Topiramate-Phentermine Combinations for Cocaine Dependence

摘要 可卡因（COC）依赖是一个重大的公共卫生问题。一种广泛有效的药物疗法， 尚未发现COC依赖性。需要创新战略，以确定有效的 COC依赖的药物治疗。测试药物有效的疾病，共享神经生物学 例如，具有药物依赖性的基质可以产生用于管理COC依赖性的治疗。 肥胖也是一个重大的公共卫生问题。虽然肥胖和COC依赖是 通常被认为是不同的临床实体，两者都涉及中枢生物胺系统的扰动。的 肥胖症的流行已经刺激了促进减肥的药物的开发。食品药品 美国食品药品监督管理局（FDA）最近批准了托吡酯（TOP）和芬特明（PHEN）的组合，用于 肥胖本申请的总体目标是证明以下药物的初始疗效、安全性和耐受性： TOP-PHEN组合用于COC依赖。将进行混合模型实验， 非寻求治疗的COC依赖性受试者的单独队列将随机分配至不同的TOP 维持剂量（即，TOP是受试者之间的因素）。每个TOP队列中的参与者（N=12）将 在PHEN上同时保持（即，PHEN是受试者内因素）。COC的强化作用将是 在每个TOP群组中的参与者以每个PHEN剂量维持7天后确定（即，COC是一个 受试者内因素）。COC（4 [安慰剂]，40，80 mg）将与TOP（0，100， 200 mg/天）和PHEN（0、15、30 mg/天）。因此，拟议的研究将确定最佳TOP-PHEN 最有效地减弱COC的增强作用的剂量组合。 这项研究将提供关于一种新药的初始疗效和最佳剂量的关键信息 组合，TOP和PHEN，用于COC依赖，这将提高成功的概率， 进行临床试验。该提案的创新包括：1）测试有效用于治疗癌症的药物组合。 与COC成瘾共享神经生物学和行为底物的疾病，肥胖; 2）药物的使用 自我管理程序; 3）为II期临床试验的进行提供动力，以进一步 证明TOP-PHEN组合对COC成瘾的功效; 4）证明TOP-PHEN组合对COC成瘾的初始功效; 商业上可获得的药物，而不是等待新的分子可用于人体测试， 从而更快地影响临床研究和实践; 5）促进科学家之间的沟通 研究不同的临床实体（例如，肥胖和COC成瘾）;以及6）激发赞助商对成瘾的兴趣 因为证明TOP-PHEN组合的疗效将支持一种新的药物治疗， 本产品在新人群中适应症，并延长专利寿命。该项目将改变目前 研究范式在药物治疗的发展，并有重大影响COC滥用治疗。

Abstract 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. While obesity and COC dependence are typically considered distinct clinical entities, both involve perturbations of central biogenic amine systems. The obesity epidemic has spurred development of medications to promote weight loss. The Food and Drug Administration (FDA) recently approved a combination of topiramate (TOP) and phentermine (PHEN) for obesity. The overarching goal of this application is to demonstrate the initial efficacy, safety, and tolerability of TOP-PHEN 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 TOP maintenance doses (i.e., TOP is a between-subject factor). Participants (N=12) in each TOP cohort will be maintained concurrently on PHEN (i.e., PHEN is a within-subject factor). The reinforcing effects of COC will be determined after participants in each TOP cohort are maintained for 7 days on each PHEN dose (i.e., COC is a within-subject factor). COC (4 [placebo], 40, 80 mg) will be tested with each dose combination of TOP (0, 100, 200 mg/day) and PHEN (0, 15, 30 mg/day). The proposed study will therefore identify the optimal TOP-PHEN dose combination that most effectively attenuates the reinforcing effects of COC. This research will provide critical information regarding the initial efficacy and optimal doses of a novel drug combination, TOP and PHEN, for COC dependence, which will enhance the probability of success when advanced to a clinical trial. Innovations of the proposal include: 1) testing a drug combination effective for a disorder, obesity, that shares neurobiological and behavioral substrates with COC addiction; 2) the use of drug self-administration procedures; 3) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of TOP-PHEN combinations for COC addiction; 4) demonstrating the initial efficacy 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; 5) facilitating communications between scientists studying distinct clinical entities (e.g., obesity and COC addiction); and 6) spurring sponsor interest in addiction pharmacotherapy because demonstrating the efficacy of the TOP-PHEN combination would support a novel indication for this product in a new population and extend patent life. The proposed project will shift the current research paradigm in pharmacotherapy development and have a significant impact on COC abuse treatment.