Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/09 11:11:24」(JST)

wiki en

Clotiazepam^[1] (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 The clotiazepam molecule differs from most other benzodiazepines in that the benzene ring has been replaced by a thiophene ring.^[2] It possesses anxiolytic,^[3] skeletal muscle relaxant,^[4] anticonvulsant, sedative properties.^[5] Stage 2 NREM sleep is significantly increased by clotiazepam.^[6]

Indications

Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.^[7] 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.^[8]^[9]

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.^[10]

Pharmacology

Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties.^[5] 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.^[11]

Clotiazepam has a relatively short elimination half-life and is less prone to accumulation after repeated dosing compared to longer-acting benzodiazepine agents. It is metabolised via oxidation.^[12] 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.^[13] 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.^[13] In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.^[14] 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.^[15]

Side effects

Drowsiness and asthenia are common side effects.^[16] There has been a report of hepatitis caused by clotiazepam.^[17]

Abuse

Clotiazepam is a recognised drug of abuse.^[18]

References

^ DE Patent 2107356
^ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A; Shiraga; Ishii; Kagayama; Takagi (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.
^ Klicpera, C.; Strian, F. (May 1978). "Autonomic perception and responses in anxiety-inducing situations.". Pharmakopsychiatr Neuropsychopharmakol 11 (3): 113–20. doi:10.1055/s-0028-1094569. PMID 27828.
^ Fukuda, T.; Tsumagari, T. (Aug 1983). "Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats." (PDF). Jpn J Pharmacol 33 (4): 885–90. doi:10.1254/jjp.33.885. PMID 6632385.
^ ^a ^b Mandrioli, R.; Mercolini, L.; Raggi, MA. (Oct 2008). "Benzodiazepine metabolism: an analytical perspective.". Curr Drug Metab 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.
^ Nakazawa Y; Kotorii M; Oshima M; Horikawa S; Tachibana H. (October 31, 1975). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives.". Psychopharmacologia. 44 (2): 165–71. doi:10.1007/BF00421005. PMID 709.
^ Martucci, N.; Manna, V.; Agnoli, A. (Apr 1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative.". Int Clin Psychopharmacol 2 (2): 121–8. doi:10.1097/00004850-198704000-00005. PMID 2885366.
^ Official Japanese Drug Information Sheet (Kusuri-no-Shiori)
^ French Guide to Medicines - Clotiazepam (Veratran)
^ C. Benvenuti, V. Bottà, M. Broggini, V. Gambaro, F. Lodi and M. Valenti (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 (inactive 2015-01-11). PMID 2575522.
^ Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N. (Nov 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones" (PDF). Br J Pharmacol 98 (3): 735–40. 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". Clin Pharmacokinet 8 (3): 233–52. doi:10.2165/00003088-198308030-00003. PMID 6133664.
^ ^a ^b Arendt, R.; Ochs, HR.; Greenblatt, DJ. (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies". Arzneimittelforschung 32 (4): 453–5. 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". Eur J Clin Pharmacol 26 (1): 55–9. doi:10.1007/BF00546709. PMID 6143670.
^ Ochs, HR.; Greenblatt, DJ.; Knüchel, M. (1986). "Effect of cirrhosis and renal failure on the kinetics of clotiazepam". Eur J Clin Pharmacol 30 (1): 89–92. doi:10.1007/BF00614202. PMID 2872061.
^ Colonna, L.; Cozzi, F.; Del Citerna, F.; Di Benedetto, A.; De Divitiis, O.; Furlanello, F.; Milazzotto, F.; Pittalis, M.; Taccola, A. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiol 38 (1–2): 45–9. PMID 1971433.
^ Habersetzer, F.; Larrey, D.; Babany, G.; Degott, C.; Corbic, M.; Pessayre, D.; Benhamou, JP. (Sep 1989). "Clotiazepam-induced acute hepatitis". J Hepatol 9 (2): 256–9. 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 (111): 47–56. PMID 7920567.

External links

Inchem.org - Clotiazepam

English Journal

Understanding the pharmacokinetics of anxiolytic drugs.

Altamura AC1, Moliterno D, Paletta S, Maffini M, Mauri MC, Bareggi S.
Expert opinion on drug metabolism & toxicology.Expert Opin Drug Metab Toxicol.2013 Apr;9(4):423-40. doi: 10.1517/17425255.2013.759209. Epub 2013 Jan 21.
INTRODUCTION: Anxiety disorders are considered the most common mental disorders and they can increase the risk for comorbid mood and substance use disorders, significantly contributing to the global burden of disease. For this reason, anxiolytics are the most prescribed psychoactive drugs, particula
PMID 23330992

The evaluation of the applicability of a high pH mobile phase in ultrahigh performance liquid chromatography tandem mass spectrometry analysis of benzodiazepines and benzodiazepine-like hypnotics in urine and blood.

Verplaetse R1, Cuypers E, Tytgat J.
Journal of chromatography. A.J Chromatogr A.2012 Aug 3;1249:147-54. doi: 10.1016/j.chroma.2012.06.023. Epub 2012 Jun 15.
A sensitive liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous detection of benzodiazepines, benzodiazepine-like hypnotics and some metabolites (7-aminoflunitrazepam, alprazolam, bromazepam, brotizolam, chlordiazepoxide, chlornordiazepam, clobazam, clo
PMID 22749457

Inclusion of thienodiazepines in prescription rate of anxiolytics.

Toda K.
Psychiatry and clinical neurosciences.Psychiatry Clin Neurosci.2009 Jun;63(3):430; author reply 430-1. doi: 10.1111/j.1440-1819.2009.01967.x.
PMID 19566784

Japanese Journal

Study on Raffenetti's P File Format in Conventional Ab Initio Self-Consistent-Field Molecular Orbital Calculations in Parallel Computational Environment

Journal of Computer Chemistry, Japan 7(5), 179-184, 2008
NAID 130000107432

Study on Raffenetti's P File Format in Conventional Ab Initio Self-Consistent-Field Molecular Orbital Calculations in Parallel Computational Environment

Journal of Computer Chemistry, Japan 7(5), 179-184, 2008
NAID 120005520441

Quantification of clotiazepam in human plasma by gas chromatography-mass spectrometry

Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 834(1), 128-133, 2006-04-13
NAID 10025782700

Related Pictures

★リンクテーブル★

リンク元

「クロチアゼパム」

Clotiazepam
Systematic (IUPAC) name
	2-(2-chlorophenyl)-9-ethyl-6-methyl-8-thia-3,6-diazabicyclo[5.3.0]deca-2,9,11-trien-5-one
Clinical data
Trade names	Veratran, Rize, Clozan
AHFS/Drugs.com	International Drug Names
Pregnancy; category	?;
Legal status	US: Schedule IV;
Routes of; administration	Oral, sublingual, liquid drops
Pharmacokinetic data
Bioavailability	~90%
Metabolism	Hepatic
Biological half-life	6-18 hr
Excretion	Renal
Identifiers
CAS Registry Number	33671-46-4
ATC code	N05BA21
PubChem	CID: 2811
DrugBank	DB01559
ChemSpider	2709
UNII	ZCN055599V
KEGG	D01328
ChEMBL	CHEMBL1697737
Chemical data
Formula	C16H15ClN2OS
Molecular mass	318.8 g/mol
	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)

　　[★]

英: clotiazepam
商: イソクリン、ナオリーゼ、リーゼ、リリフター

[1] DE Patent 2107356

[2] Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A; Shiraga; Ishii; Kagayama; Takagi (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.

[Klicpera-1978-3] Klicpera, C.; Strian, F. (May 1978). "Autonomic perception and responses in anxiety-inducing situations.". Pharmakopsychiatr Neuropsychopharmakol 11 (3): 113–20. doi:10.1055/s-0028-1094569. PMID 27828.

[Fukuda-1983-4] Fukuda, T.; Tsumagari, T. (Aug 1983). "Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats." (PDF). Jpn J Pharmacol 33 (4): 885–90. doi:10.1254/jjp.33.885. PMID 6632385.

[Mandrioli-2008-5] Mandrioli, R.; Mercolini, L.; Raggi, MA. (Oct 2008). "Benzodiazepine metabolism: an analytical perspective.". Curr Drug Metab 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.

[6] Nakazawa Y; Kotorii M; Oshima M; Horikawa S; Tachibana H. (October 31, 1975). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives.". Psychopharmacologia. 44 (2): 165–71. doi:10.1007/BF00421005. PMID 709.

[Martucci-1987-7] Martucci, N.; Manna, V.; Agnoli, A. (Apr 1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative.". Int Clin Psychopharmacol 2 (2): 121–8. doi:10.1097/00004850-198704000-00005. PMID 2885366.

[RIZE-8] Official Japanese Drug Information Sheet (Kusuri-no-Shiori)

[VRTN-9] French Guide to Medicines - Clotiazepam (Veratran)

[PHKTS-10] C. Benvenuti, V. Bottà, M. Broggini, V. Gambaro, F. Lodi and M. Valenti (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 (inactive 2015-01-11). PMID 2575522.

[Yakushiji-1989-11] Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N. (Nov 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones" (PDF). Br J Pharmacol 98 (3): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.

[Greenblatt--12] Greenblatt, DJ.; Divoll, M.; Abernethy, DR.; Ochs, HR.; Shader, RI. (1983). "Clinical pharmacokinetics of the newer benzodiazepines". Clin Pharmacokinet 8 (3): 233–52. doi:10.2165/00003088-198308030-00003. PMID 6133664.

[Arendt-1982-13] Arendt, R.; Ochs, HR.; Greenblatt, DJ. (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies". Arzneimittelforschung 32 (4): 453–5. PMID 6125154.

[Ochs-1984-14] 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". Eur J Clin Pharmacol 26 (1): 55–9. doi:10.1007/BF00546709. PMID 6143670.

[Ochs-1986-15] Ochs, HR.; Greenblatt, DJ.; Knüchel, M. (1986). "Effect of cirrhosis and renal failure on the kinetics of clotiazepam". Eur J Clin Pharmacol 30 (1): 89–92. doi:10.1007/BF00614202. PMID 2872061.

[Colonna--16] Colonna, L.; Cozzi, F.; Del Citerna, F.; Di Benedetto, A.; De Divitiis, O.; Furlanello, F.; Milazzotto, F.; Pittalis, M.; Taccola, A. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiol 38 (1–2): 45–9. PMID 1971433.

[Habersetzer-1989-17] Habersetzer, F.; Larrey, D.; Babany, G.; Degott, C.; Corbic, M.; Pessayre, D.; Benhamou, JP. (Sep 1989). "Clotiazepam-induced acute hepatitis". J Hepatol 9 (2): 256–9. doi:10.1016/0168-8278(89)90060-3. PMID 2572625.

[Shimamine-1993-18] 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 (111): 47–56. PMID 7920567.

匿名

検索

案内

案内

clotiazepam