紫外光谱法测定尿液中安眠类药物的含量

本文应用紫外可见光谱法研究了苯并二氮　类、吩噻嗪类药物的测定方法，分析的药物在０μｇ·ｍｌ－１～２０μｇ·ｍｌ－１内有良好的线性关系。提出了利用固相萃取技术测定尿液中药物的简便、快速的方法，测定尿液中药物的检出限为１．０μｇ·ｍｌ－１，回收率为７７．５％－１０１．２％。     

Compounds identified in an illicit generic Xanax tablet are the result of a failed synthesis of alprazolam

Unintended compounds produced by inexperienced clandestine chemists may present a challenge in laboratories tasked with their identification. In March 2020, an anonymously submitted tablet purchased as a generic form of Xanax was analyzed by Erowid's DrugsData.org . The gas chromatography–mass spectrometry (GC–MS) results publicly released online indicated several unidentified compounds due to a lack of database references at that time. Elucidation by our group indicated the presence of several structurally related compounds that were linked to a failed synthesis of alprazolam. For this case study, a published procedure for the synthesis of alprazolam starting with the chloroacetylation of 2-amino-5-chlorobenzophenone was identified as a potential source of this failure. The procedure was reproduced to identify pitfalls of the methodology and examine its possible link to the illicit tablet. Reaction outcomes were analyzed via GC–MS and compared to the tablet submission data. The major compound in this submission, N-(2-benzoyl-4-chlorophenyl)-2-chloroacetamide, along with several related byproducts were successfully reproduced indicating that the tablet contents potentially stem from a failure to synthesize alprazolam.     

An Unusual Case of Death Probably Triggered by the Association of Buprenorphine at Therapeutic Dose with Ethanol and Benzodiazepines and with Very Low Norbuprenorphine Level

Buprenorphine is largely prescribed for maintenance treatment in opioid dependence due to its safety profile. Nevertheless, fatalities at therapeutic dose have been described when associated with other central nervous system depressants, such as ethanol or benzodiazepines. Here, we report a case of death due to association of buprenorphine at therapeutic dose with benzodiazepines and ethanol. Although toxicity has been often attributed to its metabolite norbuprenorphine rather than to buprenorphine itself, in our case, norbuprenorphine was not detected in urine and bile and only in traces in blood. Moreover, the presence in blood of free buprenorphine but not of glucuronide metabolites argues for an unusual early death, at the beginning of buprenorphine metabolism. We propose that in the context of prior toxic impregnation, buprenorphine directly (and not via its metabolite norbuprenorphine) acted as a triggering factor by blocking the ventilatory response, rapidly leading to fatal respiratory depression.     

超分子溶剂萃取-气相色谱-串联质谱法检测尿液中苯二氮䓬类药物

目的建立一种尿液中9种苯二氮?类药物的超分子溶剂样品气相色谱-串联质谱(gas chromatography-tandem mass spectrometry,GC-MS/MS)分析方法。方法含9种苯二氮?类药物对照品的尿液样品用四氢呋喃和1-己醇组成的超分子溶剂进行液液萃取,取溶剂层氮吹至干,残余物用甲醇复溶后进行GC-MS/MS分析,数据采集方式为多反应监测模式,采用内标法定量。结果尿液中地西泮、咪达唑仑、氟硝西泮和氯氮平质量浓度在1~100ng/mL,劳拉西泮和阿普唑仑质量浓度在5~100ng/mL,硝西泮和氯硝西泮质量浓度在2~100ng/mL,艾司唑仑在质量浓度0.2~100ng/mL范围内具有良好的线性关系,相关系数为0.9991~0.9999,定量下限为0.2~5ng/mL,提取回收率为81.12%~99.52%,日内精密度[相对标准偏差(relative standard deviation,RSD)]和准确度(偏倚)分别小于9.86%、9.51%;日间精密度(RSD)和准确度(偏倚)分别小于8.74%、9.98%。室温和-20℃条件下,尿液中9种药物在15d内具有良好的稳定性。8名志愿者单摄口服阿普唑仑片后,在8~72h内尿液中阿普唑仑的质量浓度为6.54~88.28ng/mL。结论本研究建立的尿液中9种苯二氮?类药物的超分子溶剂萃取-GC-MS/MS分析方法,简便、快速、准确、灵敏,可为临床治疗及司法鉴定中苯二氮?类药物中毒监测提供技术支持。     

Parent and Metabolite Opioid Drug Concentrations in Unintentional Deaths Involving Opioid and Benzodiazepine Combinations,,

Effects of benzodiazepines on postmortem opioid parent and parent/metabolite blood concentration ratios were determined for fentanyl‐, hydrocodone‐, methadone‐, or oxycodone‐related accidental deaths. These opioids are partially metabolized by the CYP3A4 enzyme system, which is also affected by diazepam and alprazolam. Opioid/metabolite combinations examined were as follows: fentanyl/norfentanyl, hydrocodone/dihydrocodeine, methadone/EDDP, and oxycodone/oxymorphone. Parent opioid concentrations were analyzed for 877 deaths. Parent/metabolite concentration ratios were analyzed for 349 deaths, excluding cases with co‐intoxicants present known to interfere with opioid elimination. Alprazolam in combination with diazepam significantly decreased median hydrocodone concentrations by 48% (p = 0.01) compared to hydrocodone alone. The methadone parent/metabolite concentration ratio was reduced by 35% in the presence of diazepam compared to methadone alone (p = 0.03). Benzodiazepines did not statistically significantly affect fentanyl or oxycodone concentrations. Possible factors affecting opioid concentrations and possible toxicity development, including any differential effects on specific opioids, should continue to be explored.     

苯二氮卓类新精神活性物质去氯依替唑仑的定性检验方法研究

目的建立苯二氮卓类新精神活性物质去氯依替唑仑的气相色谱-质谱(GC-MS)和超高效液相色谱-四极杆-飞行时间质谱(UPLC-Q-TOF MS)定性检验方法。方法未知样品用甲醇和水提取,取上清液,采用GC-MS和UPLC-Q-TOF MS进行分析。结果经GC-MS检测,保留时间为17.73 min的未知组分的质谱碎片主要特征离子峰有m/z 279,308,239,252,225,77,126。经UPLC-Q-TOF MS检测,保留时间为4.781 min的未知组分的准分子离子峰为309.1173,碰撞诱导解离(CID)模式下二级质谱主要离子有m/z 280.0776,255.0952,240.0719,225.0604,206.0748。经缴获毒品分析科学工作组(Scientific Working Group for the Analysis of Seized Drugs,SWGDRUG)分析谱库检索和文献查询获得的信息资料进行比对,鉴定为去氯依替唑仑。结论该方法具有分析简便、快速的特点,可以用于实际案件的检测。     

Methadone‐Related Deaths – Epidemiological,Pathohistological, and Toxicological Traits in 10‐year Retrospective Study in Vojvodina,Serbia

The number of methadone‐related deaths (MRDs) during a 10‐year period (2002–2011) in the region of Vojvodina, Serbia, was increased. The cases were evaluated according to epidemiological parameters, pathohistological findings, and toxicological screening. The majority of victims were men, aged from 20 to 38. Pathohistologically, the signs of acute focal myocardial damage were present in the heart of victims with drug abuse history shorter than 2 years, while both signs of recent and chronic focal myocardial damage were developed among victims with longer drug abuse history (2–5 years). In postmortem blood samples of 54.84% of victims, methadone was detected in combination with diazepam, both in therapeutic range. Alcohol was absent in most cases. Other detected drugs were antipsychotics and antidepressants in therapeutic concentrations. These findings raise the attention to the concomitant use of methadone and benzodiazepines with the need for further studies to clarify the mechanism of death in such cases.     

苯并二氮类药物及其主要代谢物的薄层色谱分析

目的建立饮料、血、尿中 11种常见苯并二氮类药物及尿中 7种主要代谢物的薄层色谱分析法(HPTLC)。方法分析物采用GDX10 1树脂进行固相萃取 ,乙醚作为洗脱溶剂。苯 :丙酮 (10∶6)等作为展开体系 ,改良碘化铋钾显色。结果所建方法绝对灵敏度 0 3～ 0 6μg,尿检出限 0 4～ 1 0 μg/ml、血检出限 0 6～ 1 0 μg/ml、饮料检出限 0 4～ 0 8μg/ml。结论HPTLC法简便、快速 ,适合作为常规毒物分析方法     

Association between homicide injury severity and benzodiazepine influence

There are case reports of offenders inflicting excessive injuries on their victims when under the influence of benzodiazepines. However, the potential association between benzodiazepine influence on the offender and victim injury severity in a general homicide population has not been studied. We investigated associations between offender positive testing for benzodiazepines or z-drugs (zolpidem, zopiclone and zaleplon) and victim injury severity. Data were drawn from 95 Swedish homicide cases from 2007–2009 in which offenders had known toxicology. There were no significant differences in injury severity between cases in which the offender tested positive vs. negative for benzodiazepines/z-drugs. Thus, the findings do not support the hypothesis that there is an association between benzodiazepine influence on the offender and victim injury severity in a general homicide population.

Key points

• Some previous studies have linked benzodiazepines to aggression, violence and excessive homicide injuries.
• The present study analysed the association between homicide injury severity and benzodiazepine status of the offender.
• Offenders who tested positive for benzodiazepines did not inflict more severe injuries on their victims.
• These findings do not support the hypothesis that benzodiazepine influence generally causes offenders to inflict more severe injuries on homicide victims.

     

Prevalence and blood concentrations of benzodiazepines and opioids in opioid-positive death investigations in Ontario,Canada, from 2017 to 2021

The aim of this study was to investigate the incidence of benzodiazepines in opioid-positive death investigations, including trends in frequency and combination of drugs, as well as demographic data and blood concentrations, where available. Additionally, naloxone concentrations in polysubstance compared to opioid-only cases were analyzed. This was a retrospective study that consisted of all post-mortem toxicology cases in Ontario, Canada, from January 01, 2017, to December 31, 2021, with an opioid finding in any analyzed autopsy specimen. There were 11,033 death investigations identified. The overall rate of benzodiazepine co-involvement was 54.5%. Males accounted for the majority of cases (71%), and the most affected age group was 30- to 39-year-olds. The most frequently detected opioid was fentanyl and the most frequently detected benzodiazepine was etizolam, which was also the most frequently observed opioid/benzodiazepine combination. Findings related to differences in concentrations of opioids when naloxone was also present were mostly non-significant, except for methadone. The rate of benzodiazepine detection with opioids grew faster than opioid detections overall, potentially due to the increasingly toxic drug supply. Detection of novel psychoactive drugs fluctuated more unpredictably than opioids and benzodiazepines associated with clinical use. These findings can help inform policy decisions by public health agencies in exploring harm reduction efforts, for example, education and drug-checking services.