Medications Development for Stimulant Abuse

治疗兴奋剂滥用的药物开发

• 批准号: 7698500
• 负责人: Sidney S Negus
• 金额: $ 37.38万
• 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/7698500
• 关键词: Agonist; Amphetamines; Attention deficit hyperactivity disorder; Behavioral; Chronic; Classification; 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（由申请人提供）：这是一种新的R01应用程序，旨在评估单胺释放器对可卡因对恒河猴自我给药的显着持续和选择性影响的临床决定因素。可卡因滥用仍然是一个主要的药物滥用问题，而有效的药物治疗的发展仍然是NIDA的重中之重。在初步研究中，我们发现，单胺释放剂苯丙胺和苯丙胺的慢性治疗可在恒河猴中可卡因与食物维持的28天响应可卡因与食物维持的良好和选择性减少。在人类实验室研究和临床试验中，其他人证明了我们猴子结果的关键要素。我们认为，这些发现支持这样的主张，即单胺释放者保证将进一步研究作为可卡因依赖性的候选激动剂药物。为此，该应用程序提出了两个特定的目的，以评估单胺释放效应的上下文和药理决定因素。具体目标1将检查环境和药物历史上下文对可卡因自我给药减少的苯丙胺减少的影响。特定的目标1A将在替代增强剂可用性条件下评估苯甲嗪效应。在临床药物滥用治疗中，越来越多地将药物治疗与介绍和控制替代增强剂可用性的应急管理技术一起使用。我们建议对药物疗法和替代增强剂的这种双重用途进行建模，并假设替代增强剂可用性将增强苯丙胺诱导的可卡因自我给药的抑制。特定的目标1B将在从可卡因的扩展访问和退出条件下评估苯丙嗪的效应。在其他药物类别（例如阿片类药物）中，扩展的访问促进了药物消耗的增加，身体依赖的发展以及戒断期间药物增强的增强。此外，在戒断条件下，阿片类药物的药物最有效。我们假设从可卡因的扩展访问和退出将同样增强苯嗪减少可卡因自我给药的能力。特定的目标2将检查单胺释放效应的药代动力学和药效学决定因素。特定的目标2a将将势酰嗪前药和附表III兴奋剂变甲吡嗪的药代动力学和行为效应相关联。我们假设金甲酰胺将保留可卡因自我给药中苯丙胺产生选择性降低的能力，但是这种甲甲酰胺的作用将缓慢发作，这与活性势化代谢物的产生相关。特定的目标2B将评估一系列单胺释放器，这些释放剂在选择性方面释放多巴胺和5-羟色胺与去甲肾上腺素的变化。我们假设释放甲肾上腺素能降低的释放器将显示出降低的滥用责任，但保留了可卡因自我管理中选择性减少的能力。 公共卫生相关性：可卡因滥用仍然是一个重大的公共卫生问题，有效的药物治疗的发展仍然是NIDA的重中之重。该应用提出了一系列临床前研究，以评估可能影响单胺释放器作为候选激动剂药物的效用的上下文和药理因素。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，以及（b）开发滥用责任的更安全药物。