Tofisopam

Tofisopam
Clinical data
Trade namesEndaxin
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.comtofizopam International 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
ExcretionRenal
Identifiers
  • 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.040.823 Edit this at Wikidata
Chemical and physical data
FormulaC22H26N2O4
Molar mass382.460 g·mol−1
3D model (JSmol)
  • O(c3ccc(C\2=N\N=C(/C(c1c/2cc(OC)c(OC)c1)CC)C)cc3OC)C
  • InChI=1S/C22H26N2O4/c1-7-15-13(2)23-24-22(14-8-9-18(25-3)19(10-14)26-4)17-12-21(28-6)20(27-5)11-16(15)17/h8-12,15H,7H2,1-6H3 checkY
  • Key:RUJBDQSFYCKFAA-UHFFFAOYSA-N checkY
  (verify)

Tofisopam is chemically a 2,3-benzodiazepine marketed as an anxiolytic under trade names including Emandaxin and Grandaxin. Unlike other anxiolytic benzodiazepines, which are generally 1,4- or 1,5-substituted,[clarification needed] tofisopam does not have anticonvulsant, sedative, skeletal muscle relaxant, motor skill-impairing or amnestic properties.

Indications

It has been shown to enhance the anticonvulsant action of diazepam (a 1,4-benzodiazepine) and muscimol, but not of sodium valproate, carbamazepine, phenobarbital, or phenytoin.

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.[citation needed]

Approval and use

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, with moderate efficacy demonstrated in clinical trials so far.

Trade names

Tofisopam has been spelt alternatively as tofizopam and has been marketed and listed as "Grandaxin" in Hungary and other European countries, Pakistan, and Egypt.[citation needed] Japanese preparations include "Grandaxin 10%" and "Granpam". It has been marketed in India as "Nextril" and "Toficalm".[citation needed]

It is not approved in North America, including the U.S. and Canada, but it has appeared in United States patent literature and regulatory references. A U.S. patent concerning S-tofisopam was filed in 2001 and subsequently issued as U.S. Patent 6,649,607; the related patent record expired in November 2021US 7078398, "Compositions and methods for treating or preventing convulsions or seizures" 

The patent describes S-tofisopam separately from the previously marketed racemic drug and does not constitute FDA approval of tofisopam as a human medicine in the United States.

Tofisopam has also appeared in Washington State's equine drug regulations. Washington State regulatory documents list the brand names "Grandaxain" and "Seriel". They also classify it as a Class 2 substance within equine medicine.

Pharmacokinetics

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.

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

References

  1. ↑ Klebovich I, Abermann M (March 1993). "[Pharmacokinetics and metabolism of tofizopam (Grandaxin)]". Acta Pharm Hung (in Hungarian). 63 (2): 83–90. PMID 8100113.
  2. ↑ Rundfeldt C, Socała K, Wlaź P (November 2010). "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. doi:10.1007/s00702-010-0507-3. PMC 2993883. 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.
  5. ↑ Bond A, Lader M (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. S2CID 30776062.
  6. ↑ Seppälä 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. 69 (2): 209–18. doi:10.1007/BF00427652. PMID 6109345. S2CID 24063885.
  7. ↑ Saano V (1986). "Tofizopam selectively increases the action of anticonvulsants". Medical Biology. 64 (4): 201–6. PMID 3023768.
  8. ↑ Petócz L (March 1993). "[Pharmacologic effects of tofizopam (Grandaxin)]". Acta Pharmaceutica Hungarica. 63 (2): 79–82. 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. Archived from the original on May 2, 2005. Retrieved February 21, 2006.
  10. ↑ Leventer SM, Raudibaugh K, Frissora CL, Kassem N, Keogh JC, Phillips J, Mangel AW (January 2008). "Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome". Alimentary Pharmacology & Therapeutics. 27 (2): 197–206. doi:10.1111/j.1365-2036.2007.03566.x. PMID 17973974. S2CID 8557111.
  11. ↑ "Tofisopam (International database)". Drugs.com. Retrieved 2026-10-02.
  12. ↑ "Chapter 260-70 WAC" (PDF). Washington State Legislature. 2019-10-25. Retrieved 2026-10-02.
  13. ↑ Nielsen EB, Kehler J, Nielsen J, Brøsen P. Use of Tofisopam as a PDE10A inhibitor. WIPO Patent WO/2007/082546
  14. ↑ "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers". FDA. May 26, 2021. Archived from the original on May 3, 2019.
  15. ↑ Tóth M, Bajnógel J, Egyed A, Drabant S, Tömlo J, Klebovich I (2005). "[Effect of tofisopam on CYP3A4 enzyme activity on human recombinant 3A4 supersome]". Acta Pharmaceutica Hungarica. 75 (4): 195–8. PMID 16711396.
  16. ↑ Drabant S, Tóth M, Bereczki A, Bajnógel J, Tömlö J, Klebovich I (July 2006). "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. doi:10.1007/s00228-006-0160-9. PMID 16791582. S2CID 32545296.
  17. ↑ Tóth M, Drabant S, Varga B, Végso G, Cseh A, Szentpéteri I, Klebovich I (January 2008). "Tofisopam inhibits the pharmacokinetics of CYP3A4 substrate midazolam". European Journal of Clinical Pharmacology. 64 (1): 93–4. doi:10.1007/s00228-007-0397-y. PMID 17989974. S2CID 35022772.