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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/02/16 14:24:46」(JST)

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Tofisopam^[1] (Emandaxin, Grandaxin, Sériel) is an anxiolytic that is marketed in several European countries.^[2] Chemically, it is a 1,2-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 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.^[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

^ DE Patent 2122070
^ Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. p. 1041. ISBN 978-3-88763-075-1.
^ 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.
^ 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.
^ Saano, V. (1986). "Tofizopam selectively increases the action of anticonvulsants". Medical Biology 64 (4): 201–6. PMID 3023768.
^ 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. Retrieved 21 February 2006. ^{[dead link]}
^ 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
^ Nielsen EB, Kehler J, Nielsen J, Brøsen P. Use of Tofisopam as a PDE10A inhibitor. WIPO Patent WO/2007/082546
^ 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
^ 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
^ 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

External links

Inchem.org - Tofisopam

English Journal

Disorder of autonomic nervous system and its vulnerability to external stimulation in functional dyspepsia.

Tominaga K1, Fujikawa Y2, Tsumoto C1, Kadouchi K1, Tanaka F1, Kamata N1, Yamagami H1, Tanigawa T1, Watanabe T1, Fujiwara Y1, Arakawa T1.
Journal of clinical biochemistry and nutrition.J Clin Biochem Nutr.2016 Mar;58(2):161-5. doi: 10.3164/jcbn.15-140. Epub 2016 Feb 17.
PMID 27013784

Psychiatric aspects of phosphodiesterases: An overview.

Murthy VS1, Mangot AG1.
Indian journal of pharmacology.Indian J Pharmacol.2015 Nov-Dec;47(6):594-9. doi: 10.4103/0253-7613.169593.
PMID 26729948

Acute Effects of Oral Tofisopam on Plasma Concentration and Urinary Excretion of Uric Acid and Oxypurinol.

Hatayama M, Sumida C, Kurajoh M, Shiraishi J, Okazaki H, Shoji T, Koyama H, Tsutsumi Z, Moriwaki Y, Namba M, Yamamoto T1.
Current clinical pharmacology.Curr Clin Pharmacol.2015 Jan 26. [Epub ahead of print]
PMID 25619490

Japanese Journal

Synthesis of 2,3-Benzodiazepines and 2,3-Benzodiazepin-4-ones from Arynes and β-Diketones

Okuma Kentaro,Tanabe Yukiko,Nagahora Noriyoshi,Shioji Kosei
Bulletin of the Chemical Society of Japan advpub(0), 2015
… Tofisopam, well known anxiolytics, could be synthesized via C-C bond insertion of 3,4-dimethoxybenzyne with 2-ethyl-1-(3,4-dimethoxyphenyl)butane-1,3-dione, followed by the reaction with hydrazine hydrate in one pot operation. …
NAID 130005067225

NEW, LITHIATION-BASED SYNTHESIS OF TOFISOPAM, A 2,3-BENZODIAZEPINE TYPE ANXIOLYTIC DRUG (Dedicated to Professor Victor Snieckus on the occasion of his 77th birthday)

Molnarne Samu Erika,Lukacs Gyula,Volk Balazs [他]
Heterocycles : an international journal for reviews and communications in heterocyclic chemistry 88(1), 287-295, 2014-01-01
NAID 40019928256

One-pot Synthesis of 2,3-Benzodiazepines from Arynes and β-Diketones

Okuma Kentaro,Tanabe Yukiko,Itoyama Ryoichi,Nagahora Noriyoshi,Shioji Kosei
Chemistry Letters 42(10), 1260-1262, 2013
… Tofisopam, well-known anxiolytics, could be synthesized via C–C bond insertion of 4,5-dimethoxybenzyne with 2-ethyl-1-(3,4-dimethoxyphenyl)butane-1,3-dione, followed by the reaction with hydrazine hydrate in a one-pot operation. …
NAID 130004426759

★リンクテーブル★

リンク元

「トフィソパム」

Tofisopam
Systematic (IUPAC) name
	1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine
Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy; category	?;
Legal status	?;
Routes	Oral
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic
Half-life	6–8 hours
Excretion	Renal
Identifiers
CAS number	22345-47-7
ATC code	N05BA23
PubChem	CID 5502
DrugBank	DB08811
ChemSpider	5301
UNII	UZC80HAU42
KEGG	D01254
ChEMBL	CHEMBL404216
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
Chemical data
Formula	C22H26N2O4
Molecular mass	382.5
	SMILES O(c3ccc(C\2=N\N=C(/C(c1c/2cc(OC)c(OC)c1)CC)C)cc3OC)C;
	InChI 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 ; Key:RUJBDQSFYCKFAA-UHFFFAOYSA-N ;
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英: tofisopam
関: エマンダキシン、クラソパン、グランダキシン、グランパム、コバンダキシン、ツルベール、トフィール、トフィス、トフィルシン、トルバナシン、トロンヘイム、ハイミジン、バイダキシン、マイロニン

[1] DE Patent 2122070

[TaylorFrancis2000-2] Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. p. 1041. ISBN 978-3-88763-075-1.

[definitely_not_diazepam-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.

[not_diazepam-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.

[curiouser_and_curiouser-5] Saano, V. (1986). "Tofizopam selectively increases the action of anticonvulsants". Medical Biology 64 (4): 201–6. PMID 3023768.

[dtfp_ibs-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. Retrieved 21 February 2006. ^{[dead link]}

[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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tofisopam