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<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename = Veratran, Rize, Clozan
| Drugs.com = {{drugs.com|international|clotiazepam}}
| Drugs.com = {{drugs.com|international|clotiazepam}}
| pregnancy_category = ?
| pregnancy_category = ?
| legal_US = Schedule IV
| legal_US = Schedule IV
| routes_of_administration = Oral
| routes_of_administration = Oral, sublingual, liquid drops


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability = ?
| bioavailability = ~90%
| metabolism = [[Liver|Hepatic]]
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = ?
| elimination_half-life = 6-18 hr
| excretion = [[Kidney|Renal]]
| excretion = [[Kidney|Renal]]


Line 48: Line 48:


==Indications==
==Indications==
Clotiazepam has been trialed and found to be effective in the short-term management of [[anxiety]].<ref name="Martucci-1987">{{Cite journal | last1 = Martucci | first1 = N. | last2 = Manna | first2 = V. | last3 = Agnoli | first3 = A. | title = A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative. | journal = Int Clin Psychopharmacol | volume = 2 | issue = 2 | pages = 121–8 | month = Apr | year = 1987 | doi = | PMID = 2885366 }}</ref>
Clotiazepam has been trialed and found to be effective in the short-term management of [[anxiety]].<ref name="Martucci-1987">{{Cite journal | last1 = Martucci | first1 = N. | last2 = Manna | first2 = V. | last3 = Agnoli | first3 = A. | title = A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative. | journal = Int Clin Psychopharmacol | volume = 2 | issue = 2 | pages = 121–8 | month = Apr | year = 1987 | doi = | PMID = 2885366 }}</ref> 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.<ref name=RIZE>[http://di.mt-pharma.co.jp/file/shiori/s_riz_d_e.doc Official Japanese Drug Information Sheet (Kusuri-no-Shiori)]</ref><ref name=VRTN>[http://www.doctissimo.fr/medicament-VERATRAN.htm French Guide to Medicines - Clotiazepam (Veratran)]</ref>

==Pharmacokinetics==
Single dose pharmacokinetics of 5&nbsp;mg clotiazepam [[Drop (unit)|drops]], [[Tablet|oral tablets]], and [[Sublingual administration|sublingual tablets]] in a cross-over study in six healthy volunteers (median age 28 years) was conducted. 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.<ref name="PHKTS">{{Cite journal | authors = C. Benvenuti, V. Bottà, M. Broggini, V. Gambaro, F. Lodi and M. Valenti | 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 | doi = 10.1007/BF00562556 | url=http://resources.metapress.com/pdf-preview.axd?code=v72413q7v4781472&size=largest}}</ref>


==Pharmacology==
==Pharmacology==
Similar to other benzodiazepines clotiazepam has [[anxiolytic]], [[sedative]], [[hypnotic]], [[amnesic]], [[antiepileptic]] and [[muscle relaxant]] pharmacological properties.<ref name="Mandrioli-2008"/> Clotiazepam binds to the benzodiazepine site of the GABA<sub>A</sub> receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABA<sub>A</sub> receptor which results in the pharmacological effects of clotiazepam.<ref name="Yakushiji-1989">{{Cite journal | last1 = Yakushiji | first1 = T. | last2 = Fukuda | first2 = T. | last3 = Oyama | first3 = Y. | last4 = Akaike | first4 = N. | title = Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones. | format = PDF | journal = Br J Pharmacol | volume = 98 | issue = 3 | pages = 735–40 | month = Nov | year = 1989 | doi = | PMID = 2574062 | pmc=1854765 | pmid=2574062}}</ref> 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.<ref name="Greenblatt-">{{Cite journal | last1 = Greenblatt | first1 = DJ. | last2 = Divoll | first2 = M. | last3 = Abernethy | first3 = DR. | last4 = Ochs | first4 = HR. | last5 = Shader | first5 = RI. | title = Clinical pharmacokinetics of the newer benzodiazepines. | journal = Clin Pharmacokinet | volume = 8 | issue = 3 | pages = 233–52 | month = | year = 1983| doi = 10.2165/00003088-198308030-00003| pmid = 6133664 }}</ref> Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. 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.<ref name="Arendt-1982">{{Cite journal | last1 = Arendt | first1 = R. | last2 = Ochs | first2 = HR. | last3 = Greenblatt | first3 = DJ. | title = Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies. | journal = Arzneimittelforschung | volume = 32 | issue = 4 | pages = 453–5 | month = | year = 1982 | doi = | pmid = 6125154 }}</ref> In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.<ref name="Ochs-1984">{{Cite journal | last1 = Ochs | first1 = HR. | last2 = Greenblatt | first2 = DJ. | last3 = Verburg-Ochs | first3 = B. | last4 = Harmatz | first4 = JS. | last5 = Grehl | first5 = H. | title = Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol. | journal = Eur J Clin Pharmacol | volume = 26 | issue = 1 | pages = 55–9 | month = | year = 1984 | doi = | pmid = 6143670 }}</ref> Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not effect the kinetics of clotiazepam.<ref name="Ochs-1986">{{Cite journal | last1 = Ochs | first1 = HR. | last2 = Greenblatt | first2 = DJ. | last3 = Knüchel | first3 = M. | title = Effect of cirrhosis and renal failure on the kinetics of clotiazepam. | journal = Eur J Clin Pharmacol | volume = 30 | issue = 1 | pages = 89–92 | month = | year = 1986 | doi = | PMID = 2872061 }}</ref>
Similar to other benzodiazepines clotiazepam has [[anxiolytic]], [[sedative]], [[hypnotic]], [[amnesic]], [[anticonvulsant]] and [[muscle relaxant]] pharmacological properties.<ref name="Mandrioli-2008"/> Clotiazepam binds to the benzodiazepine site of the GABA<sub>A</sub> receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABA<sub>A</sub> receptor which results in the pharmacological effects of clotiazepam.<ref name="Yakushiji-1989">{{Cite journal | last1 = Yakushiji | first1 = T. | last2 = Fukuda | first2 = T. | last3 = Oyama | first3 = Y. | last4 = Akaike | first4 = N. | title = Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones. | format = PDF | journal = Br J Pharmacol | volume = 98 | issue = 3 | pages = 735–40 | month = Nov | year = 1989 | doi = | PMID = 2574062 | pmc=1854765 | pmid=2574062}}</ref>
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.<ref name="Greenblatt-">{{Cite journal | last1 = Greenblatt | first1 = DJ. | last2 = Divoll | first2 = M. | last3 = Abernethy | first3 = DR. | last4 = Ochs | first4 = HR. | last5 = Shader | first5 = RI. | title = Clinical pharmacokinetics of the newer benzodiazepines. | journal = Clin Pharmacokinet | volume = 8 | issue = 3 | pages = 233–52 | month = | year = 1983| doi = 10.2165/00003088-198308030-00003| pmid = 6133664 }}</ref> Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. After oral ingestion of a single 5&nbsp;mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed.<ref name="Arendt-1982"/> 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.<ref name="Arendt-1982">{{Cite journal | last1 = Arendt | first1 = R. | last2 = Ochs | first2 = HR. | last3 = Greenblatt | first3 = DJ. | title = Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies. | journal = Arzneimittelforschung | volume = 32 | issue = 4 | pages = 453–5 | month = | year = 1982 | doi = | pmid = 6125154 }}</ref> In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.<ref name="Ochs-1984">{{Cite journal | last1 = Ochs | first1 = HR. | last2 = Greenblatt | first2 = DJ. | last3 = Verburg-Ochs | first3 = B. | last4 = Harmatz | first4 = JS. | last5 = Grehl | first5 = H. | title = Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol. | journal = Eur J Clin Pharmacol | volume = 26 | issue = 1 | pages = 55–9 | month = | year = 1984 | doi = | pmid = 6143670 }}</ref> Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not effect the kinetics of clotiazepam.<ref name="Ochs-1986">{{Cite journal | last1 = Ochs | first1 = HR. | last2 = Greenblatt | first2 = DJ. | last3 = Knüchel | first3 = M. | title = Effect of cirrhosis and renal failure on the kinetics of clotiazepam. | journal = Eur J Clin Pharmacol | volume = 30 | issue = 1 | pages = 89–92 | month = | year = 1986 | doi = | PMID = 2872061 }}</ref>


==Side effects==
==Side effects==

Revision as of 17:47, 14 October 2011

Clotiazepam
Clinical data
Trade namesVeratran, Rize, Clozan
AHFS/Drugs.comInternational Drug Names
Pregnancy
category
  • ?
Routes of
administration		Oral, sublingual, liquid drops
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~90%
MetabolismHepatic
Elimination half-life6-18 hr
ExcretionRenal
Identifiers
  • 2-(2-chlorophenyl)-9-ethyl-6-methyl-8-thia-3,6-diazabicyclo[5.3.0]deca-2,9,11-trien-5-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
ECHA InfoCard100.046.920 Edit this at Wikidata
Chemical and physical data
FormulaC16H15ClN2OS
Molar mass318.8 g/mol g·mol−1
3D model (JSmol)
  • Clc3ccccc3C/1=N/CC(=O)N(c2sc(cc\12)CC)C
  • 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 checkY
  • Key:CHBRHODLKOZEPZ-UHFFFAOYSA-N checkY
  (verify)

Clotiazepam (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.[1] It possesses anxiolytic,[2] skeletal muscle relaxant,[3] anticonvulsant, sedative properties.[4] Stage 2 NREM sleep is significantly increased by clotiazepam.[5]

Indications

Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.[6] 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.[7][8]

Pharmacokinetics

Single dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets in a cross-over study in six healthy volunteers (median age 28 years) was conducted. 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.[9]

Pharmacology

Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties.[4] Clotiazepam binds to the benzodiazepine site of the GABAA receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAA receptor which results in the pharmacological effects of clotiazepam.[10]

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.[11] 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.[12] 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.[12] In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.[13] Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not effect the kinetics of clotiazepam.[14]

Side effects

Drowsiness and asthenia are common side effects.[15] There has been a report of hepatitis caused by clotiazepam.[16]

Abuse

Clotiazepam is a recognised drug of abuse.[17]

See also

References

  1. ^ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Klicpera, C.; Strian, F. (1978). "Autonomic perception and responses in anxiety-inducing situations". Pharmakopsychiatr Neuropsychopharmakol. 11 (3): 113–20. doi:10.1055/s-0028-1094569. PMID 27828. {{cite journal}}: Unknown parameter |month= ignored (help)
  3. ^ Fukuda, T.; Tsumagari, T. (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  4. ^ a b Mandrioli, R.; Mercolini, L.; Raggi, MA. (2008). "Benzodiazepine metabolism: an analytical perspective". Curr Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614. {{cite journal}}: Unknown parameter |month= ignored (help)
  5. ^ Nakazawa Y (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  6. ^ Martucci, N.; Manna, V.; Agnoli, A. (1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative". Int Clin Psychopharmacol. 2 (2): 121–8. PMID 2885366. {{cite journal}}: Unknown parameter |month= ignored (help)
  7. ^ Official Japanese Drug Information Sheet (Kusuri-no-Shiori)
  8. ^ French Guide to Medicines - Clotiazepam (Veratran)
  9. ^ "The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers". European Journal of Clinical Pharmacology. 37 (6): 617–619. 1989. doi:10.1007/BF00562556. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  10. ^ Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N. (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. PMC 1854765. PMID 2574062. {{cite journal}}: More than one of |PMID= and |pmid= specified (help); Unknown parameter |month= ignored (help)
  11. ^ 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. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  12. ^ 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. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  13. ^ 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. PMID 6143670. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  14. ^ 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. PMID 2872061. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  15. ^ Colonna, L.; Cozzi, F.; Del Citerna, F.; Di Benedetto, A.; De Divitiis, O.; Furlanello, F.; Milazzotto, F.; Pittalis, M.; Taccola, A. "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiol. 38 (1–2): 45–9. PMID 1971433. {{cite journal}}: Cite has empty unknown parameter: |month= (help)
  16. ^ Habersetzer, F.; Larrey, D.; Babany, G.; Degott, C.; Corbic, M.; Pessayre, D.; Benhamou, JP. (1989). "Clotiazepam-induced acute hepatitis". J Hepatol. 9 (2): 256–9. PMID 2572625. {{cite journal}}: Unknown parameter |month= ignored (help)
  17. ^ 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. {{cite journal}}: Cite has empty unknown parameter: |month= (help)

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