Sentanyl II: A Multi-State Analysis of Fentanyl/Analogs, Naloxone, and Clinical Features of Non-Fatal Opioid Overdose

摘要 PA-20-272对现有NIH赠款和合作协议的行政补充 （家长管理支持临床试验可选），我们要求家长合作协议的补充 UG 3DA 056892（Sentanyl II：芬太尼/类似物、纳洛酮和临床特征的多状态分析） 非致命阿片类药物过量）。虽然此通知不能用于此补充请求，但通知 特别 然而 目的 的 兴趣（NOSI）：甲苯噻嗪：了解其使用和后果（NOT-DA-24-009）， 鼓励对甲苯噻嗪的研究，甲苯噻嗪是补充请求的主题。 正在进行的母项目Sentanyl II（UG 3DA 056892）的2项涉及获得 人口统计学和临床数据以及来自马萨诸塞州大学医学中心急诊室的血液样本 部门（艾德）阿片类药物过量患者。血液样本接受阿片类药物和其他药物的广泛评估 法医科学研究和教育中心（CFSRE）。与以下主题高度相关： 根据这一补充要求，在26名Sentanyl II参与者中有10名（38.5%）的血液中检测到甲苯噻嗪 他们的血液样本已经由CFSRE进行了分析。 自大约2000年以来，甲苯噻嗪一直被用作非法阿片类药物中的故意掺杂物。它 越来越多地在非法阿片类药物供应和尸检标本中被发现， 芬太尼相关的过量用药关于甲苯噻嗪在人体中的药代动力学知之甚少， 赛拉嗪没有被批准用于人的治疗用途。这种知识的缺乏降低了我们 了解那些使用甲苯噻嗪的人的预期临床过程，以及治疗的发展， 调节其效果。考虑到以下情况，不可能进行人类志愿者研究来评估甲苯噻嗪的药代动力学， 用于人类使用甲苯噻嗪的研究性新药申请是不可能的， 毒品是危险的。Sentanyl II为研究甲苯噻嗪提供了自然和实用的机会 药代动力学此外，它还提供了一种方法来检查目前的现场护理尿液检测甲苯噻嗪 在最近接触过的人类参与者中 对于补充目标1，我们将招募12名马萨诸塞州艾德患者，这些患者（1）在阿片类药物过量后出现， 注射使用，和（2）在到达艾德时获得的初始血液样本表明可能存在甲苯噻嗪 暴露量，根据Randox Laboratories Evidence MultiSTAT甲苯噻嗪测定。参与者将提供更多 每小时采集一次血液样本CFSRE将对这些样本进行定量分析， 产生这些参与者的甲苯噻嗪药代动力学曲线。对于补充目标2，我们将评估 测试性能特性（例如，灵敏度、特异性、预测值） 条带），与CFSRE血液样品测试的比较“金标准”相比。

Abstract In response to PA-20-272 Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional), we are requesting a supplement to parent cooperative agreement UG3DA056892 (Sentanyl II: A Multi-State Analysis of Fentanyl/Analogs, Naloxone, and Clinical Features of Non-Fatal Opioid Overdose). Although this notice cannot be used for this supplement request, Notice Special nevertheless Aim of Interest (NOSI): Xylazine: Understanding its Use and the Consequences (NOT-DA-24-009), encourages research on xylazine, and xylazine is the topic of the supplement request. 2 of the parent project, Sentanyl II (UG3DA056892), which is in progress, involves obtaining demographic and clinical data and blood samples from University of Massachusetts Medical Center Emergency Department (ED) opioid overdose patients. Blood samples undergo extensive assessment for opioids and other substances by the Center for Forensic Science Research and Education (CFSRE). Highly relevant to the topic of this supplement request, xylazine has been detected in the blood of 10 of 26 (38.5%) Sentanyl II participants whose blood samples have been analyzed to date by CFSRE. Xylazine has been used as an intentional adulterant in illicit opioids since approximately 2000. It increasingly has been detected in the illicit opioid supply and the post-mortem specimens from people with fentanyl-associated overdoses. Little is known about the pharmacokinetics of xylazine among humans since xylazine has no approved therapeutic use in people. This absence of knowledge reduces our ability to understand the expected clinical course of those who used xylazine, as well as the development of treatments to mediate its effects. A human volunteer study to evaluate xylazine pharmacokinetics is not possible, given that an investigational new drug application for human use of xylazine is unlikely, and subjecting participants to the drug is hazardous. Sentanyl II provides a naturalistic and practical opportunity to study xylazine pharmacokinetics. Furthermore, it provides a means to examine current point-of-care urine tests for xylazine among recently exposed human participants. For Supplement Aim 1, we will recruit twelve UMass ED patients who (1) present after opioid overdose via injection use, and (2) whose initial blood sample obtained on arrival at the ED indicates a probable xylazine exposure, per the Randox Laboratories Evidence MultiSTAT xylazine assay. Participants will provide additional blood samples hourly for up to six hours. CFSRE will perform quantitative analyses of these samples to produce xylazine pharmacokinetic profiles of these participants. For Supplement Aim 2, we will evaluate the test performance characteristics (e.g., sensitivity, specificity, predictive value) of the ResponseTM Xylazine Test Strip), as compared to the comparative “gold standard” of CFSRE blood sample testing.