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

一种新型抗肥胖药物组合作为可卡因依赖的药物疗法

• 批准号: 8327334
• 负责人: CRAIG R RUSH
• 金额: $ 62.97万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327334
• 关键词: Abstinence; Accounting; Admission activity; Adult; Adverse effects; Age Reporting; American; Anti-Obesity Agents; Attenuated; Behavior Therapy; Behavioral; Biogenic Amines; Body Weight; Body Weight decreased; Bupropion; Clinical; Clinical Research; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Combination Drug Therapy; Development; Disease; Dopamine Uptake Inhibitors; Dose; Drug Addiction; Drug Combinations; Enrollment; Epidemic; Evaluation; Food; Goals; Human; Hypothalamic structure; Inpatients; Investigation; Laboratory Study; Maintenance; Modeling; Mono-S; Naltrexone; Narcotic Antagonists; Neurobiology; Obesity; Outcome Measure; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Physiological; Preventive Intervention; Probability; Procedures; Public Health; Questionnaires; Randomized; Relative (related person); Research; Safety; Self Administration; System; Testing; United States; clinical practice; cocaine use; cohort; double-blind placebo controlled trial; drug market; indexing; innovation; interest; novel; programs; reinforcer; research study; secondary outcome; success

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.

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。 COC依赖性尚未确定广泛有效的药物疗法。需要创新的策略来确定有效的COC依赖药物疗法。例如，对共享具有药物依赖性神经生物学基质的疾病有效的药物可以产生用于管理COC依赖性的治疗方法。 肥胖也是一个重大的公共卫生问题。尽管肥胖和COC依赖性通常被认为是不同的临床实体，但两种疾病都涉及中央生物胺和/或下丘脑甲状腺皮质素系统的扰动。肥胖流行促进了促进体重减轻的药物开发。安非他酮（BUP）和纳曲酮（NTX）的结合对肥胖是有效的。该应用程序的总体目标是证明BUP-NTX组合对COC依赖性的初始功效，安全性和耐受性。将进行一项混合模型实验，其中将单独的非治疗寻求，依赖COC依赖的参与者将其随机分为不同维持剂量的BUP（即BUP是对象间因素）。每个BUP队列中的参与者（n = 12）将同时维持在NTX上（即NTX是受试者内因子）。在每个NTX剂量的每个BUP队列的参与者保持4-7天之后，将确定鼻内COC的增强作用（即COC是受试者内部因素）。 COC（0、25、50、100 mg）将通过多种剂量组合（0、100、200、300 mg/day）和NTX（0、25、50 mg/day）测试。拟议的研究还将确定BUP和NTX的最佳剂量组合，最有效地减弱了COC的增强作用。 这项研究将提供有关新型药物组合，BUP和NTX的最初疗效和最佳剂量的关键信息，用于COC依赖性，这将在进行临床试验时提高成功的可能性。拟议的研究的创新包括：1）测试销售药物的组合，这些药物表现出适度的疗效，当时是单性治疗的； 2）使用复杂的药物自我管理程序； 3）为进行II期临床试验提供动力，以进一步证明BUP-NTX组合对COC依赖性的疗效； 4）证明了商用药物的最初功效和最佳剂量，而不是等待新的分子可以在人类中进行测试，从而更快地影响临床研究和实践。通过这些方式，拟议的项目将改变药物疗法开发中当前的临床研究范例，并对COC依赖性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决定一种新型药物组合，安非他酮和纳曲酮的初始功效，安全性和耐受性， 可卡因依赖的药物疗法。将进行严格的住院治疗人类实验室研究。拟议的研究具有创新性和重要性，因为它将为进行双盲，安慰剂对照试验的进行动力，以进一步证明安非他酮纳特雷酮组合对可卡因依赖性的有效性。