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。目前还没有一种广泛有效的药物治疗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，测试药物对与药物依赖有共同神经生物学基础的疾病有效，可以产生控制COC依赖的治疗方法。肥胖也是一个重大的公共健康问题。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源胺和/或下丘脑-黑素皮质素系统的扰动。肥胖的流行刺激了促进减肥的药物的发展。安非他酮（BUP）和纳曲酮（NTX）的组合对肥胖有效。本应用的首要目标是证明BUP-NTX联合治疗COC依赖的初始有效性、安全性和耐受性。将进行一项混合模型实验，其中不寻求治疗的coc依赖参与者将被随机分配到不同的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）将同时服用NTX（即NTX是受试者内因素）。鼻内COC的强化作用将在每个BUP队列的参与者在每个NTX剂量上维持4-7天后确定（即COC是受试者内因素）。COC（0、25、50、100毫克）将通过BUP（0、100、200、300毫克/天）和NTX（0、25、50毫克/天）的多剂量组合进行测试。拟议的研究还将确定BUP和NTX的最佳剂量组合，以最有效地减弱COC的强化作用。这项研究将为COC依赖的新型药物组合BUP和NTX的初始疗效和最佳剂量提供关键信息，这将提高进入临床试验时成功的可能性。拟议研究的创新包括：1)测试已上市药物的组合，这些药物在作为单一疗法进行测试时显示出适度的疗效；2)使用复杂的药物自我给药程序；3)为开展II期临床试验提供动力，以进一步证明BUP-NTX联合治疗COC依赖的有效性；4)展示市售药物组合的初始疗效和最佳剂量，而不是等待新分子可用于人体试验，从而更快地影响临床研究和实践。在这些方面，拟议的项目将改变目前药物治疗发展的临床研究范式，并对COC依赖的治疗产生重大影响。

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.