Clotiazepam

Clotiazepam
Clinical data
Trade names	Veratran, Rize, Clozan
AHFS/Drugs.com	International Drug Names
Routes of; administration	Oral, sublingual, liquid drops
ATC code	N05BA21 (WHO) ;
Legal status
Legal status	BR: Class B1 (Psychoactive drugs); CA: Schedule IV; DE: Prescription only (Anlage III for higher doses); UK: Class C; US: Schedule IV;
Pharmacokinetic data
Bioavailability	~90%
Metabolism	Hepatic
Elimination half-life	4 hours
Excretion	Renal
Identifiers
	IUPAC name 5-(2-chlorophenyl)-7-ethyl-1-methyl-3H-thieno[2,3-e][1,4]diazepin-2-one;
CAS Number	33671-46-4 ;
PubChem CID	2811;
DrugBank	DB01559 ;
ChemSpider	2709 ;
UNII	ZCN055599V;
KEGG	D01328 ;
ChEMBL	ChEMBL1697737 ;
CompTox Dashboard (EPA)	DTXSID0022852 ;
ECHA InfoCard	100.046.920
Chemical and physical data
Formula	C16H15ClN2OS
Molar mass	318.82 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES ClC1=C(C2=NCC(N(C)C3=C2C=C(CC)S3)=O)C=CC=C1;
	InChI InChI=1S/C16H15ClN2OS/c1-3-10-8-12-15(11-6-4-5-7-13(11)17)18-9-14(20)19(2)16(12)21-10/h4-8H,3,9H2,1-2H3 ; Key:CHBRHODLKOZEPZ-UHFFFAOYSA-N ;
	(what is this?) (verify)

Clotiazepam^[3] (marketed under brand name Clozan, Distensan, Trecalmo, Rize, Rizen and Veratran) is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from benzodiazepines in that the benzene ring has been replaced by a thiophene ring.^[4] It possesses anxiolytic,^[5] skeletal muscle relaxant,^[6] anticonvulsant, sedative properties.^[7] Stage 2 NREM sleep is significantly increased by clotiazepam.^[8]

Indications

Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.^[9] Clotiazepam is also used as a premedicant in minor surgery in France and Japan, where the drug is commercially available under the brand names Veratran and Rize, respectively.^[10]^[11]

Pharmacokinetics

A cross-over study in six healthy volunteers (median age 28 years) was conducted using single-dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets. The formulations had similar systemic availability. Compared with oral tablets, the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.^[12]

Pharmacology

Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties.^[7] Clotiazepam binds to the benzodiazepine site of the GABA_A receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABA_A receptor which results in the pharmacological effects of clotiazepam.^[13]

Clotiazepam has a short elimination half-life and is less prone to accumulation after repeated dosing compared to longer-acting benzodiazepine agents. It is metabolised via oxidation.^[14] Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. After oral ingestion of a single 5 mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed.^[15] The elimination half-life of the drug and its metabolites range from 6.5 hours to 18 hours. Clotiazepam is 99 percent bound to plasma protein.^[15] In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.^[16] Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not affect the kinetics of clotiazepam.^[17]

The dose equivalent to 10 mg diazepam is thought to be between 5 and 10 mg clotiazepam.

Side effects

Side effects experienced with this product will resemble those of other benzodiazepines. Drowsiness and asthenia are common side effects.^[18] There has been a report of reversible hepatitis caused by clotiazepam.^[19]

Abuse

Clotiazepam is a recognised drug of abuse.^[20]

References

^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
^ "Clotiazépam" (PDF). HAS - Direction de l'Evaluation Médicale. Economique et de Santé Publique. 20 May 2015.
^ DE 2107356, Nakanishi M, Kazuhiko A, Tetsuya T, Shiroki M, "Thieno-(2,3-E)(1,4)diazepin-2-ones", issued 3 May 1978, assigned to Yoshitomi Pharmaceutical Industries, Ltd.
^ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs". Biological & Pharmaceutical Bulletin. 28 (9): 1711–1716. doi:10.1248/bpb.28.1711. PMID 16141545.
^ Klicpera C, Strian F (May 1978). "Autonomic perception and responses in anxiety-inducing situations". Pharmakopsychiatrie, Neuro-Psychopharmakologie. 11 (3): 113–120. doi:10.1055/s-0028-1094569. PMID 27828.
^ Fukuda T, Tsumagari T (August 1983). "Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats". Japanese Journal of Pharmacology. 33 (4): 885–890. doi:10.1254/jjp.33.885. PMID 6632385.
^ ^a ^b Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. PMID 18855614.
^ Nakazawa Y, Kotorii M, Oshima M, Horikawa S, Tachibana H (October 1975). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives". Psychopharmacologia. 44 (2): 165–171. doi:10.1007/BF00421005. PMID 709. S2CID 13365554.
^ Martucci N, Manna V, Agnoli A (April 1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative". International Clinical Psychopharmacology. 2 (2): 121–128. doi:10.1097/00004850-198704000-00005. PMID 2885366.
^ "RIZE TABLETS 5mg". Official Japanese Drug Information Sheet (Kusuri-no-Shiori). February 2016.
^ "Clotiazepam (Veratran)". French Guide to Medicines.
^ Benvenuti C, Bottà V, Broggini M, Gambaro V, Lodi F, Valenti M (1989). "The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers". European Journal of Clinical Pharmacology. 37 (6): 617–619. doi:10.1007/BF00562556. PMID 2575522. S2CID 29397932.
^ Yakushiji T, Fukuda T, Oyama Y, Akaike N (November 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones". British Journal of Pharmacology. 98 (3): 735–740. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.
^ Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI (1983). "Clinical pharmacokinetics of the newer benzodiazepines". Clinical Pharmacokinetics. 8 (3): 233–252. doi:10.2165/00003088-198308030-00003. PMID 6133664. S2CID 19691487.
^ ^a ^b Arendt R, Ochs HR, Greenblatt DJ (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies". Arzneimittel-Forschung. 32 (4): 453–455. PMID 6125154.
^ Ochs HR, Greenblatt DJ, Verburg-Ochs B, Harmatz JS, Grehl H (1984). "Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol". European Journal of Clinical Pharmacology. 26 (1): 55–59. doi:10.1007/BF00546709. PMID 6143670. S2CID 44321356.
^ Ochs HR, Greenblatt DJ, Knüchel M (1986). "Effect of cirrhosis and renal failure on the kinetics of clotiazepam". European Journal of Clinical Pharmacology. 30 (1): 89–92. doi:10.1007/BF00614202. PMID 2872061. S2CID 21304989.
^ Colonna L, Cozzi F, Del Citerna F, Di Benedetto A, De Divitiis O, Furlanello F, et al. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiologica. 38 (1–2): 45–49. PMID 1971433.
^ Habersetzer F, Larrey D, Babany G, Degott C, Corbic M, Pessayre D, Benhamou JP (September 1989). "Clotiazepam-induced acute hepatitis". Journal of Hepatology. 9 (2): 256–259. doi:10.1016/0168-8278(89)90060-3. PMID 2572625.
^ Shimamine M, Masunari T, Nakahara Y (1993). "[Studies on identification of drugs of abuse by diode array detection. I. Screening-test and identification of benzodiazepines by HPLC-DAD with ICOS software system]". Eisei Shikenjo Hokoku. Bulletin of National Institute of Hygienic Sciences (111): 47–56. PMID 7920567.

External links

Inchem.org - Clotiazepam

[1] Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.

[2] "Clotiazépam" (PDF). HAS - Direction de l'Evaluation Médicale. Economique et de Santé Publique. 20 May 2015.

[3] DE 2107356, Nakanishi M, Kazuhiko A, Tetsuya T, Shiroki M, "Thieno-(2,3-E)(1,4)diazepin-2-ones", issued 3 May 1978, assigned to Yoshitomi Pharmaceutical Industries, Ltd.

[4] Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs". Biological & Pharmaceutical Bulletin. 28 (9): 1711–1716. doi:10.1248/bpb.28.1711. PMID 16141545.

[Klicpera-1978-5] Klicpera C, Strian F (May 1978). "Autonomic perception and responses in anxiety-inducing situations". Pharmakopsychiatrie, Neuro-Psychopharmakologie. 11 (3): 113–120. doi:10.1055/s-0028-1094569. PMID 27828.

[Fukuda-1983-6] Fukuda T, Tsumagari T (August 1983). "Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats". Japanese Journal of Pharmacology. 33 (4): 885–890. doi:10.1254/jjp.33.885. PMID 6632385.

[Mandrioli-2008-7] Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. PMID 18855614.

[8] Nakazawa Y, Kotorii M, Oshima M, Horikawa S, Tachibana H (October 1975). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives". Psychopharmacologia. 44 (2): 165–171. doi:10.1007/BF00421005. PMID 709. S2CID 13365554.

[Martucci-1987-9] Martucci N, Manna V, Agnoli A (April 1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative". International Clinical Psychopharmacology. 2 (2): 121–128. doi:10.1097/00004850-198704000-00005. PMID 2885366.

[RIZE-10] "RIZE TABLETS 5mg". Official Japanese Drug Information Sheet (Kusuri-no-Shiori). February 2016.

[VRTN-11] "Clotiazepam (Veratran)". French Guide to Medicines.

[PHKTS-12] Benvenuti C, Bottà V, Broggini M, Gambaro V, Lodi F, Valenti M (1989). "The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers". European Journal of Clinical Pharmacology. 37 (6): 617–619. doi:10.1007/BF00562556. PMID 2575522. S2CID 29397932.

[Yakushiji-1989-13] Yakushiji T, Fukuda T, Oyama Y, Akaike N (November 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones". British Journal of Pharmacology. 98 (3): 735–740. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.

[Greenblatt--14] Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI (1983). "Clinical pharmacokinetics of the newer benzodiazepines". Clinical Pharmacokinetics. 8 (3): 233–252. doi:10.2165/00003088-198308030-00003. PMID 6133664. S2CID 19691487.

[Arendt-1982-15] Arendt R, Ochs HR, Greenblatt DJ (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies". Arzneimittel-Forschung. 32 (4): 453–455. PMID 6125154.

[Ochs-1984-16] Ochs HR, Greenblatt DJ, Verburg-Ochs B, Harmatz JS, Grehl H (1984). "Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol". European Journal of Clinical Pharmacology. 26 (1): 55–59. doi:10.1007/BF00546709. PMID 6143670. S2CID 44321356.

[Ochs-1986-17] Ochs HR, Greenblatt DJ, Knüchel M (1986). "Effect of cirrhosis and renal failure on the kinetics of clotiazepam". European Journal of Clinical Pharmacology. 30 (1): 89–92. doi:10.1007/BF00614202. PMID 2872061. S2CID 21304989.

[Colonna--18] Colonna L, Cozzi F, Del Citerna F, Di Benedetto A, De Divitiis O, Furlanello F, et al. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiologica. 38 (1–2): 45–49. PMID 1971433.

[Habersetzer-1989-19] Habersetzer F, Larrey D, Babany G, Degott C, Corbic M, Pessayre D, Benhamou JP (September 1989). "Clotiazepam-induced acute hepatitis". Journal of Hepatology. 9 (2): 256–259. doi:10.1016/0168-8278(89)90060-3. PMID 2572625.

[Shimamine-1993-20] Shimamine M, Masunari T, Nakahara Y (1993). "[Studies on identification of drugs of abuse by diode array detection. I. Screening-test and identification of benzodiazepines by HPLC-DAD with ICOS software system]". Eisei Shikenjo Hokoku. Bulletin of National Institute of Hygienic Sciences (111): 47–56. PMID 7920567.

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Clotiazepam

Indications

Pharmacokinetics

Pharmacology

Side effects

Abuse

See also

References

External links

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