Case report: Etizolam and its major metabolites in two unnatural death cases

Nakamae, Takuma; Shinozuka, Tatsuo; Sasaki, Chizuko; Ogamo, Akira; Murakami-Hashimoto, Chikako; Irie, Wataru; Terada, Masaru; Nakamura, Shigeki; Furukawa, Masashi; Kurihara, Katsuyoshi

doi:10.1016/j.forsciint.2008.08.012

Cited by 57 publications

(27 citation statements)

References 10 publications

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“…Cocaine was the most common controlled drug detected in the study by Przepyszny and Jenkins . The designer benzodiazepine etizolam (not prescribed in the U.K.) was detected in seven cases.…”

Section: Resultsmentioning

confidence: 95%

Epidemiological Study of Carbon Monoxide Deaths in Scotland 2007–2016,

Lisbona

Hamnett

2018

Journal of Forensic Sciences

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Carbon monoxide (CO) intoxications are quite frequent in forensic toxicology. Using a sample of 209 CO-positive deaths in Scotland from 2007 to 2016, this study provides ranges of percentage CO saturations (%COHb) according to the CO source and examines any correlation with age, gender, alcohol, and preexisting disease. It also reports the full toxicological findings, including drug concentrations, in CO-positive cases. The highest numbers of fatalities involved males, occurred during autumn/winter, and the main source of CO was fire. The median %COHb in fire-related cases was significantly lower than in non-fire-related cases such as those involving exhausts, generators and gas supply systems, and portable BBQs. There was no relationship between %COHb and age, blood alcohol concentration, or the presence of preexisting cardiovascular and/or respiratory disease. Toxicology results revealed that prescription medications were the most commonly detected drug group and that the number of cases positive for controlled drugs was small.

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Section: Resultsmentioning

confidence: 95%

Epidemiological Study of Carbon Monoxide Deaths in Scotland 2007–2016,

Lisbona

Hamnett

2018

Journal of Forensic Sciences

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“…The lack of control over and safety of these NPS‐benzodiazepines is a prevalent issue and it is predicted that it will become an even more worrying trend as their misuse continues to spread. A number of these compounds were originally prescription drugs such as phenazepam (Russia) as well as etizolam and flutazolam (Japan) . Some of these compounds never gained marketing approval (eg, adinazolam) but the majority were simply patented and never brought to market and, as such, there is a deficit of physiochemical and pharmacokinetic data that would otherwise exist had they undergone clinical trials .…”

Section: Introductionmentioning

confidence: 99%

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Manchester

Maskell

Waters

2018

Drug Testing and Analysis

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The misuse of benzodiazepines as new psychoactive substances is an increasing problem around the world. Basic physicochemical and pharmacokinetic data is required on these substances to interpret and predict their effects upon humans. Experimental log D , pK and plasma protein binding values were determined for 11 benzodiazepines that have recently appeared as new psychoactive substances (3-hydroxyphenazepam, 4'-chlorodiazepam, desalkylflurazepam, deschloroetizolam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, phenazepam, and pyrazolam) and compared with values generated by various software packages (ACD/I-lab, MarvinSketch, ADMET Predictor and PreADMET). ACD/I-LAB returned the most accurate values for log D and plasma protein binding while ADMET Predictor returned the most accurate values for pK . Large variations in predictive errors were observed between compounds. Experimental values are currently preferable and desirable as they may aid with the future 'training' of predictive models for these new psychoactive substances.

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“…). Assuming similarities in the metabolism of metizolam and etizolam, hydroxylation is most likely to occur at the 2‐ethyl moiety or at the 6‐position of metizolam, resulting in 1‐[4‐(2‐chlorophenyl)‐6 H ‐thieno[3,2‐ f ][1,2,4]triazolo[4,3‐ a ][1,4]diazepin‐2‐yl]ethanol, 2‐[4‐(2‐chlorophenyl)‐6 H ‐thieno[3,2‐ f ][1,2,4]triazolo[4,3‐ a ][1,4]diazepin‐2‐yl]ethanol or 4‐(2‐chlorophenyl)‐2‐ethyl‐6 H ‐thieno[3,2‐ f ][1,2,4]triazolo[4,3‐ a ][1,4]diazepin‐6‐ol . Whichever combination of the aforementioned hydroxylation reactions lead to the detected dihydroxylated metabolite remains unclear.…”

Section: Resultsmentioning

confidence: 99%

Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines — an update comprising adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam, metizolam and nitrazolam

et al. 2016

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Designer benzodiazepines represent an emerging class of new psychoactive substances. While other classes of new psychoactive substances such as cannabinoid receptor agonists and designer stimulants are mainly consumed for hedonistic reasons, designer benzodiazepines may also be consumed as 'self-medication' by persons suffering from anxiety or other psychiatric disorders or as stand-by 'antidote' by users of stimulant and hallucinogenic drugs. In the present study, five benzodiazepines (adinazolam, cloniprazepam, fonazepam, 3-hydroxyphenazepam and nitrazolam) and one thienodiazepine (metizolam) offered as 'research chemicals' on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds, the structural formula declared by the vendor was confirmed by nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (MS), liquid chromatography MS/MS and liquid chromatography quadrupole time-of-flight MS analysis. The detected in vitro phase I metabolites of adinazolam were N-desmethyladinazolam and N-didesmethyladinazolam. Metizolam showed a similar metabolism to other thienodiazepines comprising monohydroxylations and dihydroxylation. Cloniprazepam was metabolized to numerous metabolites with the main metabolic steps being N-dealkylation, hydroxylation and reduction of the nitro function. It has to be noted that clonazepam is a metabolite of cloniprazepam, which may lead to difficulties when interpreting analytical findings. Nitrazolam and fonazepam both underwent monohydroxylation and reduction of the nitro function. In the case of 3-OH-phenazepam, no in vitro phase I metabolites were detected. Formation of licensed benzodiazepines (clonazepam after uptake of cloniprazepam) and the sale of metabolites of prescribed benzodiazepines (fonazepam, identical to norflunitrazepam, and 3-hydroxyphenazepam) present the risk of incorrect interpretation of analytical findings. Copyright © 2016 John Wiley & Sons, Ltd.

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Case report: Etizolam and its major metabolites in two unnatural death cases

Cited by 57 publications

References 10 publications

Epidemiological Study of Carbon Monoxide Deaths in Scotland 2007–2016,

Epidemiological Study of Carbon Monoxide Deaths in Scotland 2007–2016,

Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines — an update comprising adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam, metizolam and nitrazolam

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Case report: Etizolam and its major metabolites in two unnatural death cases

Cited by 57 publications

References 10 publications

Epidemiological Study of Carbon Monoxide Deaths in Scotland 2007–2016,

Epidemiological Study of Carbon Monoxide Deaths in Scotland 2007–2016,

Experimental versus theoretical log D7.4, pKa and plasma protein binding values for benzodiazepines appearing as new psychoactive substances

Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines — an update comprising adinazolam, cloniprazepam, fonazepam, 3‐hydroxyphenazepam, metizolam and nitrazolam

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Experimental versus theoretical log D_7.4, pK_a and plasma protein binding values for benzodiazepines appearing as new psychoactive substances