The amplitude of eIPSCs is lowered by thiocolchicoside (0.001, 0.1, 1, 10, 100 μM) in a concentration-dependent manner; this impact is substantial at 0.1 μM and reaches its maximum at 10 μM [1].

Absorption, Distribution and Excretion
Oral bioavailability is ~25% After intramuscular administration, thiocolchicoside Cmax occur in 30 min and .reach values of 113 ng/mL after a 4 mg dose and 175 ng/mL after a 8 mg dose. The corresponding values of AUC are respectively 283 and 417 ng.h/mL. The pharmacologically active metabolite SL18.0740 is found at lower concentrations with a Cmax of 11.7 ng/mL occurring 5 h post administration and an AUC of 83 ng.h/mL. After oral administration, no thiocolchicoside is detected in plasma. Only two metabolites are observed: The pharmacologically active metabolite SL18.0740 and an inactive metabolite SL59.0955. For both metabolites, maximum plasma concentrations occur 1hour after thiocolchicoside administration. After a single oral dose of 8 mg of thiocolchicoside the Cmax and AUC of SL18.0740 are about 60 ng/mL and 130 ng.h/mL respectively. For SL59.0955 these values are much lower: Cmax around 13 ng/mL and AUC ranging from 15.5 ng.h/mL (until 3h) to 39.7 ng.h/mL (until 24h).
Thiocolchicoside is not eliminated unchanged, rather as one of three metabolites found in either feces (~79 %) or in urine 20%. 3- demethylcolchicine (M2) and 3-O-glucurono-demethylcolchicine (M1) are found in both urine and feces, where as di-demethylcolchicine is found only in feces.
The apparent volume of distribution of thiocolchicoside is estimated to be approximately 42.7 L after an intramuscular injection of 8 mg.
Primarily extrarenal elimination (75% of the total body clearance).

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Metabolism / Metabolites
Thiocolchicoside is rapidly absorbed after oral administration and metabolized into 3 main metabolites. Firstly, in the intestines to 3-demethylcolchicine (inactive metabolite). This product is further metabolized in circulation by either conjugation to 3-O-glucurono-demethylcolchicine (active metabolite) or demethylated to didemethylcolchicine (inactive metabolite)

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Biological Half-Life
Approximately 7.7h.

Protein Binding
The binding of 3H-colchicine and its derivative 3H-thiocolchicoside to human serum, purified human proteins, as well as red blood cells was studied using equilibrium dialysis and centrifugation. Binding of colchicine and thiocolchicoside to human serum was 38.9 C +/- 4.7 and 12.8 C +/- 5.3%, respectively, to albumin.

[1]. The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system. Neuropharmacology. 2006 Sep;51(4):805-15.

N-[(7S)-1,2-dimethoxy-10-(methylthio)-9-oxo-3-[[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide is a glycoside.
Thiocolchicoside is a semi-synthetic derivative of the colchicine, a natural anti-inflammatory glycoside which originates from the flower seeds of Superba gloriosa. It is a muscle relaxant with anti-inflammatory and analgesic effects. It has potent convulsant activity and should not be administered to individuals prone to seizures.

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Drug Indication
Thiocolchicoside is a skeletal muscle-relaxant drug used in the treatment of orthopedic, traumatic and rheumatologic disorders. It is indicated as an adjuvant drug in the treatment of painful muscle contractures and is indicated in acute spinal pathology, for adults and adolescents 16 years of age and older. Recent studies have examined its effect on muscle tone, stiffness, contractures, and soreness experienced by athletes during sporting competitions.

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Mechanism of Action
Thiocolchicoside, is a synthetic sulfur derivative of colchicoside, a naturally occurring glucoside contained in the Colchicum autumnale plant. Thiocolchicoside has a selective and potent affinity for g-aminobutyric acid A (GABA-A) receptors and acts on muscular contractures by activating the GABA inhibitory pathways thereby behaving as a potent muscle relaxant. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. GABAergic neurons are involved in myorelaxation, anxiolytic treatment, sedation, and anesthetics. GABA can also modulate heart rate and blood pressure. It also has an affinity for the inhibitory glycine receptors (i.e., have glycomimetic and GABA mimetic activity), therefore acts as a muscle relaxant. Glycine is an inhibitory neurotransmitter and acts as an allosteric regulator of NMDA (N-methyl-D-aspartate) receptors. It is involved in the processing of motor and sensory data, thereby regulating movement, vision, and audition. Inhibitory neurotransmitter in spinal cord, allosteric regulator of NMDA receptors. In one study, thiocolchicoside inhibited the function of recombinant human strychnine-sensitive glycine receptors composed of the alpha1 subunit with a potency (median inhibitory concentration of 47 microM) lower than that apparent with recombinant GABA(A) receptors. The drug also inhibited the function of human nicotinic acetylcholine receptors made of the alpha4 and beta2 subunits, however, this effect was partial and moreover only apparent at high concentrations. Thiocolchicoside demonstrated no effect on the function of 5-HT(3A) serotonin receptors.

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Pharmacodynamics
Thiocholchicoside is a muscle relaxing agent that works through selective binding to the GABA-A receptor. It prevents muscle contractions by activating the GABA inhibitory motor pathway. This medication acts as a competitive GABA receptor antagonist and inhibits glycine receptors with similar potency as nicotinic acetylcholine receptors. It has powerful convulsant activity and should not be used in individuals at risk for seizures. Used in combination with glafenine and meprobamate to tranquilize patients undergoing hysterosalpingography. In the treatment of painful muscle spasms. Thiocolchicoside acts both in contractures with a central cause and in contractures of reflex type, rheumatic and traumatic. It also alleviates symptoms of spastic sequelae of hemiparesis, Parkinson's disease and iatrogenic Parkinson symptoms, particularly neurodyslectic syndrome. Some other conditions that may benefit from this medication are acute and chronic lumbar and sciatic pain, cervico-brachial neuralgia, persistent torticollis, post-traumatic and post-operative pain.

C27H33NO10S

563.618

563.182

602-41-5

9915886

Light yellow to yellow solid powder

1.5±0.1 g/cm3

929.6±65.0 °C at 760 mmHg

190-198ºC

516.0±34.3 °C

0.0±0.3 mmHg at 25°C

1.657

-1.23

5

11

7

39

1010

6

CC(=O)N[C@H]1CCC2=CC(=C(C(=C2C3=CC=C(C(=O)C=C13)SC)OC)OC)O[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O

LEQAKWQJCITZNK-AXHKHJLKSA-N

InChI=1S/C27H33NO10S/c1-12(30)28-16-7-5-13-9-18(37-27-24(34)23(33)22(32)19(11-29)38-27)25(35-2)26(36-3)21(13)14-6-8-20(39-4)17(31)10-15(14)16/h6,8-10,16,19,22-24,27,29,32-34H,5,7,11H2,1-4H3,(H,28,30)/t16-,19+,22+,23-,24+,27+/m0/s1

N-[(7S)-1,2-dimethoxy-10-methylsulfanyl-9-oxo-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6,7-dihydro-5H-benzo[a]heptalen-7-yl]acetamide

Coltramyl; R. 271; Thiocolchicoside

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~250 mg/mL (~443.56 mM)
H2O : ~50 mg/mL (~88.71 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (3.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)