Thiocolchicoside

Identification

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Name
Thiocolchicoside
Accession Number
DB11582
Type
Small Molecule
Groups
Experimental
Description

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 19.

Structure
Thumb
Synonyms
  • TCC
  • Thiocolchicine 2-glucoside analog
External IDs
210-017-7
International/Other Brands
Biocolchid (Biogalenic) / Coltramyl / Coltrax / Eusilen (Velka) / Miorel / Musco-Ril / Muscoril / Myolax (Adwya) / Myoril / Neoflax / Neuroflax / TDP (Aamorb)
Categories
UNII
T1X8S697GT
CAS number
602-41-5
Weight
Average: 563.62
Monoisotopic: 563.182517441
Chemical Formula
C27H33NO10S
InChI Key
LEQAKWQJCITZNK-AXHKHJLKSA-N
InChI
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
IUPAC Name
N-[(10S)-3,4-dimethoxy-14-(methylsulfanyl)-13-oxo-5-{[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}tricyclo[9.5.0.0²,⁷]hexadeca-1(16),2,4,6,11,14-hexaen-10-yl]acetamide
SMILES
COC1=C(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)C=C2CC[C@H](NC(C)=O)C3=CC(=O)C(SC)=CC=C3C2=C1OC

Pharmacology

Indication

Thiocolchicoside is a skeletal muscle-relaxant drug used in the treatment of orthopedic, traumatic and rheumatologic disorders 18. 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 15. Recent studies have examined its effect on muscle tone, stiffness, contractures, and soreness experienced by athletes during sporting competitions 20.

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 18.

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 18,23.

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 18.

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 18. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex 11. 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 19,12.

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 11.

TargetActionsOrganism
AGABA-A receptor (anion channel)
antagonist
Humans
UGlycine receptor subunit alpha-1
antagonist
Humans
UTumor necrosis factor ligand superfamily member 11
antagonist
Humans
Absorption

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 15.

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) 15.

Volume of distribution

The apparent volume of distribution of thiocolchicoside is estimated to be approximately 42.7 L after an intramuscular injection of 8 mg 15.

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 7.

Metabolism

Thiocolchicoside is rapidly absorbed after oral administration and metabolized into 3 main metabolites 18.

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)

Route of elimination

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 24.

Half life

Approximately 7.7h 24.

Clearance

Primarily extrarenal elimination (75% of the total body clearance) 13.

Toxicity

Has been shown to cause chromosomal aneuploidy and male infertility. Should be avoided during all stages of pregnancy, lactation and puberty. Is a potential risk factor for cancer.

In 2013, The European Medical Association (EMA) mandated that the use of thiocolchicoside-containing medicines by mouth or injection should be restricted across the European Union (EU). These drugs are now recommended only as an add-on treatment for painful muscle contractures resulting from spinal conditions in adults and adolescents 16 years old and older. Additionally, the dose of thiocolchicoside by mouth or injection should be limited. This is due to experimental evidence suggesting that thiocolchicoside was metabolized into M2 or SL59.0955, that has the propensity to damage dividing cells, resulting in aneuploidy (an abnormal number or arrangement of chromosomes). As a result, the CHMP (committee for medicinal products for human use) examined the safety profile of this medicine and consider what regulatory action might be appropriate 14.

The CHMP reviewed the evidence, with consideration of opinions from experts in medicines safety, and concluded that aneuploidy may occur with M2 at levels not significantly greater than those measured after recommended doses of thiocolchicoside ingested orally. Aneuploidy is a strong risk factor for fetal harm, decreased fertility in men, and could theoretically increase the risk of developing cancer 14.

The maximum recommended oral dose is 8 mg every 12 hours; treatment length should not exceed 7 consecutive days. When given intramuscularly (IM), the maximum dose is 4 mg every 12 hours, for a maximum of 5 days 14.

In addition to the above toxicity, a study was done on the hepatotoxic potential of thiocolchicoside. It was observed that serum AST and ALT levels increased following of the administration oral thiocolchicoside at 8 mg/day. Two weeks after discontinuing thiocolchicoside therapy, liver enzymes had decreased to levels within the normal range. Although infrequent, thiocolchicoside should be considered a rare hepatotoxic agent in clinical practice 10.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Thiocolchicoside is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Thiocolchicoside.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Thiocolchicoside.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Thiocolchicoside is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Thiocolchicoside.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinolineThe risk or severity of adverse effects can be increased when 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline is combined with Thiocolchicoside.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Thiocolchicoside.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Thiocolchicoside.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Thiocolchicoside.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Thiocolchicoside.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

References

General References
  1. Perucca E, Poitou P, Pifferi G: Comparative pharmacokinetics and bioavailability of two oral formulations of thiocolchicoside, a GABA-mimetic muscle relaxant drug, in normal volunteers. Eur J Drug Metab Pharmacokinet. 1995 Oct-Dec;20(4):301-5. [PubMed:8983937]
  2. Sandouk P, Bouvier d'Yvoire M, Chretien P, Tillement JP, Scherrmann JM: Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers. Biopharm Drug Dispos. 1994 Jan;15(1):87-92. [PubMed:8161719]
  3. Tuzun F, Unalan H, Oner N, Ozguzel H, Kirazli Y, Icagasioglu A, Kuran B, Tuzun S, Basar G: Multicenter, randomized, double-blinded, placebo-controlled trial of thiocolchicoside in acute low back pain. Joint Bone Spine. 2003 Sep;70(5):356-61. [PubMed:14563464]
  4. Ketenci A, Basat H, Esmaeilzadeh S: The efficacy of topical thiocolchicoside (Muscoril) in the treatment of acute cervical myofascial pain syndrome: a single-blind, randomized, prospective, phase IV clinical study. Agri. 2009 Jul;21(3):95-103. [PubMed:19780000]
  5. De Riu PL, Rosati G, Sotgiu S, Sechi G: Epileptic seizures after treatment with thiocolchicoside. Epilepsia. 2001 Aug;42(8):1084-6. [PubMed:11554898]
  6. Reuter S, Gupta SC, Phromnoi K, Aggarwal BB: Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. Br J Pharmacol. 2012 Apr;165(7):2127-39. doi: 10.1111/j.1476-5381.2011.01702.x. [PubMed:21955206]
  7. Sabouraud A, Chappey O, Dupin T, Scherrmann JM: Binding of colchicine and thiocolchicoside to human serum proteins and blood cells. Int J Clin Pharmacol Ther. 1994 Aug;32(8):429-32. [PubMed:7981928]
  8. Authors unspecified: Thiocolchicoside: review of adverse effects. Prescrire Int. 2016 Feb;25(168):41-3. [PubMed:27042729]
  9. Carta M, Murru L, Botta P, Talani G, Sechi G, De Riu P, Sanna E, Biggio G: The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system. Neuropharmacology. 2006 Sep;51(4):805-15. Epub 2006 Jun 30. [PubMed:16806306]
  10. Efe C, Purnak T, Ozaslan E, Milanlioglu A: Thiocolchicoside-induced liver injury. Clinics (Sao Paulo). 2011;66(3):521-2. [PubMed:21552685]
  11. Mascia MP, Bachis E, Obili N, Maciocco E, Cocco GA, Sechi GP, Biggio G: Thiocolchicoside inhibits the activity of various subtypes of recombinant GABA(A) receptors expressed in Xenopus laevis oocytes. Eur J Pharmacol. 2007 Mar 8;558(1-3):37-42. Epub 2006 Dec 12. [PubMed:17234181]
  12. Lopez-Corcuera B, Geerlings A, Aragon C: Glycine neurotransmitter transporters: an update. Mol Membr Biol. 2001 Jan-Mar;18(1):13-20. [PubMed:11396606]
  13. Sandouk P, Chappey O, d'Yvoire MB, Scherrmann JM: Pharmacokinetics of thiocolchicoside in humans using a specific radioimmunoassay. Ther Drug Monit. 1995 Oct;17(5):544-8. [PubMed:8585121]
  14. European Medicines Agency recommends restricting use of thiocolchicoside by mouth or injection [Link]
  15. Thiocolchicine EMA label [Link]
  16. Thiocolchicine Pubchem [Link]
  17. Thiocolchicine [Link]
  18. THIOCOLCHICOSIDE AS MUSCLE RELAXANT: A REVIEW [Link]
  19. To compare the efficacy and safety of fixed dose combination of thiocolchicoside and aceclofenac versus chlorzoxazone, aceclofenac and paracetamol in patients with acute lower backache associated with muscle spasm [Link]
  20. The effect of topical thiocolchicoside in preventing and reducing the increase of muscle tone, stiffness, and soreness: A real-life study on top-level road cyclists during stage competition [Link]
  21. Neurotransmitters as food supplements: the effects of GABA on brain and behavior [Link]
  22. GABA AND GLYCINE receptor modulators [Link]
  23. hiocolchicoside, 99% (HPLC) [Link]
  24. Review of the toxicology, pharmacodynamics and pharmacokinetics of thiocolchicoside, a GABA-agonist muscle relaxant with anti-inflammatory and analgesic actions [Link]
External Links
KEGG Drug
D07276
PubChem Compound
9915886
PubChem Substance
347827992
ChemSpider
8091534
BindingDB
233193
ChEBI
94557
ChEMBL
CHEMBL213907
Wikipedia
Thiocolchicoside
ATC Codes
M03BX05 — ThiocolchicosideM03BX55 — Thiocolchicoside, combinations
MSDS
Download (36.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentBack Pain Lower Back1
4CompletedTreatmentBack Pain Lower Back1
4CompletedTreatmentMyofascial Pain Syndromes1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)190-198http://henankerui.lookchem.com/products/CasNo-602-41-5-Thiocolchicoside-12752892.html
boiling point (°C)929.624http://henankerui.lookchem.com/products/CasNo-602-41-5-Thiocolchicoside-12752892.html
water solubility10 mg/mLhttps://www.sigmaaldrich.com/catalog/product/sigma/sml1476?lang=en®ion=CA
logP0.34http://www2.unipr.it/~santipat/Posters/2003/tio2003.pdf
pKa12.74https://www.ebi.ac.uk/chembldb/compound/inspect/CHEMBL1705373
Predicted Properties
PropertyValueSource
Water Solubility0.348 mg/mLALOGPS
logP0.78ALOGPS
logP-0.16ChemAxon
logS-3.2ALOGPS
pKa (Strongest Acidic)12.2ChemAxon
pKa (Strongest Basic)-1.2ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count10ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area164.01 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity145.06 m3·mol-1ChemAxon
Polarizability57.72 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

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 aryl ethers / Alkylarylthioethers / Oxanes / Acetamides / Secondary carboxylic acid amides / Secondary alcohols
show 9 more
Substituents
Phenolic glycoside / Hexose monosaccharide / O-glycosyl compound / Aryl thioether / Anisole / Tropone / Alkyl aryl ether / Alkylarylthioether / Monosaccharide / Benzenoid
show 24 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Inhibitory extracellular ligand-gated ion channel activity
Specific Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine...

Components:
References
  1. Carta M, Murru L, Botta P, Talani G, Sechi G, De Riu P, Sanna E, Biggio G: The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system. Neuropharmacology. 2006 Sep;51(4):805-15. Epub 2006 Jun 30. [PubMed:16806306]
  2. Mascia MP, Bachis E, Obili N, Maciocco E, Cocco GA, Sechi GP, Biggio G: Thiocolchicoside inhibits the activity of various subtypes of recombinant GABA(A) receptors expressed in Xenopus laevis oocytes. Eur J Pharmacol. 2007 Mar 8;558(1-3):37-42. Epub 2006 Dec 12. [PubMed:17234181]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Transmitter-gated ion channel activity
Specific Function
The glycine receptor is a neurotransmitter-gated ion channel. Binding of glycine to its receptor increases the chloride conductance and thus produces hyperpolarization (inhibition of neuronal firing).
Gene Name
GLRA1
Uniprot ID
P23415
Uniprot Name
Glycine receptor subunit alpha-1
Molecular Weight
52623.35 Da
References
  1. Mascia MP, Bachis E, Obili N, Maciocco E, Cocco GA, Sechi GP, Biggio G: Thiocolchicoside inhibits the activity of various subtypes of recombinant GABA(A) receptors expressed in Xenopus laevis oocytes. Eur J Pharmacol. 2007 Mar 8;558(1-3):37-42. Epub 2006 Dec 12. [PubMed:17234181]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Tumor necrosis factor receptor superfamily binding
Specific Function
Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be...
Gene Name
TNFSF11
Uniprot ID
O14788
Uniprot Name
Tumor necrosis factor ligand superfamily member 11
Molecular Weight
35477.81 Da
References
  1. Reuter S, Gupta SC, Phromnoi K, Aggarwal BB: Thiocolchicoside suppresses osteoclastogenesis induced by RANKL and cancer cells through inhibition of inflammatory pathways: a new use for an old drug. Br J Pharmacol. 2012 Apr;165(7):2127-39. doi: 10.1111/j.1476-5381.2011.01702.x. [PubMed:21955206]

Drug created on April 23, 2016 08:19 / Updated on June 04, 2019 07:24