Etizolam

Etizolam
Clinical data
Trade names	Etizest, Etilaam, Etizex, Depas, Sedekopan, Pasaden
Dependence; liability	Moderate
Routes of; administration	Oral, sublingual, rectal
ATC code	N05BA19 (WHO) ;
Legal status
Legal status	BR: Class B1 (Psychoactive drugs); DE: Anlage III (Special prescription form required); UK: Class C; US: Schedule I; UN: Psychotropic Schedule IV;
Pharmacokinetic data
Bioavailability	93%
Metabolism	Hepatic
Elimination half-life	3.4 hours (main metabolite is 8.2 hours)
Duration of action	5-7 hours
Excretion	Kidney
Identifiers
	IUPAC name 4-(2-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine;
CAS Number	40054-69-1 ;
PubChem CID	3307;
ChemSpider	3191 ;
UNII	A76XI0HL37;
KEGG	D01514 ;
ChEMBL	ChEMBL1289779 ;
CompTox Dashboard (EPA)	DTXSID0023030 ;
ECHA InfoCard	100.188.773
Chemical and physical data
Formula	C17H15ClN4S
Molar mass	342.85 g·mol−1
3D model (JSmol)	Interactive image;
	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 ;
	(what is this?) (verify)

Etizex brand etizolam tablets

Etizolam (marketed under numerous brand names) is a thienodiazepine derivative^[5] which is a benzodiazepine analog.^[6] The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.^[7]^[8]

Although a thienodiazepine, etizolam is clinically regarded as a benzodiazepine because of its mode of action via the benzodiazepine receptor and directly targeting GABA_A allosteric modulator receptors.^[5]

It possesses anxiolytic, amnesic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties.^[9]

It was patented in 1972^[10] and approved for medical use^[where?] in 1983.^[11]

As of April 2021, the export of etizolam has been banned in India.^[12]

Medical uses

Short-term treatment of insomnia.
Anxiety disorders such as OCD and general anxiety disorder, mostly as a short-term medication to be used purely on an at-need basis^[13]

Side effects

Long term use may result in blepharospasms,^[14] especially in women.^[14] Doses of 4 mg or more may cause anterograde amnesia.^{[citation needed]}

In rare cases, erythema annulare centrifugum skin lesions have resulted.^[15]

Tolerance, dependence and withdrawal

Abrupt or rapid discontinuation from etizolam, as with benzodiazepines, may result in the appearance of the benzodiazepine withdrawal syndrome, including rebound insomnia.^[16] Neuroleptic malignant syndrome, a rare event in benzodiazepine withdrawal, has been documented in a case of abrupt withdrawal from etizolam.^[17] This is particularly relevant given etizolam's short half life relative to benzodiazepines such as diazepam resulting in a more rapid drug level decrease in blood plasma levels.^[18]

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.^[19] Administering .5 mg etizolam twice daily did not induce cognitive deficits over 3 weeks when compared to placebo.^[20]

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).^[21] Tolerance to the anticonvulsant effects of lorazepam was observed, but no significant tolerance to the anticonvulsant effects of etizolam was observed.^[21] Etizolam therefore has a reduced liability to induce tolerance, and dependence, compared with classic benzodiazepines.^[21]

Etizolam may represent a possible anxiolytic of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.^[22]

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 3.4 hours.^[4]^[2]^[3] Etizolam possesses potent hypnotic properties,^[23] and is comparable with other short-acting benzodiazepines.^[4] Etizolam acts as a positive allosteric modulator of the GABA_A receptor by agonizing the receptor's benzodiazepine site.^[24]

According to the Italian prescribing information 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 6-8 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 no substantial changes in deep sleep; however, it may reduce REM sleep. In EEG tests of healthy volunteers, etizolam showed some similar characteristics to tricyclic antidepressants.^[25]^[26]

Etizolam's main metabolites in humans are alpha-hydroxyetizolam and 8-hydroxyetizolam. alpha-Hydroxyetizolam is pharmacologically active and has a half-life of approximately 8.2 hours.^[27]

Interactions

Itraconazole and fluvoxamine slow down the rate of elimination of etizolam, leading to accumulation of etizolam, therefore increasing its pharmacological effects.^[28]^[29] Carbamazepine speeds up the metabolism of etizolam, resulting in reduced pharmacological effects.^[30]

Overdose

Cases of intentional suicide by overdose using etizolam in combination with GABA agonists have been reported.^[27]^[31] Although etizolam has a lower LD50 than certain benzodiazepines, the LD50 is still far beyond the prescribed or recommended dose. Flumazenil, a GABA antagonist agent used to reverse benzodiazepine overdoses, inhibits the effect of etizolam as well as classical benzodiazepines such as diazepam and chlordiazepoxide.^[32]

Etizolam overdose deaths are rising - for instance, the National Records of Scotland report on drug-related deaths, 'street' Etizolam was a factor in ("implicated in, or potentially contributed to") 752, or 59%, of drug-related deaths in Scotland in 2019. It is important to highlight that more than one drug contributed to the vast majority of the deaths (by way of comparison, opiates and opioids were a factor in 1092, or 86%, of drug-related deaths).^[33]

Society and culture

Brand names

Etilaam, Sedekopan, Etizest, Etizex, Pasaden or Depas

Legal status

International drug control conventions

In 1990, it was recommended that Etizolam not be placed under international control.^[34] However, this attitude has changed due to increased abuse. On December 13, 2019, the World Health Organization recommended Etizolam be placed in Schedule 4 of the 1971 Convention on Psychotropic Substances.^[35] This recommendation was followed by the placement of Etizolam into Schedule IV in March 2020.^[36]

Australia

Etizolam is not used medically in Australia but has been found in counterfeit Xanax pills.^[37]

Denmark

Etizolam is controlled in Denmark under the Danish Misuse of Drugs Act.^[38]

Germany

Etizolam was controlled in Germany in July 2013^[39]^[40] but is not used medically.

Italy

Etizolam is licensed for the treatment of anxiety, insomnia and neurosis as a prescription-only medication.^[41]

^[42]

India

In India, it is a Narcotics prescription-only (NRx) medication used for anxiety disorders, sometimes in combination with other drugs like propranolol.

United Kingdom

In the UK, etizolam has been classified as a Class C drug by the May 2017 amendment to The Misuse of Drugs Act 1971 along with several other designer benzodiazepine drugs.^[43]

United States

Etizolam is not authorized by the FDA for medical use in the U.S. As of March 2016, etizolam is a controlled substance in the following states: Alabama,^[44] Arkansas,^[45] Florida,^[46] Georgia (as Schedule IV, whereas all other states listed here prohibit it as a Schedule I substance), Louisiana, Mississippi,^[47] Texas,^[48] South Carolina,^[49] and Virginia.^[50] It is controlled in Indiana as of July 1, 2017.^[51] It is controlled in Ohio as of February 2018.

On December 23, 2022, the DEA announced it had begun consideration on the matter of placing Etizolam under temporary Schedule I status.^[52]

Later on July 25, 2023, the DEA published a pre-print notice that Etizolam would become temporarily scheduled as a Schedule I controlled substance from 26 July 2023 to 26 July 2025.^[53]

Misuse

Etizolam is a drug of potential misuse. Cases of etizolam dependence have been documented in the medical literature.^[54] Since 1991, cases of etizolam misuse and addiction have substantially increased,^[55] due to varying levels of accessibility and cultural popularity.^[56] Pills being sold as Xanax or other benzodiazepines that are illicitly manufactured may often contain etizolam rather than their listed ingredient ^[57]^[37]

References

^ 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). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
^ ^a ^b "Etizolam". www.drugbank.ca. Retrieved 2020-09-03.
^ ^a ^b "Drug & Chemical Evaluation - Etizolam" (PDF). U.S. Drug Enforcement Administration. U.S. Department of Justice. March 2020. Archived (PDF) from the original on 2020-09-03.
^ ^a ^b ^c Fracasso C, Confalonieri S, Garattini S, Caccia S (1991-02-01). "Single and multiple dose pharmacokinetics of etizolam in healthy subjects". European Journal of Clinical Pharmacology. 40 (2): 181–185. doi:10.1007/BF00280074. PMID 2065698. S2CID 10176681.
^ ^a ^b Sanna E, Pau D, Tuveri F, Massa F, Maciocco E, Acquas C, et al. (February 1999). "Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions". Arzneimittel-Forschung. 49 (2): 88–95. doi:10.1055/s-0031-1300366. PMID 10083975. S2CID 19732765.
^ Manchester KR, Maskell PD, Waters L (March 2018). "Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances" (PDF). Drug Testing and Analysis. 10 (8): 1258–1269. doi:10.1002/dta.2387. PMID 29582576. S2CID 31098917.
^ 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): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.
^ Catabay A, Taniguchi M, Jinno K, Pesek JJ, Williamsen E (1 March 1998). "Separation of 1,4-Benzodiazepines and Analogues Using Cholesteryl-10-Undecenoate Bonded Phase in Microcolumn Liquid Chromatography". Journal of Chromatographic Science. 36 (3): 111–118. doi:10.1093/chromsci/36.3.111.
^ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. PMID 18855614.
^ US 3904641, "Triazolothienodiazepine compounds"
^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 536. ISBN 9783527607495.
^ "EGazette Home". Archived from the original on 2022-03-14. Retrieved 2021-05-14.
^ Lopedota A, Cutrignelli A, Trapani A, Boghetich G, Denora N, Laquintana V, 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". Journal of Microencapsulation. 24 (3): 214–24. doi:10.1080/02652040601058152. PMID 17454433. S2CID 31434550.
^ ^a ^b Wakakura M, Tsubouchi T, Inouye J (March 2004). "Etizolam and benzodiazepine induced blepharospasm". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (3): 506–507. doi:10.1136/jnnp.2003.019869. PMC 1738986. PMID 14966178.
^ Kuroda K, Yabunami H, Hisanaga Y (January 2002). "Etizolam-induced superficial erythema annulare centrifugum". Clinical and Experimental Dermatology. 27 (1): 34–6. doi:10.1046/j.0307-6938.2001.00943.x. PMID 11952667. S2CID 36251540.
^ Hirase M, Ishida T, Kamei C (November 2008). "Rebound insomnia induced by abrupt withdrawal of hypnotics in sleep-disturbed rats". European Journal of Pharmacology. 597 (1–3): 46–50. doi:10.1016/j.ejphar.2008.08.024. PMID 18789918.
^ Kawajiri M, Ohyagi Y, Furuya H, Araki T, Inoue N, Esaki S, et al. (February 2002). "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]" [A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]. Rinsho Shinkeigaku = Clinical Neurology (in Japanese). 42 (2): 136–9. PMID 12424963.
^ Greenblatt DJ (February 1985). "Elimination half-life of drugs: value and limitations". Annual Review of Medicine. 36 (1): 421–7. doi:10.1146/annurev.me.36.020185.002225. PMID 3994325.
^ Bertolino A, Mastucci E, Porro V, Corfiati L, Palermo M, Ecari U, Ceccarelli G (25 June 2016). "Etizolam in the treatment of generalized anxiety disorder: a controlled clinical trial". The Journal of International Medical Research. 17 (5): 455–60. doi:10.1177/030006058901700507. PMID 2572494. S2CID 43179840.
^ De Candia MP, Di Sciascio G, Durbano F, Mencacci C, Rubiera M, Aguglia E, et al. (December 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, et al. (September 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.
^ Sanna E, Busonero F, Talani G, Mostallino MC, Mura ML, Pisu MG, et al. (September 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.
^ Nakamura J, Mukasa H (December 1992). "Effects of thienodiazepine derivatives, etizolam and clotiazepam on the appearance of Fm theta". The Japanese Journal of Psychiatry and Neurology. 46 (4): 927–31. doi:10.1111/j.1440-1819.1992.tb02862.x. PMID 1363923. S2CID 11263866.
^ 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): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.
^ "Depas". Retrieved October 31, 2015.
^ "Etizolam". PubChem. U.S. National Library of Medicine. Retrieved 2020-09-03.
^ ^a ^b Nakamae T, Shinozuka T, Sasaki C, Ogamo A, Murakami-Hashimoto C, Irie W, et al. (November 2008). "Case report: Etizolam and its major metabolites in two unnatural death cases". Forensic Science International. 182 (1–3): e1-6. doi:10.1016/j.forsciint.2008.08.012. PMID 18976871.
^ Araki K, Yasui-Furukori N, Fukasawa T, Aoshima T, Suzuki A, Inoue Y, et al. (August 2004). "Inhibition of the metabolism of etizolam by itraconazole in humans: evidence for the involvement of CYP3A4 in etizolam metabolism". European Journal of Clinical Pharmacology. 60 (6): 427–30. doi:10.1007/s00228-004-0789-1. PMID 15232663. S2CID 22970567.
^ 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". Therapeutic Drug Monitoring. 26 (6): 638–42. doi:10.1097/00007691-200412000-00009. PMID 15570188. S2CID 12164244.
^ Kondo S, Fukasawa T, Yasui-Furukori N, Aoshima T, Suzuki A, Inoue Y, et al. (May 2005). "Induction of the metabolism of etizolam by carbamazepine in humans". European Journal of Clinical Pharmacology. 61 (3): 185–8. doi:10.1007/s00228-005-0904-y. PMID 15776275. S2CID 9612361.
^ Høiseth G, Tuv SS, Karinen R (November 2016). "Blood concentrations of new designer benzodiazepines in forensic cases". Forensic Science International. 268: 35–38. doi:10.1016/j.forsciint.2016.09.006. PMID 27685473.
^ Woolverton WL, Nader MA (December 1995). "Effects of several benzodiazepines, alone and in combination with flumazenil, in rhesus monkeys trained to discriminate pentobarbital from saline". Psychopharmacology. 122 (3): 230–6. doi:10.1007/bf02246544. PMID 8748392. S2CID 24836734.
^ "Drug-related deaths in Scotland 2018" (PDF). National Records of Scotland.
^ "Expert Committee on Drug Dependence's Twenty Seventh Report" (PDF). World Health Organization. September 28, 1990. Retrieved July 3, 2023.
^ "Letter of WHO Director-General to UN Secretary-General dated November 15th 2019" (PDF). www.who.int.
^ "News: Recently scheduled benzodiazepines Flualprazolam and Etizolam associated with multiple post-mortem and DUID cases in UNODC EWA". United Nations Office on Drugs and Crime. March 2020.
^ ^a ^b "Warnings over counterfeit benzodiazepines". NSW Health.
^ "Bekendtgørelse om euforiserende stoffer". retsinformation.dk (in Danish). Retrieved 2016-11-21.
^ "Verordnungsentwurf der Bundesregierung" [Federal draft regulation] (PDF). Bundesministerium für Gesundheit (Federal Ministry of Health) (in German). Archived from the original (PDF) on 18 March 2016.
^ "Gesetz über den Verkehr mit Betäubungsmitteln" [Law on traffic with tranquillizers]. Bundesministerium der Justiz und für Verbraucherschutz (Federal Ministry of Justice and Consumer Protection) (in German).
^ "DEPAS - Etizolam". 2017-08-31. Retrieved 2018-05-14.
^ PubChem. "Etizolam". pubchem.ncbi.nlm.nih.gov. Retrieved 2021-03-06.
^ "The Misuse of Drugs Act 1971 (Amendment) Order 2017".
^ "Alabama Code Title 20. Food, Drugs, and Cosmetics § 20-2-23". Findlaw.
^ "List of Controlled Substances" (PDF). State of Arkansas. Archived from the original (PDF) on 2 February 2011.
^ "Statutes & Constitution: Online Sunshine". www.leg.state.fl.us.
^ "HB1231 (As Sent to Governor) - 2014 Regular Session". billstatus.ls.state.ms.us.
^ "Health and Safety Code Chapter 481. Texas Controlled Substances Act". statutes.capitol.texas.gov. Retrieved 2019-07-12.
^ "Controlled Substance Schedule | SCDHEC". www.scdhec.gov. Retrieved 2019-03-20.
^ "18VAC110-20-322. Placement of Chemicals in Schedule I". Commonwealth of Virginia. 2 December 2015. Retrieved 11 March 2016.
^ "Ellington's bill banning two deadly drugs could soon be law - State of Indiana House of Representatives". www.indianahouserepublicans.com.
^ "(Proposed Rule) Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I". Federal Register. DEA. December 23, 2022.
^ "Schedules of Controlled Substances: Temporary Placement of Etizolam, Flualprazolam, Clonazolam, Flubromazolam, and Diclazepam in Schedule I" (PDF). Federal Register. DEA. July 25, 2023. Retrieved 2023-07-25.
^ Gupta S, Garg B (2014). "A case of etizolam dependence". Indian Journal of Pharmacology. 46 (6): 655–6. doi:10.4103/0253-7613.144943. PMC 4264086. PMID 25538342.
^ Allison D (20 April 2018). "How to tackle Dundee's fake valium epidemic". BBC News.
^ Guirguis A. "Novel psychoactive substances: understanding the new illegal drug market". Pharmaceutical Journal. Archived from the original on 2019-04-11. Retrieved 2018-10-18.
^ "Drug Data Xanax". DrugData.org. Retrieved 9 April 2020.

External links

Inchem.org - Etizolam

[1] 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). Archived from the original on 2023-08-03. Retrieved 2023-08-16.

[auto-2] "Etizolam". www.drugbank.ca. Retrieved 2020-09-03.

[DEADiv-etiz-factsheet-3] "Drug & Chemical Evaluation - Etizolam" (PDF). U.S. Drug Enforcement Administration. U.S. Department of Justice. March 2020. Archived (PDF) from the original on 2020-09-03.

[auto1-4] Fracasso C, Confalonieri S, Garattini S, Caccia S (1991-02-01). "Single and multiple dose pharmacokinetics of etizolam in healthy subjects". European Journal of Clinical Pharmacology. 40 (2): 181–185. doi:10.1007/BF00280074. PMID 2065698. S2CID 10176681.

[Molecular_and_neurochemical_evaluat-5] Sanna E, Pau D, Tuveri F, Massa F, Maciocco E, Acquas C, et al. (February 1999). "Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions". Arzneimittel-Forschung. 49 (2): 88–95. doi:10.1055/s-0031-1300366. PMID 10083975. S2CID 19732765.

[6] Manchester KR, Maskell PD, Waters L (March 2018). "Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances" (PDF). Drug Testing and Analysis. 10 (8): 1258–1269. doi:10.1002/dta.2387. PMID 29582576. S2CID 31098917.

[7] 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): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.

[8] Catabay A, Taniguchi M, Jinno K, Pesek JJ, Williamsen E (1 March 1998). "Separation of 1,4-Benzodiazepines and Analogues Using Cholesteryl-10-Undecenoate Bonded Phase in Microcolumn Liquid Chromatography". Journal of Chromatographic Science. 36 (3): 111–118. doi:10.1093/chromsci/36.3.111.

[9] Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism. 9 (8): 827–844. doi:10.2174/138920008786049258. PMID 18855614.

[10] US 3904641, "Triazolothienodiazepine compounds"

[Fis2006-11] Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 536. ISBN 9783527607495.

[12] "EGazette Home". Archived from the original on 2022-03-14. Retrieved 2021-05-14.

[13] Lopedota A, Cutrignelli A, Trapani A, Boghetich G, Denora N, Laquintana V, 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". Journal of Microencapsulation. 24 (3): 214–24. doi:10.1080/02652040601058152. PMID 17454433. S2CID 31434550.

[Wakakura_2004-14] Wakakura M, Tsubouchi T, Inouye J (March 2004). "Etizolam and benzodiazepine induced blepharospasm". Journal of Neurology, Neurosurgery, and Psychiatry. 75 (3): 506–507. doi:10.1136/jnnp.2003.019869. PMC 1738986. PMID 14966178.

[15] Kuroda K, Yabunami H, Hisanaga Y (January 2002). "Etizolam-induced superficial erythema annulare centrifugum". Clinical and Experimental Dermatology. 27 (1): 34–6. doi:10.1046/j.0307-6938.2001.00943.x. PMID 11952667. S2CID 36251540.

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

[17] Kawajiri M, Ohyagi Y, Furuya H, Araki T, Inoue N, Esaki S, et al. (February 2002). "[A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]" [A patient with Parkinson's disease complicated by hypothyroidism who developed malignant syndrome after discontinuation of etizolam]. Rinsho Shinkeigaku = Clinical Neurology (in Japanese). 42 (2): 136–9. PMID 12424963.

[18] Greenblatt DJ (February 1985). "Elimination half-life of drugs: value and limitations". Annual Review of Medicine. 36 (1): 421–7. doi:10.1146/annurev.me.36.020185.002225. PMID 3994325.

[19] Bertolino A, Mastucci E, Porro V, Corfiati L, Palermo M, Ecari U, Ceccarelli G (25 June 2016). "Etizolam in the treatment of generalized anxiety disorder: a controlled clinical trial". The Journal of International Medical Research. 17 (5): 455–60. doi:10.1177/030006058901700507. PMID 2572494. S2CID 43179840.

[20] De Candia MP, Di Sciascio G, Durbano F, Mencacci C, Rubiera M, Aguglia E, et al. (December 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-21] Sanna E, Busonero F, Talani G, Mostallino MC, Mura ML, Pisu MG, et al. (September 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.

[22] Sanna E, Busonero F, Talani G, Mostallino MC, Mura ML, Pisu MG, et al. (September 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.

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