A Liquid-Chromatography High-Resolution Mass Spectrometry Method for Non-FDA Approved Benzodiazepines

Wijk, Xander M R van; Yun, Cassandra; Hooshfar, Shirin; Arens, Ann M.; Lung, Derrick; Wu, Alan H.B.; Lynch, Kara L.

doi:10.1093/jat/bky092

Cited by 18 publications

(10 citation statements)

References 13 publications

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“…The patients may not be aware of the identity or concentration of DBZD in a drug product before suffering symptoms of intoxication [135]. When a DBZD is the only drug identified, it provides the opportunity to characterize its associated sedative-hypnotic toxidrome as seen in cases [45,74,77,79,80,82,[84][85][86][89][90][91]98,106,109,111,113,115]. However, since few pharmacokinetics studies were performed [82,109], it is currently hard to associate concentrations in biological matrices with presumable related adverseeffects.…”

Section: Discussionmentioning

confidence: 99%

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Designer Benzodiazepines: A Review of Toxicology and Public Health Risks

et al. 2021

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The rising use of designer benzodiazepines (DBZD) is a cat-and-mouse game between organized crime and law enforcement. Non-prohibited benzodiazepines are introduced onto the global drug market and scheduled as rapidly as possible by international authorities. In response, DBZD are continuously modified to avoid legal sanctions and drug seizures and generally to increase the abuse potential of the DBZD. This results in an unpredictable fluctuation between the appearance and disappearance of DBZD in the illicit market. Thirty-one DBZD were considered for review after consulting the international early warning database, but only 3-hydroxyphenazepam, adinazolam, clonazolam, etizolam, deschloroetizolam, diclazepam, flualprazolam, flubromazepam, flubromazolam, meclonazepam, phenazepam and pyrazolam had sufficient data to contribute to this scoping review. A total of 49 reports describing 1 drug offense, 2 self-administration studies, 3 outpatient department admissions, 44 emergency department (ED) admissions, 63 driving under the influence of drugs (DUID) and 141 deaths reported between 2008 and 2021 are included in this study. Etizolam, flualprazolam flubromazolam and phenazepam were implicated in the majority of adverse-events, drug offenses and deaths. However, due to a general lack of knowledge of DBZD pharmacokinetics and toxicity, and due to a lack of validated analytical methods, total cases are much likely higher. Between 2019 and April 2020, DBZD were identified in 48% and 83% of postmortem and DUID cases reported to the UNODC, respectively, with flualprazolam, flubromazolam and etizolam as the most frequently detected substances. DBZD toxicology, public health risks and adverse events are reported.

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Section: Discussionmentioning

confidence: 99%

“…There are few data available on deschloroetizolam. In a self-administration study, one of the authors ingested one-half pink tablet of deschloroetizolam, about 6 mg, bought on the Internet [79]. After 15 min, the subject's overall behavior changed rapidly; both physical and cognitive effects were described.…”

Section: Deschloroetizolammentioning

confidence: 99%

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks

et al. 2021

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“…The concentration of clonazolam within the body is dependent on its metabolite intensity and duration of action, which can range from 20 to 60 minutes and persist for 8 to 14 hours 1,15 . However, with clonazolam being effective at low doses, it is imperative that identification and quantitative methods are optimized to identify both the parent compound and its metabolites, as clonazolam's elimination half-life is only 3.6 hours 3,17 . Therefore, if toxicological testing is unable to be performed within the 3 hours of ingestion, it is best to test for clonazolam's active metabolites, such as 8-aminoclonazolam, to detect for its presence.…”

Section: Discussionmentioning

confidence: 99%

“…1,15 However, with clonazolam being effective at low doses, it is imperative that identification and quantitative methods are optimized to identify both the parent compound and its metabolites, as clonazolam's elimination half-life is only 3.6 hours. 3,17 Therefore, if toxicological testing is unable to be performed within the 3 hours of ingestion, it is best to test for clonazolam's active metabolites, such as 8-aminoclonazolam, to detect for its presence. Urine samples have been successfully tested using nano-LC high-resolution MS (HRMS) to identify clonazolam's active metabolites.…”

Section: Discussionmentioning

confidence: 99%

Clonazolam Intoxication Case Report

Moore

Hammers

Marshall

2022

Am J Forensic Med Pathol

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Clonazolam is a derivative of the Xanax active ingredient, alprazolam. Classified as a designer benzodiazepine, clonazolam availability has been rising because of its circulation on illegal internet drug markets and marginal cost in comparison to its parent analogs. Clonazolam's accessibility encourages abuse prevalence and use of designer benzodiazepines. In our case, a 14-year-old male was found unresponsive the morning after ingesting multiple tablets believed to be Xanax. Toxicology testing indicated 140 ng/mL of 8-aminoclonazolam, a clonazolam metabolite, in the decedent's system. Alprazolam was not identified. Pathological analysis determined cerebral and respiratory depression to be the mechanism of death, resulting from acute clonazolam intoxication. This case presents the first death induced by clonazolam alone. Current literature identifies a gap in designer benzodiazepine confirmatory testing and a lack of awareness within the forensic and medical communities. Knowledge of designer benzodiazepines is needed to better understand their potency and to help prevent future intoxications. We present this case to aid in the recognition of novel benzodiazepines by medical examiners and coroners, to encourage their consideration in suspected Xanax and other substance related investigations, and to be aware of the capabilities of toxicological testing to improve novel benzodiazepine identification and subsequent interpretation.

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“…Angier et al reported on the use of liquid chromatography (LC) coupled to triple quadrupole tandem mass spectrometry (QQQ) for the analysis of 22 benzodiazepines in urine (19). Similarly, Drummer et al reported on the quantification of 32 benzodiazepines and Z-drugs in urine by LC-QQQ and Van Wijk et al on that of 15 benzodiazepines in urine by quadrupole time-of-flight mass spectrometry (20,21). Pettersson Bergstrand et al published a method for the specific detection of 11 designer benzodiazepines in urine by LC-QQQ (22).…”

Section: Introductionmentioning

confidence: 99%

Quantification of 54 Benzodiazepines and Z-Drugs, Including 20 Designer Ones, in Plasma

Degreef

Vits

Berry

et al. 2020

Journal of Analytical Toxicology

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Benzodiazepines are widely used in the treatment of sleep and anxiety disorders, as well as epileptic seizures and alcohol withdrawal because of their broad therapeutic index and low cost. Due to their central nervous system depressant effects they are also often implicated in traffic accidents and drug-related intoxications. With the increasing number of designer benzodiazepines used in a recreational setting, there is a need for analytical methods able to quantify both the prescribed and designer benzodiazepines. A liquid chromatography–triple quadrupole mass spectrometry method was developed for the quantification of 34 prescribed and 20 designer benzodiazepines in plasma. Different sample preparation strategies, including protein precipitation, liquid-liquid extraction, solid-phase extraction and mini-QuEChERS, were tested. The best recoveries for all compounds of interest were obtained with a liquid-liquid extraction using methyl-tertiary-butyl-ether and 500 μL plasma. The method was fully validated according to the European Medicines Agency guidelines for all compounds, except pivoxazepam, which is included for qualitative purposes only. In-sample stability issues were observed for cloxazolam, both at ambient temperature and during long-term storage at −20 °C. Due to the large number of compounds included, the simple and time-efficient sample preparation, and the relatively inexpensive instrumentation used, the presented method can be readily implemented in both therapeutic drug monitoring and forensic analyses.

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A Liquid-Chromatography High-Resolution Mass Spectrometry Method for Non-FDA Approved Benzodiazepines

Cited by 18 publications

References 13 publications

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks

Designer Benzodiazepines: A Review of Toxicology and Public Health Risks

Clonazolam Intoxication Case Report

Quantification of 54 Benzodiazepines and Z-Drugs, Including 20 Designer Ones, in Plasma

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