tofisopam

{{Short description|Anxiolytic medication}}

{{Use mdy dates|date=February 2024}}

{{Drugbox

| verifiedrevid = 443236809

| IUPAC_name = 1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine

| image = Tofisopam structure.svg

| width = 170

| image2 = Tofisopam ball-and-stick model.png

| width2 = 200

| tradename =

| Drugs.com = {{drugs.com|international|tofisopam}}

| pregnancy_category =

| legal_status = Rx-only

| routes_of_administration = By mouth (tablets)

| bioavailability =

| metabolism = Hepatic

| elimination_half-life = 3 hours{{cite journal |vauthors=Klebovich I, Abermann M |title=[Pharmacokinetics and metabolism of tofizopam (Grandaxin)] |language=Hungarian |journal=Acta Pharm Hung |volume=63 |issue=2 |pages=83–90 |date=March 1993 |pmid=8100113 |doi= |url=}}{{cite journal |vauthors=Rundfeldt C, Socała K, Wlaź P |title=The atypical anxiolytic drug, tofisopam, selectively blocks phosphodiesterase isoenzymes and is active in the mouse model of negative symptoms of psychosis |journal=J Neural Transm (Vienna) |volume=117 |issue=11 |pages=1319–25 |date=November 2010 |pmid=20967473 |pmc=2993883 |doi=10.1007/s00702-010-0507-3 |url=}}

| excretion = Renal

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 22345-47-7

| ATC_prefix = N05

| ATC_suffix = BA23

| PubChem = 5502

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB08811

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 5301

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = UZC80HAU42

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D01254

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 404216

| C=22 | H=26 | N=2 | O=4

| smiles = O(c3ccc(C\2=N\N=C(/C(c1c/2cc(OC)c(OC)c1)CC)C)cc3OC)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = RUJBDQSFYCKFAA-UHFFFAOYSA-N

| 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

}}

TofisopamDE Patent 2122070 (Emandaxin, Grandaxin, Sériel) is an anxiolytic that is marketed in several European countries.{{cite book | title = Index Nominum 2000: International Drug Directory | url = https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA1041 | date = January 2000 | publisher = Taylor & Francis | isbn = 978-3-88763-075-1 | page = 1041}} 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,{{cite journal | vauthors = Bond A, Lader M | title = A comparison of the psychotropic profiles of tofisopam and diazepam | journal = European Journal of Clinical Pharmacology | volume = 22 | issue = 2 | pages = 137–42 | year = 1982 | pmid = 6124424 | doi = 10.1007/BF00542458 | s2cid = 30776062 }} skeletal muscle relaxant, motor skill-impairing or amnestic{{cite journal | vauthors = Seppälä T, Palva E, Mattila MJ, Korttila K, Shrotriya RC | title = Tofisopam, a novel 3,4-benzodiazepine: multiple-dose effects on psychomotor skills and memory. Comparison with diazepam and interactions with ethanol | journal = Psychopharmacology | volume = 69 | issue = 2 | pages = 209–18 | year = 1980 | pmid = 6109345 | doi = 10.1007/BF00427652 | s2cid = 24063885 }} 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.{{cite journal | vauthors = Saano V | title = Tofizopam selectively increases the action of anticonvulsants | journal = Medical Biology | volume = 64 | issue = 4 | pages = 201–6 | year = 1986 | pmid = 3023768 }}{{cite journal | vauthors = Petócz L | title = [Pharmacologic effects of tofizopam (Grandaxin)] | journal = Acta Pharmaceutica Hungarica | volume = 63 | issue = 2 | pages = 79–82 | date = March 1993 | pmid = 8100112 }} 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,{{cite web|author=Vela Pharmaceuticals |year=2005 |url=http://www.velapharm.com/news/press050104.html |title=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 |work=VelaPharm - News |access-date=February 21, 2006 |url-status=dead |archive-url=https://web.archive.org/web/20050502010007/http://www.velapharm.com/news/press050104.html |archive-date=May 2, 2005 }} with moderate efficacy demonstrated in clinical trials so far.{{cite journal | vauthors = Leventer SM, Raudibaugh K, Frissora CL, Kassem N, Keogh JC, Phillips J, Mangel AW | title = Clinical trial: dextofisopam in the treatment of patients with diarrhoea-predominant or alternating irritable bowel syndrome | journal = Alimentary Pharmacology & Therapeutics | volume = 27 | issue = 2 | pages = 197–206 | date = January 2008 | pmid = 17973974 | doi = 10.1111/j.1365-2036.2007.03566.x | s2cid = 8557111 }}

Tofisopam is also claimed to be a PDE_10A 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.[http://www.freepatentsonline.com/WO2007082546.html Nielsen EB, Kehler J, Nielsen J, Brøsen P. Use of Tofisopam as a PDE10A inhibitor. WIPO Patent WO/2007/082546]

Tofisopam has been shown to act as an inhibitor of the liver enzyme CYP3A4,{{cite journal |title=Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers |journal=FDA|date=May 26, 2021|url=https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers}}{{cite journal | vauthors = Tóth M, Bajnógel J, Egyed A, Drabant S, Tömlo J, Klebovich I | title = [Effect of tofisopam on CYP3A4 enzyme activity on human recombinant 3A4 supersome] | journal = Acta Pharmaceutica Hungarica | year = 2005 | volume = 75 | issue = 4 | pages = 195–8 | pmid = 16711396 }} and some researches suspect that this could cause dangerous drug interactions with other medications metabolised by this enzyme,{{cite journal | vauthors = Drabant S, Tóth M, Bereczki A, Bajnógel J, Tömlö J, Klebovich I | title = Effect of tofisopam on the single-oral-dose pharmacokinetics and pharmacodynamics of the cyp3a4 probe drug alprazolam | journal = European Journal of Clinical Pharmacology | volume = 62 | issue = 7 | pages = 587–8 | date = July 2006 | pmid = 16791582 | doi = 10.1007/s00228-006-0160-9 | s2cid = 32545296 }}{{cite journal | vauthors = Tóth M, Drabant S, Varga B, Végso G, Cseh A, Szentpéteri I, Klebovich I | title = Tofisopam inhibits the pharmacokinetics of CYP3A4 substrate midazolam | journal = European Journal of Clinical Pharmacology | volume = 64 | issue = 1 | pages = 93–4 | date = January 2008 | pmid = 17989974 | doi = 10.1007/s00228-007-0397-y | s2cid = 35022772 }} although the clinical significance of these findings remains unclear.