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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/07 22:24:27」(JST)

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Etizolam (marketed under the brand name Etilaam, Etizola, Sedekopan, Etizest, Pasaden or Depas) is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring, making the drug a thienodiazepine.^[1] It possesses amnesic, anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.^[2]

Indications

Short-term treatment of insomnia^[3]
Short-term treatment of anxiety or panic attacks, if a benzodiazepine is required^[4]

Dosage

Anxiety disorders associated with depression: 1 mg two to three times a day (maximum 3 mg per day)
For panic disorder (associated with agoraphobia): 0.5 mg two times per day (maximum 1 mg per day)
For insomnia: 1–2 mg once daily before bedtime^[5]

A 1 mg dose of etizolam is approximately equivalent to a 10 mg dose of diazepam, see List of benzodiazepines.

Side effects

Blepharospasms with long term use^[6]

Very Rare

Erythema annulare centrifugum skin lesions^[7]

Tolerance, dependence and withdrawal

Abrupt or rapid withdrawal from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.^[8] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.^[9]

In a study that compared the effectiveness of etizolam, alprazolam, and bromazepam for the treatment of generalized anxiety disorder, all three drugs retained their effectiveness over 2 weeks, but etizolam became more effective from 2 weeks to 4 weeks, a type of reverse tolerance.^[10] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.^[11]

When multiple doses of etizolam, or lorazepam, were administered to rat neurons, lorazepam caused downregulation of alpha-1 benzodiazepine binding sites (tolerance/dependence), while etizolam caused an increase in alpha-2 benzodiazepine binding sites (reverse tolerance to anti-anxiety effects).^[12] Tolerance to the anticonvulsant effects of lorazepam were observed, but no significant tolerance to the anticonvulsant effects of etizolam were observed.^[12] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.^[12]

Contraindications and special caution

Etizolam is metabolised by the liver and is contraindicated in those with severely impaired hepatic function. It may impair the ability to drive and operate machinery so caution should be applied. Elderly patients should start on a lower dose as they are more susceptible to the sedative effects of etizolam. It is not recommended to be taken during pregnancy or breastfeeding.^[5]

Etizolam can increase the sedative and antidepressant actions of other medication such as neuroleptics, analgesics, anaesthetics, antiepileptics, sedatives and first-generation antihistamines. Co-administration with these medications should be avoided unless instructed by a medical professional. Alcohol should also be avoided.^[5]

Drugs inhibiting the enzymes CYP2C19 and CYP3A4, such as fluvoxamine, should not be taken concurrently as etizolam can increase the plasma levels of these enzymes.^[5]

Pharmacology

Etizolam, a thienodiazepine derivative, is absorbed fairly rapidly, with peak plasma levels achieved between 30 minutes and 2 hours. It has a mean elimination half life of about 3.5 hours.^[13] Etizolam possesses potent hypnotic properties,^[14] and is comparable with other short-acting benzodiazepines.^[13] Etizolam acts as a full agonist at the benzodiazepine receptor to produce its range of therapeutic and adverse effects.^[15] Similar to other benzodiazepines, etizolam binds non-selectively to benzodiazepine receptor subtypes.^{[dubious – discuss]}^[16]

In addition, etizolam, unlike most other benzodiazepines (some of which can increase levels of estradiol), has prolactogenic effects, leading to an increase in blood levels of prolactin.^[17]

According to the Italian P.I. sheet^{[citation needed]}, etizolam belongs to a new class of diazepines, thienotriazolodiazepines. This new class is easily oxidized, rapidly metabolized, and has a lower risk of accumulation, even after prolonged treatment. Etizolam has an anxiolytic action about 6 times greater than that of diazepam. Etizolam produces, especially at higher dosages, a reduction in time taken to fall asleep, an increase in total sleep time, and a reduction in the number of awakenings. During tests, there were not substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some characteristics of tricyclic antidepressants.^[4]

Legal status

United States

Etizolam is not authorized for medical use in the U.S. However, it currently remains unscheduled and is legal for research purposes. As it is a thienodiazepine, an analog of benzodiazepines, which are Schedule IV drug under Federal Scheduling Guidelines, it does not fall under the Federal Analog Act, which only applies to Schedule I and II drugs.^[18]

Etizolam is a controlled substance in the following states: Alabama, Arkansas^[19] and Mississippi.^[20]

United Kingdom

Unlike other thienodiazepines such as brotizolam and clotiazepam, etizolam is not controlled under the Misuse of Drugs Act 1971 or licensed as a medicine in the United Kingdom.^[21]

Germany

Etizolam was controlled in Germany in July 2013.^[22]

Poland

Etizolam may be scheduled under the Act on Counteracting Drug Addiction and the State Sanitary Inspection -Article 27c

Interactions

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.^[23]^[24] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.^[25]

Etizolam, similarly to other GABAergic agonists including the benzodiazepines has a strong synergistic effect with ethanol and the consequences of co-ingestion of the two drugs can drastically compound the side effects of either drug.^{[medical citation needed]} This can result in (among other effects) anterograde amnesia (blackouts) and severe respiratory depression which in extreme cases can lead to death.^{[medical citation needed]}

Overdose

Cases of intentional suicide by overdose using etizolam in combination with GABA antagonists have been reported.^[26] Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose.

Abuse

Etizolam is a drug of potential abuse. However, conflicting reports from the World Health Organization, made public in 1991, dispute the abuse claims.^[27]

References

^ 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" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.
^ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Curr. Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.
^ Lopedota A, Cutrignelli A, Trapani A et al. (May 2007). "Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam". J Microencapsul 24 (3): 214–24. doi:10.1080/02652040601058152. PMID 17454433.
^ ^a ^b "Depas". Retrieved February 3, 2009.
^ ^a ^b ^c ^d Pharmaceuticals, Intas. "Etilaam - .25mg, .50mg,.1mg". Etilaam's prescribing info sheet for doctors in India. Intas Pharmaceuticals.
^ Wakakura M, Tsubouchi T, Inouye J (March 2004). "Etizolam and benzodiazepine induced blepharospasm". J. Neurol. Neurosurg. Psychiatr. 75 (3): 506–7. doi:10.1136/jnnp.2003.019869. PMC 1738986. PMID 14966178.
^ Kuroda K, Yabunami H, Hisanaga Y (January 2002). "Etizolam-induced superficial erythema annulare centrifugum". Clin. Exp. Dermatol. 27 (1): 34–6. doi:10.1046/j.0307-6938.2001.00943.x. PMID 11952667.
^ Hirase M, Ishida T, Kamei C (November 2008). "Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats". Eur. J. Pharmacol. 597 (1–3): 46–50. doi:10.1016/j.ejphar.2008.08.024. PMID 18789918.
^ Kawajiri M, Ohyagi Y, Furuya H et al. (February 2002). "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]". Rinsho Shinkeigaku (in Japanese) 42 (2): 136–9. PMID 12424963.
^ Bertolino, A; Mastucci, E; Porro, V; Corfiati, L; Palermo, M; Ecari, U; Ceccarelli, G (1989). "Etizolam in the treatment of generalized anxiety disorder: A controlled clinical trial". The Journal of international medical research 17 (5): 455–60. PMID 2572494.
^ De Candia, MP; Di Sciascio, G; Durbano, F; Mencacci, C; Rubiera, M; Aguglia, E; Garavini, A; Bersani, G; Di Sotto, A; Placidi, G; Cesana, BM (2009). "Effects of treatment with etizolam 0.5 mg BID on cognitive performance: A 3-week, multicenter, randomized, double-blind, placebo-controlled, two-treatment, three-period, noninferiority crossover study in patients with anxiety disorder". Clinical therapeutics 31 (12): 2851–9. doi:10.1016/j.clinthera.2009.12.010. PMID 20110024.
^ ^a ^b ^c Sanna, E; Busonero, F; Talani, G; Mostallino, MC; Mura, ML; Pisu, MG; MacIocco, E; Serra, M; Biggio, G (2005). "Low tolerance and dependence liabilities of etizolam: Molecular, functional, and pharmacological correlates". European Journal of Pharmacology 519 (1–2): 31–42. doi:10.1016/j.ejphar.2005.06.047. PMID 16107249.
^ ^a ^b Fracasso C, Confalonieri S, Garattini S, Caccia S (1991). "Single and multiple dose pharmacokinetics of etizolam in healthy subjects". Eur. J. Clin. Pharmacol. 40 (2): 181–5. doi:10.1007/BF00280074. PMID 2065698.
^ Nakamura J, Mukasa H (December 1992). "Effects of thienodiazepine derivatives, etizolam and clotiazepam on the appearance of Fm theta". Jpn. J. Psychiatry Neurol. 46 (4): 927–31. doi:10.1111/j.1440-1819.1992.tb02862.x. PMID 1363923.
^ 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". Br. J. Pharmacol. 98 (3): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.
^ Ozawa M, Nakada Y, Sugimachi K et al. (March 1994). "Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates". Jpn. J. Pharmacol. 64 (3): 179–87. doi:10.1254/jjp.64.179. PMID 7912751.
^ Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869.
^ http://www.law.cornell.edu/uscode/text/21/802
^ http://www.healthy.arkansas.gov/aboutADH/RulesRegs/ControlledSubstanceListSummary.pdf
^ http://billstatus.ls.state.ms.us/documents/2014/html/HB/1200-1299/HB1231SG.htm
^ http://www.legislation.gov.uk/ukpga/1971/38/contents.
^ http://www.bundesgesundheitsministerium.de/fileadmin/dateien/Downloads/B/Betaeubungsmittelgesetz/27_BtMAEndV.pdf and http://www.gesetze-im-internet.de/btmg_1981/index.html.
^ Araki K, Yasui-Furukori N, Fukasawa T et al. (August 2004). "Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism". Eur. J. Clin. Pharmacol. 60 (6): 427–30. doi:10.1007/s00228-004-0789-1. PMID 15232663.
^ Suzuki Y, Kawashima Y, Shioiri T, Someya T (December 2004). "Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients: wide interindividual variation in the drug interaction". Ther Drug Monit 26 (6): 638–42. doi:10.1097/00007691-200412000-00009. PMID 15570188.
^ Kondo S, Fukasawa T, Yasui-Furukori N et al. (May 2005). "Induction of the metabolism of etizolam by carbamazepine in humans". Eur. J. Clin. Pharmacol. 61 (3): 185–8. doi:10.1007/s00228-005-0904-y. PMID 15776275.
^ Nakamae T, Shinozuka T, Sasaki C et al. (November 2008). "Case report: Etizolam and its major metabolites in two unnatural death cases". Forensic Sci. Int. 182 (1–3): e1–6. doi:10.1016/j.forsciint.2008.08.012. PMID 18976871.
^ WHO Expert Committee on Drug Dependence

External links

Inchem.org - Etizolam

English Journal

Overdose of etizolam: the abuse and rise of a benzodiazepine analog.

O'Connell CW1, Sadler CA2, Tolia VM2, Ly BT1, Saitman AM3, Fitzgerald RL3.
Annals of emergency medicine.Ann Emerg Med.2015 Apr;65(4):465-6. doi: 10.1016/j.annemergmed.2014.12.019.
PMID 25805032

Lethal poisonings with AH-7921 in combination with other substances.

Karinen R1, Tuv SS2, Rogde S3, Peres MD4, Johansen U2, Frost J5, Vindenes V2, Øiestad ÅM2.
Forensic science international.Forensic Sci Int.2014 Nov;244:e21-4. doi: 10.1016/j.forsciint.2014.08.013. Epub 2014 Aug 26.
AH-7921 is a synthetic μ-opioid agonist, approximately equipotent with morphine. We report the death of two young individuals after ingestion of AH-7921 in combination with other psychoactive drugs. In the first case a young man died shortly after ingesting Internet drugs. Toxicological analysis of
PMID 25216892

A case of etizolam dependence.

Gupta S1, Garg B1.
Indian journal of pharmacology.Indian J Pharmacol.2014 Nov-Dec;46(6):655-6. doi: 10.4103/0253-7613.144943.
Etizolam is a thienodiazepine anxiolytic which is said to have lower dependence potential than other benzodiazepines. We report a case of etizolam dependence in a young male with social anxiety disorder and moderate depression. This case report highlights the fact that the same caution be exercised
PMID 25538342

Japanese Journal

福山型先天性筋ジストロフィーにおける不眠の検討

佐藤孝俊/石垣景子/梶野幸子/齊藤崇/村上てるみ/加藤郁子/舟塚真/齋藤加代子/大澤眞木子
東京女子医科大学雑誌 83(E1), E42-E46, 2013-01-31
福山型先天性筋ジストロフィー(Fukuyama congenital muscular dystrophy: FCMD)は,顔面筋罹患および中枢神経系の合併を特徴とし,本邦において,Duchenne型筋ジストロフィーに次いで,二番目に多い筋ジストロフィーである.不眠は,FCMD患者にしばしば合併し,在宅療養での問題の一つとなる.特に,外泊先での不眠が問題となることが多く,家族は,その管理に難渋する …
NAID 110009559371

私のカルテから Benzodiazepine系薬物により奇異反応を呈したうつ病の1例

武田隆綱
精神医学 54(12), 1257-1259, 2012-12-00
NAID 40019532284

ベンゾジアゼピン系薬物とその代謝物の検出における4種類の薬物検査デバイスの比較--主としてチエノジアゼピン系薬物エチゾラムの検出について

奈女良昭,牧田亨介,長尾正崇 [他]
中毒研究 24(1), 27-34, 2011-00-00
NAID 40018756121

Related Pictures

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リンク元

「エチゾラム」

Etizolam
Systematic (IUPAC) name
	7-(2-Chlorophenyl)-4-ethyl-13-methyl-3-thia-1,8,11,12-tetraazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaene
Clinical data
Trade names	Etilaam, Etizest
Pregnancy; category	N;
Legal status	UK: Unscheduled; US: Unscheduled; not FDA approved;
Dependence; liability	Moderate
Routes of; administration	Oral, sublingual, rectal
Pharmacokinetic data
Bioavailability	93%
Metabolism	Hepatic
Biological half-life	3.4 hours (main metabolite is 8.2 hours)
Excretion	Renal
Identifiers
CAS Registry Number	40054-69-1
ATC code	N05BA19
PubChem	CID: 3307
ChemSpider	3191
UNII	A76XI0HL37
KEGG	D01514
ChEMBL	CHEMBL1289779
Chemical data
Formula	C17H15ClN4S
Molecular mass	342.07
	SMILES ClC1=CC=CC=C1C2=NCC3=NN=C(C)N3C4=C2C=C(CC)S4 ;
	InChI InChI=1S/C17H15ClN4S/c1-3-11-8-13-16(12-6-4-5-7-14(12)18)19-9-15-21-20-10(2)22(15)17(13)23-11/h4-8H,3,9H2,1-2H3 ; Key:VMZUTJCNQWMAGF-UHFFFAOYSA-N ;
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　　[★]

英: etizolam
商: アロファルム、エチカーム、エチセダン、エチゾラン、カプセーフ、グペリース、セデコパン、デゾラム、デパス、プロモーション、デムナット、ノンネルブ、パルギン、メディピース、モーズン

[1] 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" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.

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

[3] Lopedota A, Cutrignelli A, Trapani A et al. (May 2007). "Effects of different cyclodextrins on the morphology, loading and release properties of poly (DL-lactide-co-glycolide)-microparticles containing the hypnotic agent etizolam". J Microencapsul 24 (3): 214–24. doi:10.1080/02652040601058152. PMID 17454433.

[depas-4] "Depas". Retrieved February 3, 2009.

[intas-5] Pharmaceuticals, Intas. "Etilaam - .25mg, .50mg,.1mg". Etilaam's prescribing info sheet for doctors in India. Intas Pharmaceuticals.

[6] Wakakura M, Tsubouchi T, Inouye J (March 2004). "Etizolam and benzodiazepine induced blepharospasm". J. Neurol. Neurosurg. Psychiatr. 75 (3): 506–7. doi:10.1136/jnnp.2003.019869. PMC 1738986. PMID 14966178.

[7] Kuroda K, Yabunami H, Hisanaga Y (January 2002). "Etizolam-induced superficial erythema annulare centrifugum". Clin. Exp. Dermatol. 27 (1): 34–6. doi:10.1046/j.0307-6938.2001.00943.x. PMID 11952667.

[8] Hirase M, Ishida T, Kamei C (November 2008). "Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats". Eur. J. Pharmacol. 597 (1–3): 46–50. doi:10.1016/j.ejphar.2008.08.024. PMID 18789918.

[9] Kawajiri M, Ohyagi Y, Furuya H et al. (February 2002). "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]". Rinsho Shinkeigaku (in Japanese) 42 (2): 136–9. PMID 12424963.

[10] Bertolino, A; Mastucci, E; Porro, V; Corfiati, L; Palermo, M; Ecari, U; Ceccarelli, G (1989). "Etizolam in the treatment of generalized anxiety disorder: A controlled clinical trial". The Journal of international medical research 17 (5): 455–60. PMID 2572494.

[11] De Candia, MP; Di Sciascio, G; Durbano, F; Mencacci, C; Rubiera, M; Aguglia, E; Garavini, A; Bersani, G; Di Sotto, A; Placidi, G; Cesana, BM (2009). "Effects of treatment with etizolam 0.5 mg BID on cognitive performance: A 3-week, multicenter, randomized, double-blind, placebo-controlled, two-treatment, three-period, noninferiority crossover study in patients with anxiety disorder". Clinical therapeutics 31 (12): 2851–9. doi:10.1016/j.clinthera.2009.12.010. PMID 20110024.

[Missingor-12] Sanna, E; Busonero, F; Talani, G; Mostallino, MC; Mura, ML; Pisu, MG; MacIocco, E; Serra, M; Biggio, G (2005). "Low tolerance and dependence liabilities of etizolam: Molecular, functional, and pharmacological correlates". European Journal of Pharmacology 519 (1–2): 31–42. doi:10.1016/j.ejphar.2005.06.047. PMID 16107249.

[singmultdose-13] Fracasso C, Confalonieri S, Garattini S, Caccia S (1991). "Single and multiple dose pharmacokinetics of etizolam in healthy subjects". Eur. J. Clin. Pharmacol. 40 (2): 181–5. doi:10.1007/BF00280074. PMID 2065698.

[14] Nakamura J, Mukasa H (December 1992). "Effects of thienodiazepine derivatives, etizolam and clotiazepam on the appearance of Fm theta". Jpn. J. Psychiatry Neurol. 46 (4): 927–31. doi:10.1111/j.1440-1819.1992.tb02862.x. PMID 1363923.

[15] 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". Br. J. Pharmacol. 98 (3): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.

[16] Ozawa M, Nakada Y, Sugimachi K et al. (March 1994). "Pharmacological characterization of the novel anxiolytic beta-carboline abecarnil in rodents and primates". Jpn. J. Pharmacol. 64 (3): 179–87. doi:10.1254/jjp.64.179. PMID 7912751.

[17] Kaneda Y (2000). "Short Communication: Prolactogenic effects of etizolam". Neuro Endocrinol. Lett. 21 (6): 475–476. PMID 11335869.

[18] ttp://www.law.cornell.edu/uscode/text/21/802

[19] ttp://www.healthy.arkansas.gov/aboutADH/RulesRegs/ControlledSubstanceListSummary.pdf

[20] ttp://billstatus.ls.state.ms.us/documents/2014/html/HB/1200-1299/HB1231SG.htm

[21] ttp://www.legislation.gov.uk/ukpga/1971/38/contents.

[22] ttp://www.bundesgesundheitsministerium.de/fileadmin/dateien/Downloads/B/Betaeubungsmittelgesetz/27_BtMAEndV.pdf and http://www.gesetze-im-internet.de/btmg_1981/index.html.

[23] Araki K, Yasui-Furukori N, Fukasawa T et al. (August 2004). "Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism". Eur. J. Clin. Pharmacol. 60 (6): 427–30. doi:10.1007/s00228-004-0789-1. PMID 15232663.

[24] Suzuki Y, Kawashima Y, Shioiri T, Someya T (December 2004). "Effects of concomitant fluvoxamine on the plasma concentration of etizolam in Japanese psychiatric patients: wide interindividual variation in the drug interaction". Ther Drug Monit 26 (6): 638–42. doi:10.1097/00007691-200412000-00009. PMID 15570188.

[25] Kondo S, Fukasawa T, Yasui-Furukori N et al. (May 2005). "Induction of the metabolism of etizolam by carbamazepine in humans". Eur. J. Clin. Pharmacol. 61 (3): 185–8. doi:10.1007/s00228-005-0904-y. PMID 15776275.

[26] Nakamae T, Shinozuka T, Sasaki C et al. (November 2008). "Case report: Etizolam and its major metabolites in two unnatural death cases". Forensic Sci. Int. 182 (1–3): e1–6. doi:10.1016/j.forsciint.2008.08.012. PMID 18976871.

[27] WHO Expert Committee on Drug Dependence

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etizolam