The Metabolism and Detection of New Psychoactive Substances and Emerging Drug Threats in a Poly-drug Context

该项目的背景：2017年，苏格兰记录了934例与毒品有关的死亡，这是欧洲报告的最高死亡率，是英格兰和威尔士记录的近3倍。几乎所有死亡都涉及多种药物滥用，最常见的所涉物质是阿片剂和类阿片（如海洛因和美沙酮）;苯二氮卓类药物（如依替唑仑和地西泮）和加巴喷丁类药物（加巴喷丁和普瑞巴林）。吸毒者表示，在海洛因（扑热息痛，咖啡因和二乙酰吗啡的混合物）之前服用加巴喷丁类药物，以提高和延长海洛因的效果。目前尚不清楚这种效应的机制。使用者也会服用大量的“街头安定”，通常一次多达10-30片。这些是非法制造的片剂，含有各种各样的苯二氮卓类药物，通常是在英国未经许可使用的新型药物类似物，是苏格兰非法药物市场的一个独特特征。药物的存在，其浓度和效力将随着时间的推移而变化很大，这意味着用户参与了一种“俄罗斯轮盘赌”的形式。当使用标准的多面板药物测试现场尿液测试设备对用户进行药物测试时，他们通常提供苯二氮卓类药物的阴性尿液测试结果，即使客户声称最近服用了“街头安定”片剂，表明与新化合物的交叉反应性很差。由于苯二氮卓类药物与如此多的药物相关死亡有关，该项目还调查了快速现场测试方法的发展，以区分“街头安定”中不同类型的苯二氮卓类药物。片剂利用经典的比色和新的技术解决方案。该项目还将评估常用尿液检测试剂盒的检测极限和选择性，目的是使用先进的质谱检测技术。（四极杆飞行时间（QToF-MS/MS）和三重四极杆（QQQ-MS/MS）串联质谱仪研究代谢，共同代谢或抑制代谢的常用滥用药物，以评估代谢的影响，这些物质的共同摄入对用户。开发分析技术是为了确定是否形成了特定的有毒代谢物，如果存在，该项目将验证检测方法。项目的新物理科学/工程方面先进的质谱法通常应用于制药工业和药物发现，以研究可能共同处方或摄入的法律的物质之间的药物相互作用，但很少应用于本研究中药物生产的药物和非法生产的新药之间的药物相互作用的研究。现时市面上并没有现成的实地测试方法，可迅速分辨与苯二氮卓类药物有密切关系的药物，而前线人员现时使用的尿液测试套件，亦未经过充分验证，可用于检测新的苯二氮卓类药物。该项目旨在评估此类试剂盒在多药背景下的性能，并研究简单的比色技术和新技术。

Context of the project:934 drug related deaths were recorded in Scotland in 2017, the highest rate reported in Europe and nearly 3 times that recorded in England and Wales. Almost all deaths involved poly-drug abuse and the most common substances involved are opiates and opioids (e.g. heroin and methadone); benzodiazepines (e.g. etizolam and diazepam) and gabapentinoid drugs (gabapentin and pregabalin). Drug users state that gabapentanoids are taken prior to heroin (a mixture of paracetamol, caffeine and diamorphine) to heighten and prolong the effects of the heroin. The mechanism of this reported effect is currently unknown. Users will also take large amounts, often up to 10-30 tablets at a time, of 'street diazepam'. These are illicitly manufactured tablets containing a wide variety of benzodiazepine drugs, often novel drug analogues unlicensed for use in the UK and which are a unique feature of the illicit drug market in Scotland. The drug present, its concentration and its potency will vary widely over time, meaning that users are involved in a form of 'Russian roulette' with the drugs they are taking. When users are tested for drugs using a standard multi-panel drug test field urine test device, they often provide a negative urine test result for benzodiazepines even though the client claims to have recently consumed 'street diazepam' tablets suggesting poor cross reactivity with novel compounds.Aims and Objectives:As benzodiazepines are implicated in so many drug related deaths the project also investigates the development of rapid field test methods to distinguish between the different types of benzodiazepines in 'street diazepam' tablets utilising both classical colorimetric and novel technological solutions. It will also assess the limits of detection and selectivity of commonly used urine test kits forThe aim of this project is to use advanced mass spectrometry detection techniques (quadrupole time of flight (QToF-MS/MS) and triple quadrupole (QQQ-MS/MS) tandem mass spectrometry instruments to investigate the metabolism, co-metabolism or inhibition of metabolism of commonly abused drugs to assess the metabolic impact of co-ingestion of these substances on users. The analytical techniques are developed to determine if specific toxic metabolites are formed and the project will validate measurement methods for their detection if present. Novel physical sciences/engineering aspects of the projectAdvanced mass spectrometry is normally applied in the pharmaceutical industry and drug discovery to investigate drug interactions between legal substances which might be co-prescribed or ingested but is rarely applied to the study of drug interactions between pharmaceutically produced drugs and illicitly produced novel drugs of the types in this study. It will adapt and optimise the existing methodologies to new applications.There are currently no commercially available field tests to rapidly distinguish between closely benzodiazepine drugs and the urine test kits currently being used by front-line staff are not fully validated for the detection of novel benzodiazepines. This project aims to assess the performance of such kits in a polydrug context and to investigate both simple colourometric techniques and novel technologies.