A Human Laboratory Study of Exenatide for Reducing the Reinforcing Effects of Cocaine

艾塞那肽减少可卡因增强作用的人体实验室研究

• 批准号: 10573011
• 负责人: CHRISTOPHER D VERRICO
• 金额: $ 25.43万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573011
• 关键词: Abstinence; Acceleration; Acute; Adverse effects; Adverse event; Agonist; Attenuated; Behavior; Behavior Therapy; Blood Pressure; Chronic; Clinical; Clinical Pharmacology; Clinical Research; Cocaine; Cocaine Users; Cocaine use disorder; Cognitive Therapy; Data; Development; Dopamine; Dose; Drug Interactions; Eating; Evaluation; Experimental Designs; FDA approved; GLP-I receptor; Goals; Heart Rate; Human; Laboratories; Laboratory Study; Legal; Maintenance; Mediating; Medical; Molecular Target; National Institute of Drug Abuse; Nucleus Accumbens; Outcome; Outcome Measure; Participant; Persons; Pharmaceutical Preparations; Pharmacology Study; Pharmacotherapy; Phase II Clinical Trials; Physiological; Placebos; Procedures; Psychological reinforcement; Public Health; Questionnaires; Randomized; Rodent; Safety; Self Administration; Serum; Strategic Planning; Testing; Therapeutic; Translational Research; Treatment Effectiveness; Treatment outcome; abuse liability; clinical efficacy; clinical practice; clinical predictors; cocaine seeking; cocaine self-administration; cocaine use; conditioned place preference; design; drug seeking behavior; exenatide; glucagon-like peptide 1; improved; laboratory experiment; novel; pre-clinical; preclinical study; primary outcome; secondary outcome; social; subcutaneous; treatment effect; treatment strategy

PROJECT SUMMARY/ABSTRACT Cocaine (COC) use disorder (CUD) remains a significant medical, social, and legal public-health concern. Because behavioral therapies alone have limited efficacy, identification of pharmacotherapy that improves CUD treatment outcomes is sorely needed. Emerging preclinical evidence supports the potential clinical utility of stimulating the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) for treating CUD. Preclinical studies show that administration of a GLP-1R agonist attenuates COC self-administration, as well as COC-induced locomotor stimulation4, conditioned place preference, and dopamine release in the nucleus accumbens. Significantly, administering a GLP-1R agonist during abstinence following COC self-administration attenuated the reinstatement of drug-seeking behavior at doses that did not affect food intake or produce other adverse effects. Despite promising preclinical findings, and that COC administration significantly reduces serum concentrations of GLP-1 in humans, there has been only one human laboratory study in which administration of the GLP-1R agonist, exenatide, did not alter either the self-administration or subjective effects of COC in people with CUD. Multiple study limitations, including the use of an acute dose of exenatide rather than chronic pre-treatment, evaluation of only a single dose of COC, as well as the lack of both a placebo COC dose and an alternative to COC (i.e., a choice) in the free-access self-administration paradigm preclude drawing firm conclusions about the efficacy of exenatide for CUD. The overall objective of this application is to determine if GLP-1R agonism is a viable treatment strategy for CUD. This goal will be achieved through the conduct of a rigorous human clinical pharmacology study in which non-treatment seeking COC users (n=44) will be randomized (1:1) to a maintenance dose (0 mg (i.e., placebo) or 2 mg subcutaneously once a week) of extended-release (XR) exenatide for six weeks. The 6-week maintenance period, sufficient to achieve steady-state, will result in more stable concentrations of clinically effective doses before assessing treatment effects. Before and after the 6-week maintenance period, we will determine COC (0, 20, 40 mg: IV) self-administration rates. To accurately predict clinical efficacy, we will use forced-choice procedures in which participants choose to either self-administer COC or receive money. Our central hypothesis is that XR-exenatide will reduce COC self-administration compared to placebo. We expect that by (1) using a rigorous human laboratory experimental design, (2) testing treatment effects after achieving steady-state levels, and (3) employing appropriate endpoints for demonstrating treatment effectiveness in a laboratory setting, this project will provide definitive data regarding the potential of exenatide for reducing COC self-administration. The GLP-1R represents a substantial departure from previous treatment targets for CUD, and the drug-drug interaction safety data will provide the impetus for conducting a Phase II clinical trial. By repurposing an FDA-approved medication that does not have abuse potential, exenatide can advance through the development pipeline, thereby impacting clinical research and practice more quickly.

项目摘要/摘要 可卡因（COC）使用障碍（CUD）仍然是重要的医学，社会和法律公共卫生。 因为仅行为疗法的疗效有限，所以鉴定药物疗法可以改善CUD 迫切需要治疗结果。新兴的临床前证据支持 刺激胰高血糖素样肽1（GLP-1）受体（GLP-1R）治疗CUD。临床前研究表明 GLP-1R激动剂的给药会减弱COC自我给药，以及COC诱导的运动器 刺激4，条件的位置偏好和伏拟核中的多巴胺释放。显著地， 在COC自我管理后，在禁欲期间管理GLP-1R激动剂使 以不影响食物摄入或产生其他不良影响的剂量恢复寻求药物行为。 尽管有希望的临床前发现，并且COC给药可显着降低血清浓度 在人类中，GLP-1的掌握只有一项人类实验室研究，其中GLP-1R给药 激动剂，艾烯二胺并未改变COC对CUD的自我管理或主观影响。 多次研究局限 仅评估单剂量的COC，以及缺乏安慰剂COC剂量和COC的替代方案 （即选择）在自由访问的自我管理范式中 艾替尼对CUD的功效。该应用的总体目的是确定GLP-1R激动剂是否为 可行的CUD治疗策略。通过进行严格的人类临床，将实现此目标 药理学研究中，寻求COC使用者（n = 44）的药理学研究将被随机分配（1：1） 维持剂量（每周0 mg（即安慰剂）或2 mg皮下注射一次）延长释放（XR）艾塞那肽 六个星期。足以实现稳态的6周维护期将导致更稳定 在评估治疗效果之前，临床有效剂量的浓度。 6周之前和之后 维护期，我们将确定COC（0、20、40 mg：iv）自我管理率。准确预测 临床疗效，我们将使用强制选择程序，参与者选择自我管理COC 或收到钱。我们的核心假设是，与 安慰剂。我们希望通过（1）使用严格的人类实验室实验设计，（2）测试处理 达到稳态水平后的影响，（3）使用适当的终点进行治疗 在实验室环境中的有效性，该项目将提供有关Etenatide潜力的明确数据 用于减少COC自我管理。 GLP-1R代表了与以前的治疗的重大不同 CUD的目标，药物相互作用安全数据将为进行II期的动力提供动力 临床试验。通过重新利用没有滥用潜力的FDA批准的药物，Etenatide可以 通过开发管道发展，从而更快地影响临床研究和实践。