%), sodium phosphate monobasic monohydrate (0.83%), sodium phosphate dibasic dodecahydrate (0.23%) and nerolene lavender (0.20%). propane and butane gas were used as gas propellent and formulation made to dispense foam. The innovative foam formulation was found to have similar or better tolerability compared with the reference product²⁵.

5. Omega 3 Fatty Acid-Enriched Nano-emulsion of Thiocolchicoside:

Thiocolchicoside (TCC) used in rheumatologic, orthopedic and traumatic and disorders. It is having low bioavailability, comprehensive first pass metabolism and low permeation via oral route. Aim behind to study the research conducted by Dinesh Kumar et .al is to evaluate the potential of nano emulsion for bioavailability enhancement of thiocolchicoside through the transdermal route. Linseed and sesfol were used as oil phase in ratio of 1:1 to prepare nano emulsion along with Span 80, distilled water, transcutol P, Co-surfactants and aquious phase. Overall, From the results we observed that water-in-oil Nanoemulsions are safe and good carriers for transdermal delivery of thiocolchicoside. Formulation of Nano emulsion-containing thiocolchicoside were formulated by the method called pseudo ternary phase diagram method. The utility of w/o nano emulsion as vehicles for transdermal delivery of thiocolchicoside was studied. The nano emulsions were shown to increase the transdermal delivery of thiocolchicoside 5-fold over the control. Altogether w/o nano emulsions were found to be good in transdermal delivery of thiocolchicoside providing anti-inflammatory activity²⁶.

Studies Carried Out with Thiocolchicoside:

According to a study conducted on 48 pregnant women’s, 31 results came up with healthy live birth, 4 resulted abortion and 7 ended with termination. Among those 31 live births 26 were normal outcomes, 2 were major and 3 were with minor congenital malformations, and drug was found unlikely to be teratogenic²⁷. A study for permeation of thiocolchicoside across the skin wasperformedusing permeation enhancers (lauric acid) and physical technique of iontophoresis. In the investigation, it is found that as compared to use of penetration enhancer, iontophoresis boost up the flux of thiocolchicoside across the skin through elecro-osmosis mechanism^28-29.

It has been studied thatthiocolchicoside having the effective convulsant activity in the rat. These drugs can produce focal andgeneralised convulsive status epilepticus which justifies the further investigation. From the result it confirmsthat the data obtained in humans indicating the convulsant activity of thiocolchicoside occurs mainly when there are less lesions of the arachnoids membranes and dura. The convulsant properties of thiocolchicoside in rats are discovered in this study and also the article explainsabout the electro clinical patterns of epileptic seizures^30-33.

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Received on 11.03.2022 Modified on 16.05.2022

Asian J. Res. Pharm. Sci. 2022; 12(3):213-218.

DOI: 10.52711/2231-5659.2022.00038