Medications Development for Stimulant Abuse

治疗兴奋剂滥用的药物开发

基本信息

批准号：
8470144
负责人：
Sidney S Negus
金额：
$ 35.82万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470144
关键词：
Agonist Amphetamines Attention deficit hyperactivity disorder Behavioral Chronic Clinical Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Consumption Development Dimensions Dopamine Dose Drug Exposure Drug Kinetics Drug abuse Drug usage Effectiveness Elements Evaluation Food Generations Human Knowledge Laboratory Study Macaca mulatta Modeling Monkeys National Institute of Drug Abuse Norepinephrine Opioid Pattern Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phenmetrazine Physical Dependence Pre-Clinical Model Prodrugs Public Health Recording of previous events Relative (related person)Schedule Self Administration Series Serotonin Stimulus Techniques Treatment Efficacy Withdrawal clinically relevant contextual factors contingency management design drug reinforcement interest monoamine noradrenergic preclinical study public health relevance reinforcer stimulant abuse

项目摘要

DESCRIPTION (provided by applicant): This is a new R01 application designed to evaluate clinically relevant determinants of the remarkably sustained and selective effects of monoamine releasers on cocaine self-administration in rhesus monkeys. Cocaine abuse remains a major drug abuse problem, and the development of effective pharmacotherapies continues to be a high priority for NIDA. In preliminary studies, we have found that chronic treatment with modest doses of the monoamine releasers amphetamine and PHENMETRAZINE produced robust and selective reductions in cocaine- vs. food-maintained responding for up to 28 days in rhesus monkeys. Key elements of our results from monkeys have been demonstrated by others in human laboratory studies and clinical trials. We believe these findings support the proposition that monoamine releasers warrant further study as candidate agonist medications for cocaine dependence. Toward that end, this application proposes two Specific Aims to evaluate contextual and pharmacologic determinants of monoamine releaser effects. Specific Aim 1 will examine effects of environmental and drug-history contexts on phenmetrazine-induced reductions in cocaine self-administration. Specific Aim 1a will evaluate phenmetrazine effects under conditions of alternative reinforcer availability. In clinical drug abuse treatment, pharmacotherapies are increasingly used in conjunction with contingency management techniques that introduce and control availability of alternative reinforcers. We propose to model this dual use of pharmacotherapies and alternative reinforcers, and we hypothesize that alternative reinforcer availability will enhance phenmetrazine-induced suppression of cocaine self- administration. Specific Aim 1b will evaluate phenmetrazine effects under conditions of extended access to and withdrawal from cocaine. In other drug classes (e.g. opioids), extended access promotes increased drug consumption, the development of physical dependence, and heightened drug reinforcement during withdrawal. Moreover, opioid agonist medications are most effective under conditions of withdrawal. We hypothesize that extended access to and withdrawal from cocaine will similarly enhance the ability of phenmetrazine to reduce cocaine self-administration. Specific Aim 2 will examine pharmacokinetic and pharmacodynamic determinants of monoamine releaser effects. Specific Aim 2a will correlate pharmacokinetic and behavioral effects of PHENDIMETRAZINE, a phenmetrazine prodrug and Schedule III stimulant. We hypothesize that phendimetrazine will retain phenmetrazine's ability to produce selective decreases in cocaine self- administration, but that phendimetrazine will have a slow onset of action that correlates with generation of the active phenmetrazine metabolite. Specific Aim 2b will evaluate a series of monoamine releasers that vary in selectivity to release dopamine and serotonin vs. norepinephrine. We hypothesize that releasers with reduced noradrenergic effects will display reduced abuse liability but retain an ability to produce selective reductions in cocaine self-administration.

描述（由申请人提供）：这是一项新的 R01 申请，旨在评估单胺释放剂对恒河猴自我给药可卡因的显着持续和选择性影响的临床相关决定因素。可卡因滥用仍然是一个主要的药物滥用问题，开发有效的药物疗法仍然是 NIDA 的高度优先事项。在初步研究中，我们发现，用中等剂量的单胺释放剂安非他明和苯甲嗪进行长期治疗，可卡因与食物维持的反应相比，可选择性地显着降低恒河猴长达 28 天的反应。我们在猴子身上得到的结果的关键要素已被其他人在人体实验室研究和临床试验中得到证明。我们相信这些发现支持这样的主张：单胺释放剂值得进一步研究作为可卡因依赖的候选激动剂药物。为此，本申请提出了两个具体目标来评估单胺释放剂效应的背景和药理学决定因素。具体目标 1 将研究环境和药物史背景对芬美嗪引起的可卡因自我给药减少的影响。具体目标 1a 将评估芬美嗪在有替代强化剂可用的情况下的效果。在临床药物滥用治疗中，药物疗法越来越多地与引入和控制替代强化剂的可用性的应急管理技术结合使用。我们建议对药物疗法和替代强化剂的双重使用进行建模，并且我们假设替代强化剂的可用性将增强芬美嗪诱导的对可卡因自我给药的抑制。具体目标 1b 将评估芬美嗪在长期接触和戒断可卡因的情况下的作用。在其他药物类别（例如阿片类药物）中，扩大使用范围会促进药物消费增加、身体依赖性的发展以及戒断期间药物强化的加强。此外，阿片类激动剂药物在戒断条件下最有效。我们假设延长可卡因的使用和戒断时间同样会增强芬美嗪减少可卡因自我给药的能力。具体目标 2 将检查单胺释放剂效应的药代动力学和药效学决定因素。具体目标 2a 将关联苯甲嗪（一种苯甲嗪前药和 Schedule III 兴奋剂）的药代动力学和行为效应。我们假设苯甲嗪将保留苯甲嗪选择性降低可卡因自我给药的能力，但苯甲嗪将具有缓慢起效的作用，这与活性苯甲嗪代谢物的产生相关。具体目标 2b 将评估一系列单胺释放剂，这些释放剂与去甲肾上腺素相比，释放多巴胺和血清素的选择性不同。我们假设去甲肾上腺素能作用降低的释放剂将表现出降低的滥用倾向，但保留选择性减少可卡因自我给药的能力。