Evaluation of Novel Treatments for Stimulant Dependence

兴奋剂依赖性新疗法的评价

• 批准号: 7275954
• 负责人: Sharon L. Walsh
• 金额: $ 61.52万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275954
• 关键词: Abstinence; Acute; Adult; Adverse effects; Affinity; Agonist; Antipsychotic Agents; Attenuated; Behavioral; Chronic; Cigarette Smoker; Class; Clinical Research; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Condition; Coupled; Crack Cocaine; Data; Dependence; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor; Dopamine Receptor; Dopaminergic Agents; Dose; Double-Blind Method; Drug Kinetics; Enrollment; Environment; Evaluation; Exhibits; Homeostasis; Human; Individual; Inpatients; Interdisciplinary Study; Laboratories; Laboratory Procedures; Marketing; Measures; Mediating; Methodology; Methods; Otsuka brand of aripiprazole; Outcome; Outpatients; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Physiological; Placebos; Play; Procedures; Property; Psychostimulant dependence; Public Health; Randomized; Range; Rate; Relative (related person); Reporting; Research; Risk; Role; Safety; Schizophrenia; Self Administration; Serotonin; Site; Smoke; Smoker; Smoking; Smoking Behavior; Supervision; Surveys; Synapses; System; Tobacco; Tobacco Dependence; Treatment Efficacy; United States; Withdrawal Symptom; aripiprazole; atypical antipsychotic; cigarette smoking; craving; day; design; dopamine system; improved; mood regulation; novel; receptor; reinforcer; relating to nervous system; response; restoration; theories; volunteer

DESCRIPTION (provided by applicant): Recent surveys in the U.S. reveal that about 2.6 million individuals reported use of cocaine/crack in the past month. Despite a concerted research effort to develop an effective pharmacotherapy, no broadly effective therapies have been discovered. Cocaine exerts its reinforcing effects largely through interactions with central dopamine pathways, and chronic use of cocaine leads to dysregulation of these neural systems. This application proposes to examine a novel agent, aripiprazole (Abilify(r)), for its potential efficacy against cocaine by employing well-controlled experimental methods in a human laboratory setting. Aripiprazole is the newest atypical antipsychotic marketed in the U.S.; its neuropharmacological profile is truly unique and sets it apart from all other atypical neuroleptics. Aripiprazole has a high affinity for D2 and 5-HT1a receptors where it acts as a partial agonist, and at 5-HT2 receptors where it acts as an antagonist. We hypothesize that aripiprazole may both block the synaptic effects of cocaine and improve the neural perturbations resulting from chronic cocaine use. Healthy, adult, cocaine-dependent volunteers (n=36) who also smoke cigarettes will be enrolled as inpatients for 45 days. Following a brief wash-out and single-blind placebo lead-in, they will be randomly assigned to 1 of 3 treatment groups (0,15 or 30 mg aripiprazole p.o/day) under double-blind conditions. Cocaine challenge sessions will be conducted during the placebo lead-in, acute dosing phase, and at steady-state. During each phase, the direct pharmacodynamic and pharmacokinetic interaction between cocaine and aripiprazole will be examined in cocaine dose-effect challenge sessions. The effects of aripiprazole treatment on the reinforcing effects of cocaine will be examined directly with a self-administration procedure that employs alternative reinforcers and has been well-characterized by our laboratory. Cocaine will be examined over a range of doses relevant to those used illicitly, and pharmacodynamic assessments will be multi-dimensional, including subjective, objective, physiological and behavioral outcomes. In addition, because preliminary data suggest that atypical antipsychotics may reduce cigarette smoking, a secondary aim is to examine directly the effects of aripiprazole on smoking behavior in comparison to placebo. This study provides a unique opportunity to examine smoking under controlled conditions during a period of confinement; both smoking topography procedures and naturalistic smoking measures will be employed. Overall, this project will explore the potential therapeutic efficacy of a novel agent, aripiprazole, for the treatment of cocaine dependence while simultaneously providing the requisite safety data needed to launch an outpatient clinical trial and exploring the potential efficacy of this agent for smoking reduction or cessation.

描述（由申请人提供）：美国最近的调查显示，过去一个月约有 260 万人报告使用可卡因/强效快克。尽管进行了一致的研究努力来开发有效的药物疗法，但尚未发现广泛有效的疗法。可卡因主要通过与中枢多巴胺通路相互作用来发挥其增强作用，长期使用可卡因会导致这些神经系统失调。本申请拟通过在人体实验室环境中采用严格控制的实验方法来检查一种新型药物阿立哌唑 (Abilify(r)) 对抗可卡因的潜在功效。阿立哌唑是在美国上市的最新非典型抗精神病药物；其神经药理学特征确实是独一无二的，使其有别于所有其他非典型抗精神病药。阿立哌唑对 D2 和 5-HT1a 受体具有高亲和力，可作为部分激动剂，而对 5-HT2 受体则可作为拮抗剂。我们假设阿立哌唑既可以阻断可卡因的突触作用，又可以改善长期使用可卡因引起的神经紊乱。健康、成年、可卡因依赖且吸烟的志愿者 (n=36) 将作为住院患者入组，为期 45 天。经过短暂的清除和单盲安慰剂导入后，他们将在双盲条件下被随机分配到 3 个治疗组中的 1 个（0.15 或 30 毫克阿立哌唑口服/天）。可卡因挑战课程将在安慰剂导入、急性给药阶段和稳态期间进行。在每个阶段，可卡因和阿立哌唑之间的直接药效学和药代动力学相互作用将在可卡因剂量效应挑战会议中进行检查。阿立哌唑治疗对可卡因增强作用的影响将通过自我给药程序直接检查，该程序采用替代增强剂，并且已被我们的实验室充分表征。可卡因将在与非法使用相关的一系列剂量范围内进行检查，药效学评估将是多维的，包括主观、客观、生理和行为结果。此外，由于初步数据表明非典型抗精神病药物可能会减少吸烟，因此第二个目的是直接检查阿立哌唑与安慰剂相比对吸烟行为的影响。这项研究提供了一个独特的机会来检查禁闭期间受控条件下的吸烟情况；将采用吸烟地形程序和自然吸烟措施。总体而言，该项目将探索新型药物阿立哌唑治疗可卡因依赖的潜在治疗功效，同时提供开展门诊临床试验所需的必要安全数据，并探索该药物减少或戒烟的潜在功效。