Phenazepam: The drug that came in from the cold

Maskell, Peter; Paoli, Giorgia De; Seetohul, L. Nitin; Pounder, Derrick J.

doi:10.1016/j.jflm.2011.12.014

Cited by 43 publications

(30 citation statements)

References 11 publications

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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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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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“…According to information from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), 101 and 100 NPS were detected for the first time in Europe in 2014 and 2015, respectively, which are the highest yearly numbers recorded. [3] Benzodiazepines are psychoactive drugs that are used in the treatment of anxiety, insomnia, agitation, seizures, muscle spasms, and in alcohol withdrawal. Of more recent date is the occurrence of designer benzodiazepines, which was first highlighted by the EMCDDA in 2011.…”

Section: Introductionmentioning

confidence: 99%

Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays

Bergstrand

Helander

Hansson

et al. 2016

Drug Testing and Analysis

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The emerging new psychoactive substances made available for recreational drug use have recently started to include designer benzodiazepines. As a consequence, the routine immunoassay drug testing for benzodiazepines may become less effective, due to an increased occurrence of 'false negative' and 'false positive' results. This work aimed to extend the knowledge of analytical cross-reactivity of 13 designer benzodiazepines in the CEDIA, EMIT II Plus, HEIA, and KIMS II immunoassays. Urine standards were prepared by spiking blank urine with clonazolam, deschloroetizolam, diclazepam, estazolam, etizolam, flubromazepam, flubromazolam, flutazolam, 3-hydroxyphenazepam, meclonazepam, nifoxipam, phenazepam, and pyrazolam. Authentic urine samples from intoxication cases identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) were also investigated. For the spiked standard samples, the 13 designer benzodiazepines generally showed a high cross-reactivity in all assays. This was further confirmed when investigating their detectability in authentic urine samples from cases of drug intake. The test responses also indicated additional reactivity from metabolites. The lowest detectability in spiked samples was observed for flutazolam, which shows the most divergent chemical structure compared with the other benzodiazepines. Overall, the KIMS II and CEDIA immunoassays, which both include enzymatic hydrolysis of conjugated forms, showed the highest, and EMIT II Plus the lowest degree of reactivity, for spiked parent substances and authentic urine specimens. The results of this study demonstrated that designer benzodiazepines can be detected in standard urine immunoassay drug screening and this should be taken into consideration when performing confirmation analysis. Copyright © 2016 John Wiley & Sons, Ltd.

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“…KEYWORDS: pharmacogenetics; alcohol withdrawal syndrome; benzodiazepine tranquilizers; CYP2C19 мейства CYP3A [34,35]. В то же время для многих бензодиа-зепинов характерно участие CYP2C19 и других цитохромов в их метаболизме [19,21].…”

Section: Introductionunclassified

Pharmacogenetic evaluation of adverse events’ risk in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine: The role of CYP2C19 gene polymorphisms

Ivashchenko¹,

Ryzhykova²,

Созаева³

et al. 2017

W J Person Med

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1 1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия 2 ГБУ «Московский научно-практический центр наркологии» ДЗМ, Москва, Россия ВВЕДЕНИЕ. Бромдигидрохлорфенилбензодиазепин -отечественный транквилизатор, широко применяемый в психиа-трии, неврологии, наркологии и общей медицине. В частности, данный препарат используется при купировании синдрома отмены алкоголя (СОА). Изофермент CYP2C19 участвует в метаболизме многих бензодиазепинов, поэтому его ген может быть включен в фармакогенетическое исследование бромдигидрохлорфенилбензодиазепина. Ранее не проводились ис-следования роли полиморфизмов гена CYP2C19 как биомаркеров безопасности данного препарата.МЕТОДЫ. В исследование были включены 102 пациента мужского пола с диагнозом неосложненного СОА (F10.30 по МКБ-10). Динамическое наблюдение длилось 6 сут, в течение которых пациенты принимали бромдигидрохлорфенилбен-зодиазепин (феназепам). Часть пациентов (n=38) принимали дополнительно паглюферал (комбинированный препарат, содержит фенобарбитал, кофеин-бензоат натрия, папаверин, бромурал) и/или карбамазепин. От каждого пациента было получено 5 мл венозной крови для генотипирования: с применением полимеразной цепной реакции в реальном времени определялось носительство полиморфных вариантов гена CYP2C19*2 (rs4244285), *3 (rs4986893) и *17 (rs12248560). Безо-пасность терапии оценивалась при помощи Шкалы оценки нежелательных эффектов -UKU Side Eff ects Rating Scale. Анализ данных проводился в программном пакете SPPS Statistics 21.0.РЕЗУЛЬТАТЫ. У носителей CYP2C19*2 GA+AA по сравнению с гомозиготами GG значимо чаще наблюдались такие неже-лательные побочные реакции (НПР), как «полиурия/полидипсия» средней степени выраженности (33,3% vs 9%, p=0,016) и «сердцебиение/тахикардия» (16,7% vs 3,8%, p=0,018). Наблюдаемая ассоциация «Полиурии/полидипсии» с генотипами CYP2C19*2 GA+AA сохранялась в подгруппе «Комбинированная фармакотерапия» (37,5% vs 0%, p=0,006). Полиморфизм CYP2C19*17 на уровне слабого тренда ассоциировался с меньшей частотой НПР «полиурия/полидипсия» среди пациентов, принимавших бромдигидрохлорфенилбензодиазепин в виде монотерапии -носители аллели T отмечали НПР в 16,9% слу-чаев, тогда как гомозиготы CC -в 24,2% (p=0,067).ВЫВОДЫ. Обнаружены значимые ассоциации полиморфизма CYP2C19*2 с отдельными НПР при приеме бромдигидро-хлорфенилбензодиазепина в составе терапии СОА. Не отмечено значимой роли CYP2C19*17 в прогнозировании риска развития НПР бромдигидрохлорфенилбензодиазепина. Ген CYP2C19 является значимым предиктором безопасности бром-дигидрохлорфенилбензодиазепина и нуждается в дальнейшем изучении.КЛЮЧЕВЫЕ СЛОВА: фармакогенетика; синдром отмены алкоголя; бензодиазепиновые транквилизаторы; CYP2C19

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Phenazepam: The drug that came in from the cold

Cited by 43 publications

References 11 publications

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

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

Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays

Pharmacogenetic evaluation of adverse events’ risk in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine: The role of CYP2C19 gene polymorphisms

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Phenazepam: The drug that came in from the cold

Cited by 43 publications

References 11 publications

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

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

Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays

Pharmacogenetic evaluation of adverse events’ risk in patients with alcohol withdrawal syndrome taking bromdihydrochlorphenylbenzodiazepine: The role of CYP2C19 gene polymorphisms

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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

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