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，过去一个月中约有260万个人报告使用可卡因/裂缝。尽管进行了共同开发有效的药物治疗的研究工作，但尚未发现广泛有效的疗法。可卡因在很大程度上通过与中央多巴胺途径的相互作用施加了增强作用，可卡因的长期使用会导致这些神经系统的失调。该应用建议通过在人类实验室中采用良好控制的实验方法来检查新型药物Aripiprazole（Abilify（R））对可卡因的潜在疗效。 Aripiprazole是美国销售的最新非典型抗精神病药。它的神经药物形象确实是独一无二的，并将其与所有其他非典型神经化学植物区分开来。 Aripiprazole对D2和5-HT1A受体具有高亲和力，在该受体中充当部分激动剂，在5-HT2受体中充当拮抗剂。我们假设Aripiprazole可能会阻止可卡因的突触作用，并改善慢性可卡因使用引起的神经扰动。健康，成人，可卡因依赖的志愿者（n = 36）也将吸烟为住院病人45天。在短暂的洗涤和单盲安慰剂铅插入后，它们将在双盲条件下随机分配给3个治疗组中的1个（0,15或30 mg Aripiprazole P.O/天）。可卡因挑战会议将在安慰剂引导，急性给药阶段和稳态中进行。在每个阶段，可卡因和阿立哌唑之间的直接药效动力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。阿立哌唑处理对可卡因增强作用的影响将通过一种自我管理程序进行检查，该程序采用了替代增强剂，并已由我们的实验室进行了很好的特征。可卡因将在与非法使用的剂量的一系列剂量上进行检查，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可能会减少吸烟，因此与安慰剂相比，次要目的是直接检查阿立哌唑对吸烟行为的影响。这项研究提供了一个独特的机会，可以在受控条件下检查吸烟。都将采取吸烟地形程序和自然主义的吸烟措施。总体而言，该项目将探讨一种新型药物Aripiprazole的潜在治疗功效，以治疗可卡因依赖性，同时提供了发射门诊临床试验所需的必要安全数据，并探索了该药物减少吸烟或减少吸烟的潜在功效。