Targeting GABA and Opioid Systems for a Pharmacotherapy for Methamphetamine Abuse

针对甲基苯丙胺滥用的药物治疗的 GABA 和阿片类药物系统

• 批准号: 8737216
• 负责人: CRAIG R RUSH
• 金额: $ 60.53万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737216
• 关键词: Abstinence; Admission activity; Adverse effects; Alprazolam; Aminobutyric Acids; Amphetamines; Animals; Attenuated; Behavior Therapy; Behavioral; Cardiovascular system; Chronic; Clinical Research; Clinical Trials; Cocaine Dependence; Cognitive Therapy; Communicable Diseases; Crime; Data; Data Analyses; Dependence; Development; Dopamine; Dose; Drug Combinations; Drug-sensitive; Enrollment; Human; Impaired cognition; Laboratories; Maintenance; Mediating; Medical; Methamphetamine; Methamphetamine dependence; Mono-S; Naltrexone; Narcotic Antagonists; National Institute of Drug Abuse; Opioid; Outcome Measure; Oxazepam; Participant; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase II Clinical Trials; Physiological; Play; Premature Mortality; Probability; Procedures; Productivity; Public Health; Questionnaires; Relative (related person); Reporting; Research; Role; Safety; Self Administration; System; Testing; United States; addiction; attenuation; clinical practice; contingency management; cost; dopamine system; double-blind placebo controlled trial; drug efficacy; drug market; drug reinforcement; indexing; innovation; methamphetamine abuse; novel; novel strategies; public health relevance; receptor; research study; secondary outcome; stimulant abuse; success; tool; treatment program

DESCRIPTION (provided by applicant): Methamphetamine (MA) abuse and dependence are significant public-health concerns. Treatment admissions for MA use increased at an alarming rate from 1998 to 2007 in the US. Behavioral treatments reduce MA use. However, many patients enrolled in behavioral treatment programs are unable to achieve a significant period of abstinence suggesting other strategies like pharmacotherapy are urgently needed. G-Aminobutyric-acid (GABA) and opioid systems modulate dopamine. GABAA receptor modulators (e.g., oxazepam [OXP]) and opioid antagonists (e.g., naltrexone [NTX]) attenuate the abuse-related effects of amphetamines. The attenuation of the abuse-related effects of amphetamine by GABAA receptor modulators or opioid antagonists, while statistically significant, is modest in magnitude. Novel strategies are needed to enhance the efficacy of these drugs. Targeting GABA and opioid systems simultaneously is an innovative strategy in that combining NTX and OXP may produce greater attenuation of the abuse-related effects of MA. A rigorous within-subject experiment will be conducted in non-treatment-seeking, MA-abusing participants. NTX (0 and 50 mg/day) and OXP (0 and 40 mg/day), alone and in combination, will be tested with MA (0, 10, 20 and 30 mg). The four NTX-OXP maintenance conditions will be tested in random order. Similarly, within each NTX-OXP condition, the MA doses will be tested in random order. The reinforcing effects of intranasal MA doses will be determined after four days of maintenance on each of the NTX-OXP conditions using a sensitive progressive-ratio procedure. The ability to attenuate the reinforcing effects of drugs is a reliable predictor of an effective pharmacotherapy. We hypothesize that combining NTX and OXP will produce an additive or supra-additive reduction in the reinforcing effects of MA relative to the constituent drugs alone. This research will provide critical information regarding the initil efficacy a novel drug combination, NTX and OXP, for MA dependence. Innovations of the proposed research include: 1) testing a combination of marketed drugs that demonstrated some efficacy when tested as mono-therapies; 2) testing a GABAA receptor modulator that has minimal abuse potential and dependence liability, which will likely be more acceptable to clinicians; 3) the use of a sensitive drug self-administration procedure; 4) providing the impetus for the conduct of a Phase II clinical trial to further demonstrate the efficacy of NTX-OXP combinations for MA dependence; and 5) demonstrating the initial efficacy of commercially available drugs, as opposed to waiting for novel molecules to be available for testing in humans, thereby impacting clinical research and practice more quickly. In these ways, the proposed project will shift the current clinical research paradigm in pharmacotherapy development and have a significant impact on the treatment of MA dependence.

描述（由申请人提供）：甲基苯丙胺（MA）滥用和依赖是重大的公共卫生问题。1998年至2007年，美国因使用MA而接受治疗的人数以惊人的速度增加。行为治疗减少MA的使用。然而，许多参加行为治疗计划的患者无法达到明显的禁欲期，这表明迫切需要其他策略，如药物治疗。G-氨基丁酸（GABA）和阿片系统调节多巴胺。GABAA受体调节剂（例如，奥沙西泮[OXP]）和阿片样物质拮抗剂（例如，纳洛酮[NTX]）减弱安非他明的滥用相关作用。GABAA受体调节剂或类阿片拮抗剂对苯丙胺滥用相关效应的减弱虽然具有统计学意义，但幅度不大。需要新的策略来提高这些药物的疗效。同时靶向GABA和阿片系统是一种创新策略，因为NTX和OXP的组合可能会更大程度地减弱MA的滥用相关作用。将在非寻求治疗、滥用MA的受试者中进行严格的受试者内实验。NTX（0和50 mg/天）和OXP（0和40 mg/天）单独和联合使用时，将与MA（0、10、20和30 mg）一起进行检测。四种NTX-OXP维护条件将以随机顺序进行测试。同样，在每种NTX-OXP条件下，将以随机顺序检测MA剂量。鼻内MA剂量的增强作用将在每种NTX-OXP条件下维持4天后使用敏感的渐进比率程序确定。减弱药物强化作用的能力是 有效药物治疗的可靠预测指标。我们假设，NTX和OXP的组合将产生一个加和或超加和减少MA相对于单独的组成药物的增强作用。这项研究将提供关于一种新型药物组合NTX和OXP对MA依赖的初始疗效的关键信息。拟议研究的创新包括：1）测试市售药物的组合，这些药物在作为单一疗法测试时表现出一定的疗效; 2）测试具有最小滥用潜力和依赖性的GABAA受体调节剂，这可能更容易被临床医生接受; 3）使用敏感的药物自我给药程序; 4）为II期临床试验的进行提供动力，以进一步证明NTX-OXP组合对MA依赖的功效;和5）证明市售药物的初始功效，而不是等待新的分子可用于人体测试，从而更快地影响临床研究和实践。通过这些方式，拟议的项目将改变目前药物治疗开发的临床研究范式，并对MA依赖的治疗产生重大影响。