Selective Monoamine Release as a Treatment for Cocaine Use Disorders

选择性单胺释放作为可卡因使用障碍的治疗

• 批准号: 8753852
• 负责人: William Walton Stoops
• 金额: $ 50.05万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753852
• 关键词: Abstinence; Amphetamines; Attenuated; Behavior Therapy; Behavioral; Binding; Cardiovascular system; Clinical Research; Clinical Trials; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Communities; Data; Development; Dextroamphetamine; Disease; Dopamine; Dose; Enrollment; Goals; Human; Laboratories; Laboratory Procedures; Laboratory Study; Maintenance; Methamphetamine; Methods; Modeling; Monkeys; National Institute of Drug Abuse; Norepinephrine; Obesity; Oral Administration; Outcome Measure; Parents; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Phenmetrazine; Placebos; Presynaptic Terminals; Probability; Procedures; Psychostimulant dependence; Public Health; Research; Safety; Schedule; Self Administration; Serotonin; Specificity; Testing; clinical efficacy; clinical practice; cocaine use; drug reinforcement; indexing; innovation; meetings; monoamine; novel; pre-clinical; preclinical study; prevent; primary outcome; programs; public health relevance; reinforcer; research study; reuptake; success

DESCRIPTION (provided by applicant): Cocaine (COC) addiction is an unrelenting public health concern. An effective medication has not been identified for COC dependence despite being a high priority for the National Institute on Drug Abuse for nearly 30 years and extensive efforts by the scientific and treatment communities. The results of preclinical studies have shown that monoamine releasers attenuate the reinforcing effects of COC. The results of human laboratory studies also suggest that monoamine releasers attenuate the reinforcing effects of COC although the effects are small in magnitude and dependent on the methods used to assess drug reinforcement. The results of clinical trials that tested monoamine releasers for COC abuse are mixed. Monoamine releasers vary along a continuum from DA/NE selective to 5-HT selective. Theoreticians have postulated that the 5-HT/DA releasing ratio is a critical determinant of the efficacy and specificity of a monoamine releaser to attenuate the reinforcing effects of COC. Compounds with intermediate 5-HT/DA release ratios (i.e., 30-40) were the most effective and specific in terms of reducing cocaine taking. For example, methamphetamine (5-HT/DA ratio = 31) completely and specifically eliminated responding for COC. Consistent with these findings, methamphetamine dramatically reduced COC use in a clinical trial although it is NOT a viable option for managing COC abuse because of its high abuse and diversion potential. Compounds with a desirable 5- HT/DA releasing ratio and minimal abuse potential need to be tested for COC dependence. Phendimetrazine (PHEN) is indicated for treating obesity. After oral administration, PHEN is converted to phenmetrazine, which is largely responsible for its behavioral and neuropharmacological effects. Consistent with the notion that compounds with intermediate 5-HT/DA release ratios selectively attenuate the reinforcing effects of COC, phenmetrazine (5-HT/DA ratio = 37) also completely and specifically eliminated COC-maintained responding. Moreover, PHEN reduces COC-maintained responding, but does not maintain self-administration or produce high magnitude positive subjective effects suggesting that its abuse potential is low. Although PHEN has not yet been tested as a potential pharmacotherapy for COC dependence in human laboratory experiments or clinical trials to our knowledge, the results of extant preclinical experiments suggest it may be a viable option. We will conduct two rigorous within-subject experiments to fill this gap. These studies will 1) establish the safety and tolerability of PHEN-COC combinations and 2) demonstrate that PHEN reduces COC self- administration. The results of this project will provide critical information regarding the initial efficacy of PHEN for COC dependence, which will enhance the probability of success when advanced to a clinical trial.

描述（由申请人提供）：可卡因（COC）成瘾是不懈的公共卫生问题。尽管美国国家药物滥用研究所的重点是近30年，并且科学和治疗界的广泛努力是，尽管尚未确定有效的COC依赖药物。临床前研究的结果表明，单胺释放器减弱了COC的增强作用。人类实验室研究的结果还表明，单胺释放器减弱了COC的增强作用，尽管大小的影响很小，并且取决于评估药物加强的方法。测试单胺释放剂COC滥用的临床试验的结果混合了。单胺释放器沿连续体从da/ne选择性到5-HT选择性变化。理论家假设5-HT/DA释放比是单胺释放器衰减COC的增强作用的疗效和特异性的关键决定因素。具有中间体5-HT/DA释放比（即30-40）的化合物在减少可卡因的情况下是最有效和特异性的。例如，甲基苯丙胺（5-HT/DA比= 31）完全，专门消除了COC的响应。与这些发现一致，甲基苯丙胺在临床试验中大幅降低了COC使用，尽管由于其高滥用和转移潜力，它不是管理COC滥用的可行选择。需要对COC依赖性测试具有理想的5-HT/DA释放比和最小滥用潜力的化合物。金甲酰胺（PEN）用于治疗肥胖症。口服给药后，将PEN转化为苯丙嗪，这在很大程度上是其行为和神经药物作用的原因。与中间5-HT/DA释放比的化合物有选择地衰减COC的增强作用，苯丙嗪（5-HT/DA比= 37）的增强作用，也完全且专门消除了COC维护的响应。此外，PEN可以减少COC维护的响应，但不能保持自我管理或产生高幅度的积极主观效应，这表明其滥用潜力很低。尽管尚未将PEN作为我们所知的人类实验室实验或临床试验中COC依赖性的潜在药物治疗，但现有的临床前实验的结果表明它可能是可行的选择。我们将进行两个严格的受试者内实验，以填补这一空白。这些研究将1）建立PEN-COC组合的安全性和耐受性，2）证明PEN可以减少COC自我给药。该项目的结果将提供有关COC依赖性PEN初始功效的关键信息，这将在进行临床试验时提高成功的可能性。