Medications Development for Stimulant Abuse

治疗兴奋剂滥用的药物开发

• 批准号: 7877054
• 负责人: Sidney S Negus
• 金额: $ 39.79万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7877054
• 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

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. PUBLIC HEALTH RELEVANCE: Cocaine abuse remains a major public health problem, and the development of effective pharmacotherapies continues to be a high priority for NIDA. This application proposes a series of preclinical studies to assess contextual and pharmacologic factors that may influence the utility of monoamine releasers as candidate agonist medications. These studies may contribute to both (a) more effective implementation of existing monoamine releasers as agonist medications, and (b) the development of safer medications with reduced abuse liability.

描述（由申请方提供）：这是一项新的R 01申请，旨在评价单胺释放剂对恒河猴可卡因自我给药的显著持续和选择性作用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的一个高度优先事项。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哌嗪长期治疗在恒河猴中产生了长达28天的可卡因与食物维持反应的稳健和选择性降低。我们从猴子身上获得的结果的关键要素已经在人类实验室研究和临床试验中得到了证明。我们相信这些发现支持了单胺释放剂作为可卡因依赖的候选激动剂药物值得进一步研究的主张。为此，本申请提出了两个特定目的，以评估单胺氧化酶效应的背景和药理学决定因素。具体目标1将研究环境和药物历史背景对苯甲哌嗪诱导的可卡因自我给药减少的影响。具体目标1a将在替代药物可用性条件下评价苯甲曲嗪的作用。在临床药物滥用治疗中，药物治疗越来越多地与引入和控制替代药物可用性的应急管理技术结合使用。我们建议对药物治疗和替代药物的双重使用进行建模，我们假设替代药物的可用性将增强苯甲曲嗪诱导的可卡因自我给药抑制。具体目标1b将评价苯甲曲嗪在长期接触可卡因和戒断可卡因条件下的作用。在其他药物类别（如阿片类药物）中，扩大获取范围会促进药物消费增加，形成身体依赖性，并在戒断期间加强药物强化。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同样会增强苯甲曲嗪减少可卡因自我给药的能力。具体目标2将检查单胺受体效应的药代动力学和药效学决定因素。具体目标2a将使苯甲曲嗪（一种苯甲曲嗪前药和附表III兴奋剂）的药代动力学和行为效应相关。我们假设苯甲曲嗪将保留苯甲曲嗪在可卡因自我给药中产生选择性减少的能力，但是苯甲曲嗪将具有与活性苯甲曲嗪代谢物的产生相关的缓慢起效。具体目标2b将评价一系列单胺释放剂，这些单胺释放剂对释放多巴胺和5-羟色胺与去甲肾上腺素的选择性不同。我们推测，释放与减少去甲肾上腺素能的影响将显示减少滥用的倾向，但保留了能力，以产生选择性减少可卡因自我管理。 公共卫生相关性：可卡因滥用仍然是一个主要的公共卫生问题，开发有效的药物治疗仍然是NIDA的一个高度优先事项。本申请提出了一系列临床前研究，以评估可能影响单胺释放剂作为候选激动剂药物的效用的背景和药理学因素。这些研究可能有助于（a）更有效地实施现有的单胺释放剂作为激动剂药物，和（B）开发更安全的药物，减少滥用倾向。