Chemistry:Tofisopam

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Short description: Chemical compound
Tofisopam
Tofisopam structure.svg
Tofisopam ball-and-stick model.png
Clinical data
Other names6-(3,4-Dimethoxyphenyl)-2-ethyl-9,10-dimethoxy-3-methyl-4,5-diazabicyclo[5.4.0]undeca-3,5,7,9,11-pentaene
AHFS/Drugs.comInternational Drug Names
Routes of
administration		By mouth (tablets)
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
MetabolismHepatic
Elimination half-life3 hours[1][2]
ExcretionRenal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC22H26N2O4
Molar mass382.5 g·mol−1
3D model (JSmol)
  (verify)

Tofisopam[3] (Emandaxin, Grandaxin, Sériel) is an anxiolytic that is marketed in several European countries.[4] 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,[5] skeletal muscle relaxant, motor skill-impairing or amnestic[6] 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) and muscimol, but not sodium valproate, carbamazepine, phenobarbital, or phenytoin.[7][8] 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,[9] with moderate efficacy demonstrated in clinical trials so far.[10]

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.[11]

Tofisopam has been shown to act as an inhibitor of the liver enzyme CYP3A4,[12][13] and some researches suspect that this could cause dangerous drug interactions with other medications metabolised by this enzyme,[14][15] although the clinical significance of these findings remains unclear.

References

  1. ↑ "[Pharmacokinetics and metabolism of tofizopam (Grandaxin)]" (in Hungarian). Acta Pharm Hung 63 (2): 83–90. March 1993. PMID 8100113. 
  2. ↑ "The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis". J Neural Transm (Vienna) 117 (11): 1319–25. November 2010. doi:10.1007/s00702-010-0507-3. PMID 20967473. 
  3. ↑ DE Patent 2122070
  4. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. p. 1041. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1041. 
  5. ↑ "A comparison of the psychotropic profiles of tofisopam and diazepam". European Journal of Clinical Pharmacology 22 (2): 137–42. 1982. doi:10.1007/BF00542458. PMID 6124424. 
  6. ↑ "Tofisopam, a novel 3,4-benzodiazepine: multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol". Psychopharmacology 69 (2): 209–18. 1980. doi:10.1007/BF00427652. PMID 6109345. 
  7. ↑ "Tofizopam selectively increases the action of anticonvulsants". Medical Biology 64 (4): 201–6. 1986. PMID 3023768. 
  8. ↑ "[Pharmacologic effects of tofizopam (Grandaxin)]". Acta Pharmaceutica Hungarica 63 (2): 79–82. March 1993. PMID 8100112. 
  9. ↑ 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. http://www.velapharm.com/news/press050104.html. 
  10. ↑ "Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome". Alimentary Pharmacology & Therapeutics 27 (2): 197–206. January 2008. doi:10.1111/j.1365-2036.2007.03566.x. PMID 17973974. 
  11. ↑ Nielsen EB, Kehler J, Nielsen J, Brøsen P. Use of Tofisopam as a PDE10A inhibitor. WIPO Patent WO/2007/082546
  12. ↑ "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". FDA. 26 May 2021. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
  13. ↑ "[Effect of tofisopam on CYP3A4 enzyme activity on human recombinant 3A4 supersome]". Acta Pharmaceutica Hungarica 75 (4): 195–8. 2005. PMID 16711396. 
  14. ↑ "Effect of tofisopam on the single-oral-dose pharmacokinetics and pharmacodynamics of the cyp3a4 probe drug alprazolam". European Journal of Clinical Pharmacology 62 (7): 587–8. July 2006. doi:10.1007/s00228-006-0160-9. PMID 16791582. 
  15. ↑ "Tofisopam inhibits the pharmacokinetics of CYP3A4 substrate midazolam". European Journal of Clinical Pharmacology 64 (1): 93–4. January 2008. doi:10.1007/s00228-007-0397-y. PMID 17989974. 

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