Laboratories for Early Clinical Evaluation of Pharmacotherapies for Substance Use Disorders

在过去的4年里，我们的研究小组由药物开发中心资助（U 54 DA 038999）， 弗吉尼亚联邦大学的药物和酒精研究所（IDAS）建立了 专业知识和资源，以执行潜在药物治疗药物使用的早期临床试验 包括阿片样物质和可卡因使用障碍以及阿片样物质+可卡因共病使用障碍的疾病。下 资金，药物开发研究使用临床前模型进行，I期住院 用于阿片类药物的新化合物的研究、脑成像研究和行为实验室表型研究 和可卡因使用障碍我们已经检查了阿片类药物，可卡因和共病的新化合物之一 阿片类药物+可卡因使用障碍的最佳治疗药物是5-HT 2CR激动剂氯卡色林。这项研究是基于我们的临床前 氯卡色林显著减少阿片类药物自我给药以及阿片类药物和可卡因提示的数据 在啮齿动物中的反应8.为回应RFA-DA-19-018，我们建议维持和加强 在IDAS建立药物开发基础设施，以支持I期和II期临床 与NIDA的治疗和医学后果部门合作进行试验。作为 IDAS进行早期临床试验能力的示范项目，我们建议评估安全性， 氯卡色林与丁丙诺啡联合治疗 阿片类药物使用障碍 示范项目的具体目标： 实验1（0-18个月）。 目的1：检查氯卡色林和丁丙诺啡-纳洛酮治疗中的副作用和药物相互作用。 接受丁丙诺啡-纳洛酮MAT的阿片类药物使用障碍受试者。 目的2：检查与安慰剂相比，氯卡色林对药物渴求主观指标的影响， 接受丁丙诺啡-纳洛酮MAT的阿片类药物使用障碍受试者。 实验2（实验I后，如果NIDA批准）。 目的1：检查氯卡色林对阿片样物质线索相关脑定向（有效）连接的影响， 安慰剂用于接受丁丙诺啡-纳洛酮MAT的阿片类药物使用障碍受试者。 目的2：检查与安慰剂相比，氯卡色林对冲动相关有效连接的影响， 接受丁丙诺啡-纳洛酮MAT的阿片类药物使用障碍受试者。 探索性目的：使用MRI光谱法，无创检查氯卡色林与 安慰剂对接受丁丙诺啡MAT的阿片类药物使用障碍参与者的脑GABA浓度的影响- 纳洛酮

Funded for the last 4 years by a medication development center grant (U54DA038999), our research group at the Institute for Drug and Alcohol Studies (IDAS) at Virginia Commonwealth University has established the expertise and resources to execute early clinical trials of potential pharmacotherapies for substance use disorders including opioid and cocaine use disorders as well as comorbid opioid+cocaine use disorder. Under that funding, medication development studies were carried out using preclinical models, phase I inpatient studies, brain imaging studies, and behavioral laboratory phenotyping studies for novel compounds for opioid and cocaine use disorders. One of the novel compounds we have examined for opioid, cocaine, and comorbid opioid+cocaine use disorders is the 5-HT2CR agonist lorcaserin. This research was based on our preclinical data that lorcaserin significantly reduces opioid self-administration and opioid and cocaine cue elicited responding in rodents8. In response to RFA-DA-19-018, we propose to maintain and enhance the established medication development infrastructure at IDAS to support Phase I and Phase 2 clinical trials in collaboration with the Division of Therapeutics and Medical Consequences at NIDA. As a demonstration project of the ability of IDAS to conduct early phase clinical trials, we propose to assess safety, target engagement, and preliminary measures of efficacy, for lorcaserin in combination with buprenorphine for opioid use disorder. Specific Aims for Demonstration Project: Experiment 1 (0-18 months). Aim 1: Examine side effects and drug interactions between lorcaserin and buprenorphine-naloxone in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Aim 2: Examine effects of lorcaserin on subjective measures of drug craving compared to placebo in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Experiment 2 (Post Experiment I if approved by NIDA). Aim 1: Examine effect of lorcaserin on opioid cue related brain directional (effective) connectivity compared to placebo in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Aim 2: Examine effect of lorcaserin on impulsivity related effective connectivity compared to placebo in participants with opioid use disorder who are in MAT with buprenorphine-naloxone. Exploratory Aim: Examine noninvasively, using MRI spectroscopy, the effects of lorcaserin compared to placebo on brain GABA concentrations in opioid use disorder participants who are in MAT with buprenorphine- naloxone.