Topiramate-Phentermine Combinations for Cocaine Dependence

托吡酯-芬特明组合治疗可卡因依赖

• 批准号: 9100670
• 负责人: CRAIG R RUSH
• 金额: $ 63.21万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100670
• 关键词: Abstinence; Adverse effects; Attenuated; Behavior Therapy; Behavioral; Biogenic Amines; Body Weight; Body Weight decreased; Clinical; Clinical Research; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Communication; Development; Disease; Dose; Drug Addiction; Drug Combinations; Drug usage; Enrollment; Epidemic; Excitatory Amino Acid Antagonists; Food; GABA Agonists; Goals; Human; Inpatients; Investigation; Laboratory Study; Legal patent; Life; Maintenance; Medication Management; Modeling; Mono-S; Neurobiology; Obesity; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phentermine; Physiological; Placebos; Population; Probability; Procedures; Public Health; Questionnaires; Randomized; Research; Research Design; Safety; Scientist; Self Administration; System; Testing; United States Food and Drug Administration; Work; addiction; clinical practice; cocaine use; cohort; double-blind placebo controlled trial; experimental study; indexing; innovation; interest; monoamine; novel; novel drug combination; programs; public health relevance; reinforcer; secondary outcome; success; topiramate

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.

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。目前还没有针对COC依赖的广泛有效的药物治疗方法。需要创新的策略来确定治疗COC依赖的有效药物疗法。例如，测试对具有相同神经生物学底物和药物依赖的疾病有效的药物，可能会产生控制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起源AMIE系统的扰动。肥胖症的流行刺激了促进减肥的药物的开发。美国食品和药物管理局(FDA)最近批准了托吡酯(TOP)和苯丙氨酸(PHEN)的组合治疗肥胖症。这项应用的首要目标是证明TOP-PHEN联合治疗COC依赖的初步疗效、安全性和耐受性。将进行一项混合模型实验，将不寻求治疗、依赖COC的不同队列的参与者随机分配到不同的最高维持剂量(即TOP是受试者之间的因素)。每个顶级队列中的参与者(N=12)将同时保留在PHEN上(即，PHEN是受试者内的一个因素)。COC的强化效果将在每个顶级队列中的参与者在每个phen剂量上保持7天后确定(即，COC是受试者内的一个因素)。COC(4[安慰剂]，40，80毫克)将用TOP(0,100,200毫克/天)和PHEN(0，15，30毫克/天)的每个剂量组合进行测试。因此，这项拟议的研究将确定最有效地减弱COC增强效应的最佳TOP-PHEN剂量组合。这项研究将提供关于COC依赖的新型药物组合TOP和PHEN的初始疗效和最佳剂量的关键信息，这将在推进到临床试验时提高成功的可能性。该提案的创新包括：1)测试一种对疾病有效的药物组合， 肥胖，与COC成瘾有共同的神经生物学和行为基础；2)药物自我给药程序的使用；3)为进行第二阶段临床试验提供动力，以进一步证明TOP-phen组合对COC成瘾的疗效；4)展示商业上可获得的药物的初步疗效，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；5)促进研究不同临床的科学家之间的交流 这些研究包括：(1)研究药物成瘾性(例如肥胖和COC成瘾)；(6)激发赞助商对成瘾药物疗法的兴趣，因为证明TOP-PHEN组合的有效性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。