Clotiazepam
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| Clinical data | |
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| Trade names | Veratran, Rize, Clozan |
| AHFS/Drugs | International Drug Names |
| Routes of administration | Oral, sublingual, liquid drops |
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| Pharmacokineticdata | |
| Bioavailability | ~90% |
| Metabolism | Hepatic |
| Eliminationhalf-life | 4 hours[2] |
| Excretion | Renal |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.046.920 |
| Chemical and physical data | |
| Formula | C16H15ClN2OS |
| Molar mass | 318.82g·mol−1 |
| 3D model (JSmol) | |
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Clotiazepam[3](marketed under brand nameClozan,Distensan,Trecalmo,Rize,RizenandVeratran) is athienodiazepinedrug which is abenzodiazepineanalog. The clotiazepam molecule differs from benzodiazepines in that the benzene ring has been replaced by athiophenering.[4]It possessesanxiolytic,[5]skeletal muscle relaxant,[6]anticonvulsant,sedativeproperties.[7]Stage 2NREMsleep is significantly increased by clotiazepam.[8]
Indications[edit]
Clotiazepam has been trialed and found to be effective in the short-term management ofanxiety.[9]Clotiazepam is also used as apremedicantin minor surgery inFranceandJapan,where the drug is commercially available under the brand namesVeratranandRize,respectively.[10][11]
Pharmacokinetics[edit]
A cross-over study in six healthy volunteers (median age 28 years) was conducted using single-dose pharmacokinetics of 5 mg clotiazepamdrops,oral tablets,andsublingual 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[edit]
Similar to other benzodiazepines clotiazepam hasanxiolytic,sedative,hypnotic,amnesic,anticonvulsantandmuscle relaxantpharmacological properties.[7]Clotiazepam binds to the benzodiazepine site of the GABAAreceptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAAreceptor which results in the pharmacological effects of clotiazepam.[13]
Clotiazepam has a shortelimination half-lifeand 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[edit]
Side effects experienced with this product will resemble those of other benzodiazepines. Drowsinessandastheniaare common side effects.[18]There has been a report of reversiblehepatitiscaused by clotiazepam.[19]
Abuse[edit]
Clotiazepam is a recogniseddrug of abuse.[20]
See also[edit]
References[edit]
- ^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).Archivedfrom the original on 2023-08-03.Retrieved2023-08-16.
- ^"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.PMID16141545.
- ^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.PMID27828.
- ^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.PMID6632385.
- ^abMandrioli R, Mercolini L, Raggi MA (October 2008)."Benzodiazepine metabolism: an analytical perspective".Current Drug Metabolism.9(8): 827–844.doi:10.2174/138920008786049258.PMID18855614.
- ^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.PMID709.S2CID13365554.
- ^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.PMID2885366.
- ^"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.PMID2575522.S2CID29397932.
- ^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.PMC1854765.PMID2574062.
- ^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.PMID6133664.S2CID19691487.
- ^abArendt R, Ochs HR, Greenblatt DJ (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies".Arzneimittel-Forschung.32(4): 453–455.PMID6125154.
- ^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.PMID6143670.S2CID44321356.
- ^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.PMID2872061.S2CID21304989.
- ^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.PMID1971433.
- ^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.PMID2572625.
- ^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.PMID7920567.