Topiramate-Phentermine Combinations 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，但两者都涉及中枢生物源性神经系统的扰动。肥胖症的流行刺激了药物的发展，以促进减肥。美国食品和药物管理局（FDA）最近批准了一种托吡酯（TOP）和芬特明（PHEN）的组合用于肥胖症。本申请的首要目标是证明TOP-PHEN组合用于COC依赖的初始功效、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）将同时维持PHEN（即，PHEN是受试者内因素）。COC的强化作用将在每个TOP组群中的参与者对每个PHEN剂量维持7天后确定（即，COC是受试者内因素）。将使用TOP（0、100、200 mg/天）和PHEN（0、15、30 mg/天）的每个剂量组合测试COC（4 [安慰剂]、40、80 mg）。因此，拟议的研究将确定最有效地减弱COC增强作用的最佳TOP-PHEN剂量组合。这项研究将提供关于一种新型药物组合TOP和PHEN对COC依赖的初始疗效和最佳剂量的关键信息，这将提高进入临床试验时成功的可能性。该提案的创新包括：1）测试对疾病有效的药物组合， 肥胖，其与COC成瘾共享神经生物学和行为基质; 2）使用药物自我给药程序; 3）为进行II期临床试验提供动力，以进一步证明TOP-PHEN组合对COC成瘾的功效; 4）证明市售药物的初始功效，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）促进研究不同临床研究的科学家之间的交流 实体（例如，肥胖和COC成瘾）;和6）刺激申办者对成瘾药物治疗的兴趣，因为证明TOP-PHEN组合的功效将支持该产品在新人群中的新适应症并延长专利寿命。拟议的项目将改变目前药物治疗开发的研究范式，并对COC滥用治疗产生重大影响。

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. While obesity and COC dependence are typically considered distinct clinical entities, both involve perturbations of central biogenic amie 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.