Tofisopam

Tofisopam
Clinical data
AHFS/Drugs.com International Drug Names
Routes of
administration		 Oral
ATC code N05BA23 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Metabolism Hepatic
Biological half-life 6–8 hours
Excretion Renal
Identifiers
Synonyms 6-(3,4-dimethoxyphenyl)-2-ethyl-9,10-dimethoxy-3-methyl-4,5-diazabicyclo[5.4.0]undeca-3,5,7,9,11-pentaene
CAS Number 22345-47-7 YesY
PubChem (CID) 5502
DrugBank DB08811 YesY
ChemSpider 5301 YesY
UNII UZC80HAU42 YesY
KEGG D01254 YesY
ChEMBL CHEMBL404216 YesY
ECHA InfoCard 100.040.823
Chemical and physical data
Formula C22H26N2O4
Molar mass 382.5
3D model (Jmol) Interactive image
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Tofisopam[1] (Emandaxin, Grandaxin, Sériel) is an anxiolytic that is marketed in several European countries.[2] Chemically, it is a 2,3-benzodiazepine. Unlike other anxiolytic benzodiazepines (which are generally 1,4- or 1,5-substituted) however, tofisopam does not have anticonvulsant, sedative,[3] skeletal muscle relaxant, motor skill-impairing or amnestic[4] properties. While it may not be an anticonvulsant in and of itself, it has been shown to enhance the anticonvulsant action of classical 1,4-benzodiazepines such as diazepam (but not sodium valproate, carbamazepine, phenobarbital, or phenytoin).[5] Tofisopam is indicated for the treatment of anxiety and alcohol withdrawal, and is prescribed in a dosage of 50–300 mg per day divided into three doses. Peak plasma levels are attained two hours after an oral dose. Tofisopam is not reported as causing dependence to the same extent as other benzodiazepines, but is still recommended to be prescribed for a maximum of 12 weeks.

Tofisopam is not approved for sale in the United States or Canada. However, Vela Pharmaceuticals of New Jersey is developing the D-enantiomer (dextofisopam) as a treatment for irritable bowel syndrome,[6] with moderate efficacy demonstrated in clinical trials so far.[7]

Tofisopam is also claimed to be a PDE10A inhibitor, which may provide an alternative mechanism of action for its various therapeutic effects, and this action has been proposed to make tofisopam potentially useful as a treatment for schizophrenia.[8]

Tofisopam has been shown to act as an inhibitor of the liver enzyme CYP3A4,[9] and this could potentially cause dangerous drug interactions with other medications metabolised by this enzyme,[10][11] although the clinical significance of these findings remains unclear.

References

  1. ↑ DE Patent 2122070
  2. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. p. 1041. ISBN 978-3-88763-075-1.
  3. ↑ Bond, A; M. Lader (1982). "A comparison of the psychotropic profiles of tofisopam and diazepam.". European Journal of Clinical Pharmacology. 22 (2): 137–42. doi:10.1007/BF00542458. PMID 6124424.
  4. ↑ Seppala, T; Palva E; Mattila MJ; Korttila K; Shrotriya RC (1980). "Tofisopam, a novel 3,4-benzodiazepine: multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol". Psychopharmacology (Berlin). 69 (2): 209–18. doi:10.1007/BF00427652. PMID 6109345.
  5. ↑ Saano, V. (1986). "Tofizopam selectively increases the action of anticonvulsants". Medical Biology. 64 (4): 201–6. PMID 3023768.
  6. ↑ Vela Pharmaceuticals (2005). "Vela Announces Positive Phase 2 Results for Dextofisopam in Treating Irritable Bowel Syndrome - IBS: Results Show Effects of Dextofisopam Both in Women and in Men". VelaPharm - News. Archived from the original on May 2, 2005. Retrieved 21 February 2006.
  7. ↑ Leventer SM, Raudibaugh K, Frissora CL, Kassem N, Keogh JC, Phillips J, Mangel AW. Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome. Alimentary Pharmacology and Therapeutics. 2008 Jan 15;27(2):197-206. PMID 17973974
  8. ↑ Nielsen EB, Kehler J, Nielsen J, Brøsen P. Use of Tofisopam as a PDE10A inhibitor. WIPO Patent WO/2007/082546
  9. ↑ Tóth M, Bajnógel J, Egyed A, Drabant S, Tömlo J, Klebovich I. Effect of tofisopam on CYP3A4 enzyme activity on human recombinant 3A4 supersome. (Hungarian) Acta Pharmaceutica Hungarica. 2005;75(4):195-8. PMID 16711396
  10. ↑ Drabant S, Tóth M, Bereczki A, Bajnógel J, Tömlö J, Klebovich I. Effect of tofisopam on the single-oral-dose pharmacokinetics and pharmacodynamics of the cyp3a4 probe drug alprazolam. European Journal of Clinical Pharmacology. 2006 Jul;62(7):587-8. PMID 16791582
  11. ↑ Tóth M, Drabant S, Varga B, Végso G, Cseh A, Szentpéteri I, Klebovich I. Tofisopam inhibits the pharmacokinetics of CYP3A4 substrate midazolam. European Journal of Clinical Pharmacology. 2008 Jan;64(1):93-4. PMID 17989974


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