Laboratories for Early Clinical Evaluation of Pharmacotherapies for Substance Use Disorders

过去4年由药物开发中心拨款(U54DA038999)资助，我们的研究小组位于 弗吉尼亚联邦大学药物和酒精研究所(IDAS)成立了 执行药物使用潜在药物疗法早期临床试验的专业知识和资源 障碍包括阿片类药物和可卡因使用障碍以及共病的阿片类可卡因使用障碍。在……下面 这笔资金、药物开发研究是使用I期住院患者的临床前模型进行的 阿片类药物新化合物的研究、脑成像研究和行为实验室表型研究 和可卡因使用障碍。我们检查过的阿片类药物、可卡因和合并症的一种新化合物 阿片类可卡因使用障碍是5-HT2CR激动剂氯酪蛋白。这项研究是基于我们的临床前研究 氯卡瑟林显著减少阿片类药物自我给药和阿片类药物和可卡因线索的数据 用杆状物回应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2期临床 与NIDA治疗和医学后果司合作进行的试验。作为一名 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， 氯卡瑟林与丁丙诺啡联合治疗的靶向接触和初步疗效测量 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：研究氯卡瑟林与丁丙诺啡-纳洛酮的副作用和药物相互作用。 患有阿片类药物使用障碍的参与者与丁丙诺啡-纳洛酮在一起。 目的2：与安慰剂相比，研究氯酪蛋白对药物渴求主观测量的影响。 患有阿片类药物使用障碍的参与者与丁丙诺啡-纳洛酮在一起。 实验2(实验I后，如果得到NIDA的批准)。 目的1：检测氯酪蛋白对阿片线索相关脑定向(有效)连接的影响。 服用丁丙诺啡-纳洛酮的阿片类药物使用障碍患者的安慰剂。 目的2：与安慰剂比较，考察氯卡瑟林对冲动相关有效连接的影响。 患有阿片类药物使用障碍的参与者与丁丙诺啡-纳洛酮在一起。 探索性目的：用磁共振波谱无创性地检查氯卡瑟林与 安慰剂对服用丁丙诺啡的阿片类药物使用障碍患者大脑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.