clotiazepam

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 447551242

| IUPAC_name = 5-(2-chlorophenyl)-7-ethyl-1-methyl-3H-thieno[2,3-e][1,4]diazepin-2-one

| image = Clotiazepam structure.svg

| image_class = skin-invert-image

| width = 180

| image2 = Clotiazepam3d.png

| image_class2 = bg-transparent

| width2 = 160

| tradename = Veratran, Rize, Clozan

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

| pregnancy_category =

| legal_BR = B1

| legal_BR_comment = {{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}

| legal_CA = Schedule IV

| legal_DE = Rx-only/Anlage III

| legal_UK = Class C

| legal_US = Schedule IV

| routes_of_administration = Oral, sublingual, liquid drops

| bioavailability = ~90%

| metabolism = Hepatic

| elimination_half-life = 4 hours{{cite web | title = Clotiazépam | work = HAS - Direction de l'Evaluation Médicale | publisher = Economique et de Santé Publique | date = 20 May 2015 | url = https://www.has-sante.fr/upload/docs/evamed/CT-14195_VERATRAN_PIC_REEVAL_RI_Avis2_CT14195.pdf }}

| excretion = Renal

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

| CAS_number = 33671-46-4

| ATC_prefix = N05

| ATC_suffix = BA21

| PubChem = 2811

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 1697737

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

| DrugBank = DB01559

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

| ChemSpiderID = 2709

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

| UNII = ZCN055599V

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

| KEGG = D01328

| C=16 | H=15 | Cl=1 | N=2 | O=1 | S=1

| smiles = ClC1=C(C2=NCC(N(C)C3=C2C=C(CC)S3)=O)C=CC=C1

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

| StdInChI = 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

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

| StdInChIKey = CHBRHODLKOZEPZ-UHFFFAOYSA-N

}}

File:Vératran.png

Clotiazepam{{cite patent | country = DE | number = 2107356 | title = Thieno-(2,3-E)(1,4)diazepin-2-ones | inventor = Nakanishi M, Kazuhiko A, Tetsuya T, Shiroki M | gdate = 3 May 1978 | assign1 = Yoshitomi Pharmaceutical Industries, Ltd. }} (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.{{cite journal | vauthors = Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A | title = Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs | journal = Biological & Pharmaceutical Bulletin | volume = 28 | issue = 9 | pages = 1711–1716 | date = September 2005 | pmid = 16141545 | doi = 10.1248/bpb.28.1711 | doi-access = free }} It possesses anxiolytic,{{cite journal | vauthors = Klicpera C, Strian F | title = Autonomic perception and responses in anxiety-inducing situations | journal = Pharmakopsychiatrie, Neuro-Psychopharmakologie | volume = 11 | issue = 3 | pages = 113–120 | date = May 1978 | pmid = 27828 | doi = 10.1055/s-0028-1094569 }} skeletal muscle relaxant,{{cite journal | vauthors = Fukuda T, Tsumagari T | title = Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats | journal = Japanese Journal of Pharmacology | volume = 33 | issue = 4 | pages = 885–890 | date = August 1983 | pmid = 6632385 | doi = 10.1254/jjp.33.885 | doi-access = }} anticonvulsant, sedative properties.{{cite journal | vauthors = Mandrioli R, Mercolini L, Raggi MA | title = Benzodiazepine metabolism: an analytical perspective | journal = Current Drug Metabolism | volume = 9 | issue = 8 | pages = 827–844 | date = October 2008 | pmid = 18855614 | doi = 10.2174/138920008786049258 | url = https://zenodo.org/record/1067769 }} Stage 2 NREM sleep is significantly increased by clotiazepam.{{cite journal | vauthors = Nakazawa Y, Kotorii M, Oshima M, Horikawa S, Tachibana H | title = Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives | journal = Psychopharmacologia | volume = 44 | issue = 2 | pages = 165–171 | date = October 1975 | pmid = 709 | doi = 10.1007/BF00421005 | s2cid = 13365554 }}

Indications

Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.{{cite journal | vauthors = Martucci N, Manna V, Agnoli A | title = A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative | journal = International Clinical Psychopharmacology | volume = 2 | issue = 2 | pages = 121–128 | date = April 1987 | pmid = 2885366 | doi = 10.1097/00004850-198704000-00005 }} 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.{{cite web | url = http://di.mt-pharma.co.jp/file/shiori/s_riz_d_e.doc | title = RIZE TABLETS 5mg | work = Official Japanese Drug Information Sheet (Kusuri-no-Shiori) | date = February 2016 }}{{cite web | url = http://www.doctissimo.fr/medicament-VERATRAN.htm | work = French Guide to Medicines | title = Clotiazepam (Veratran) }}

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.{{cite journal | vauthors = Benvenuti C, Bottà V, Broggini M, Gambaro V, Lodi F, Valenti M | title = The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers | journal = European Journal of Clinical Pharmacology | volume = 37 | issue = 6 | pages = 617–619 | year = 1989 | pmid = 2575522 | doi = 10.1007/BF00562556 | s2cid = 29397932 }}

Pharmacology

Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties. 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.{{cite journal | vauthors = Yakushiji T, Fukuda T, Oyama Y, Akaike N | title = Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones | journal = British Journal of Pharmacology | volume = 98 | issue = 3 | pages = 735–740 | date = November 1989 | pmid = 2574062 | pmc = 1854765 | doi = 10.1111/j.1476-5381.1989.tb14600.x }}

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.{{cite journal | vauthors = Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI | title = Clinical pharmacokinetics of the newer benzodiazepines | journal = Clinical Pharmacokinetics | volume = 8 | issue = 3 | pages = 233–252 | year = 1983 | pmid = 6133664 | doi = 10.2165/00003088-198308030-00003 | s2cid = 19691487 }} 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. 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.{{cite journal | vauthors = Arendt R, Ochs HR, Greenblatt DJ | title = Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies | journal = Arzneimittel-Forschung | volume = 32 | issue = 4 | pages = 453–455 | year = 1982 | pmid = 6125154 }} In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.{{cite journal | vauthors = Ochs HR, Greenblatt DJ, Verburg-Ochs B, Harmatz JS, Grehl H | title = Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol | journal = European Journal of Clinical Pharmacology | volume = 26 | issue = 1 | pages = 55–59 | year = 1984 | pmid = 6143670 | doi = 10.1007/BF00546709 | s2cid = 44321356 }} 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.{{cite journal | vauthors = Ochs HR, Greenblatt DJ, Knüchel M | title = Effect of cirrhosis and renal failure on the kinetics of clotiazepam | journal = European Journal of Clinical Pharmacology | volume = 30 | issue = 1 | pages = 89–92 | year = 1986 | pmid = 2872061 | doi = 10.1007/BF00614202 | s2cid = 21304989 }}

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.{{cite journal | vauthors = Colonna L, Cozzi F, Del Citerna F, Di Benedetto A, De Divitiis O, Furlanello F, Milazzotto F, Pittalis M, Taccola A | display-authors = 6 | title = [Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology] | journal = Minerva Cardioangiologica | volume = 38 | issue = 1–2 | pages = 45–49 | year = 1990 | pmid = 1971433 }} There has been a report of reversible hepatitis caused by clotiazepam.{{cite journal | vauthors = Habersetzer F, Larrey D, Babany G, Degott C, Corbic M, Pessayre D, Benhamou JP | title = Clotiazepam-induced acute hepatitis | journal = Journal of Hepatology | volume = 9 | issue = 2 | pages = 256–259 | date = September 1989 | pmid = 2572625 | doi = 10.1016/0168-8278(89)90060-3 }}

Abuse

Clotiazepam is a recognised drug of abuse.{{cite journal | vauthors = Shimamine M, Masunari T, Nakahara Y | title = [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] | journal = Eisei Shikenjo Hokoku. Bulletin of National Institute of Hygienic Sciences | issue = 111 | pages = 47–56 | year = 1993 | pmid = 7920567 }}

References

External links

[http://www.inchem.org/documents/pims/pharm/pim922.htm Inchem.org - Clotiazepam]

Category:2-Chlorophenyl compounds

Category:GABAA receptor positive allosteric modulators

Category:Lactams

Category:Thienodiazepines