A Novel Anti Obesity Drug Combination as a Pharmacotherapy for Cocaine Dependence

描述（由申请人提供）：可卡因（COC）依赖是一个重大的公共卫生问题。尚未确定广泛有效的药物疗法用于COC依赖。需要创新的策略来确定有效的药物治疗COC依赖。例如，测试对与药物依赖共享神经生物学底物的疾病有效的药物，可以产生管理COC依赖的治疗方法。 肥胖也是一个重大的公共卫生问题。虽然肥胖和COC依赖通常被认为是不同的临床实体，但这两种疾病都涉及中枢生物胺和/或下丘脑-黑皮质素系统的扰动。肥胖症的流行刺激了药物的发展，以促进减肥。安非他酮（BUP）和纳洛酮（NTX）的组合对肥胖症有效。本申请的首要目标是证明BUP-NTX组合用于COC依赖的初始疗效、安全性和耐受性。将进行混合模型实验，其中非寻求治疗的COC依赖性参与者的单独队列将被随机分配至不同的BUP维持剂量（即，BUP是受试者之间的因素）。每个BUP队列中的参与者（N=12）将同时维持NTX（即，NTX是受试者内因素）。鼻内COC的增强作用将在每个BUP组群中的参与者以每个NTX剂量维持4-7天后确定（即，COC是受试者内因素）。COC（0、25、50、100 mg）将与BUP（0、100、200、300 mg/天）和NTX（0、25、50 mg/天）的多次剂量组合进行检测。拟议的研究还将确定BUP和NTX的最佳剂量组合，最有效地减弱COC的增强作用。 这项研究将提供关键信息的初始疗效和最佳剂量ofa新的药物组合，BUP和NTX，COC依赖，这将提高成功的概率时，先进的临床试验。拟议研究的创新包括：1）测试市售药物的组合，这些药物在作为单一疗法测试时表现出适度的疗效; 2）使用复杂的药物自我给药程序; 3）为II期临床试验的进行提供动力，以进一步证明BUP-NTX组合对COC依赖的疗效;和4）证明市售药物组合的初始功效和最佳剂量，而不是等待新分子可用于人体测试，从而更快地影响临床研究和实践。通过这些方式，拟议的项目将改变目前药物治疗开发的临床研究范式，并对COC依赖的治疗产生重大影响。 公共卫生相关性：本申请中提出的研究将确定新型药物组合安非他酮和纳洛酮的初始疗效、安全性和耐受性， 可卡因依赖的药物疗法将进行严格的住院人体实验室研究。拟议的研究是创新和重要的，因为它将为双盲，安慰剂对照试验的进行提供动力，以进一步证明安非他酮-纳洛酮组合用于管理可卡因依赖的疗效。

DESCRIPTION (provided by applicant): Cocaine (COC) dependence is a significant public health concern. A widely effective pharmacotherapy has not yet been identified for COC dependence. Innovative strategies are needed to identify an effective pharmacotherapy for COC dependence. Testing medications effective for disorders that share neurobiological substrates with drug dependence, for example, could yield treatments for managing COC dependence. Obesity is also a significant public health concern. Although obesity and COC dependence are typically considered distinct clinical entities, both diseases involve perturbations of central biogenic amine and/or hypothalamic-melanocortin systems. The obesity epidemic has spurred development of medications to promote weight loss. A combination of bupropion (BUP) and naltrexone (NTX) is effective for obesity. The overarching goal of this application is to demonstrate the initial efficacy, safety, and tolerability of BUP-NTX combinations for COC dependence. A mixed-model experiment will be conducted in which separate cohorts of non-treatment-seeking, COC-dependent participants will be randomized to different maintenance doses of BUP (i.e., BUP is a between-subject factor). Participants (N=12) in each BUP cohort will be maintained concurrently on NTX (i.e., NTX is a within-subject factor). The reinforcing effects of intranasal COC will be determined after participants in each BUP cohort are maintained for 4-7 days on each of the NTX doses (i.e., COC is a within-subject factor). COC (0, 25, 50, 100 mg) will be tested with multiple dose combinations of BUP (0, 100, 200, 300 mg/day) and NTX (0, 25, 50 mg/day). The proposed study will also identify the optimal dose combination of BUP and NTX that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses ofa novel drug combination, BUP and NTX, for COC dependence, which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated modest efficacy when tested as mono-therapies; 2) the use of a sophisticated drug self-administration procedure; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of BUP-NTX combinations for COC dependence; and 4) demonstrating the initial efficacy and optimal doses of a combination of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly. In these ways, the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of COC dependence. PUBLIC HEALTH RELEVANCE: The research proposed in this application will determine the initial efficacy, safety and tolerability of a novel drug combination, bupropion and naltrexone, as a pharmacotherapy for cocaine dependence. A rigorous, inpatient human laboratory study will be conducted. The proposed study is innovative and important because it will provide the impetus for the conduct of double blind, placebo-controlled trials to further demonstrate the efficacy of bupropion-naltrexone combinations for managing cocaine dependence.