Using Pharmacogenetics to Better Evaluate Naltrexone for Treating Stimulant Abuse

利用药物遗传学更好地评估纳曲酮治疗兴奋剂滥用的效果

• 批准号: 9320832
• 负责人: JERMAINE D JONES
• 金额: $ 20.25万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9320832
• 关键词: ANKK1 gene; Address; Alcohol abuse; Alcohols; Alleles; Amphetamine Abuse; Amphetamines; Brain region; Candidate Disease Gene; Clinical Research; Clinical assessments; Cocaine; Conflict (Psychology); DRD2 gene; DSM-V; Data; Development; Disease; Dopamine; Dose; Drug Kinetics; Drug abuse; Effectiveness; FDA approved; Genes; Genetic; Genetic Polymorphism; Genetic Techniques; Genetic Variation; Genomics; Genotype; Heroin; Homozygote; Individual; Investigation; Measurement; Measures; Meta-Analysis; Methamphetamine; Modeling; Naltrexone; Narcotic Antagonists; Nicotine; Nucleus Accumbens; Oral; Participant; Patient Self-Report; Pharmaceutical Preparations; Pharmacogenetics; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Public Health; Reporting; Resolution; Review Literature; Route; Sampling; Self Administration; Substance Use Disorder; System; Testing; Treatment Efficacy; Treatment outcome; Variant; Ventral Tegmental Area; amphetamine use; dopaminergic neuron; endogenous opioids; genetic variant; personalized medicine; preclinical study; psychostimulant; public health relevance; stimulant abuse; transmission process; treatment response

 DESCRIPTION (provided by applicant) There is thought to be over 75 million abusers of amphetamines (AMPHs) and cocaine worldwide. Unlike drugs such as heroin, alcohol or nicotine, there is no FDA-approved medication to facilitate the treatment of psychostimulant abuse. Several preclinical and clinical studies have provided data suggesting that naltrexone (NTX) may have potential for this indication. However, a review of the literature reveals conflicting findings that require resolutio. Several clinical studies have shown that genetic variation moderates the effects of a number of medications used to treat substance use disorders. A recent meta-analysis concluded that the OPRM1 A118G SNP (rs1799971) significantly moderates the treatment efficacy of NTX in treating alcohol abuse, increasing the treatment efficacy by over 2 fold among G-allele carriers (AG/GG). The proposed application would be the first to investigate the moderating effect of this genotype in the efficacy of NTX to treat stimulant abuse. More specifically, we propose investigating the interaction between NTX and intranasal (IN) methamphetamine (50mg/70kg). Participants who meet DSM-V criteria for moderate-to-severe stimulant use disorder will complete testing sessions where the abuse liability of IN methamphetamine (M-AMPH) is assessed following pretreatment with NTX (0, 25, 50 mg). Naltrexone's effects upon the abuse potential of IN M-AMPH will be assessed using self-report measurements of positive subjective effects and drug self- administration. Medication effects on these validated predictors of abuse will be compared between A118G A allele homozygotes (AA) and G-allele carriers (AG/GG; an anticipated 25% of the total sample), in order to assess genetic moderation of treatment outcome. The advantage of this approach is that it may help to define individuals in which the treatment exerts its greatest effects. As a secondary aim of the study we will simultaneously assess for possible moderating effects of several functionally relevant genetic variants to predict the how NTX alters the subjective and reinforcing effects of IN M-AMPH [ANKK1 (rs1800497); DβH (rs1611115); DRD2 (rs2283265); OPRM1 (rs6912029); SLC6A3 (rs28363170)]. This study therefore utilizes a focused approach to assess the influence of a genetic polymorphism whose influence has been substantiated by other investigations, and an exploratory approach to assess the individual and combined influence of several likely genetic moderators. Combined, the two studies in this proposal will contribute to the assessment of the clinical utility of NTX fr treating psychostimulant abuse, and may help identify gene x pharmacological interactions contributing to the personalization of treatment.

 描述(由申请人提供) 据认为，全世界有超过7500万人滥用苯丙胺(AMPH)和可卡因。与海洛因、酒精或尼古丁等药物不同，没有FDA批准的药物来促进精神刺激剂滥用的治疗。一些临床前和临床研究提供的数据表明，纳曲酮(NTX)可能具有这一适应症的潜力。然而，回顾文献发现了相互矛盾的发现，需要解决。几项临床研究表明，遗传变异会减缓用于治疗物质使用障碍的一些药物的效果。最近的一项荟萃分析得出结论，OPRM1A118G SNP(Rs1799971)显著减缓了NTX治疗酒精滥用的疗效，使G等位基因携带者(AG/GG)的治疗效果提高了2倍以上。这项拟议中的应用将是第一次调查这种基因在NTX治疗兴奋剂滥用效果中的缓和作用。更具体地说，我们建议研究NTX和鼻腔(IN)甲基苯丙胺(50 mg/70 kg)之间的相互作用。符合DSM-V中重度兴奋剂使用障碍标准的参与者将完成测试，在测试过程中，在NTX(0、25、50毫克)预处理后评估IN甲基苯丙胺(M-AMPH)的滥用倾向。纳曲酮对IN M-AMPH滥用潜力的影响将通过对积极主观效果和药物自我给药的自我报告测量来评估。将比较A118G A等位基因纯合子(AA)和G等位基因携带者(AG/GG；预计占总样本的25%)对这些被证实的滥用预测因素的药物效果，以评估治疗结果的遗传适宜性。这种方法的优点是，它可以帮助确定治疗效果最大的个体。作为这项研究的次要目标，我们将同时评估几个功能相关的遗传变异的可能缓和效应，以预测 NTX如何改变IN M-AMPH的主观和增强效果[ANKK1(Rs1800497)；DβH(Rs1611115)；DRD2(Rs2283265)；OPRM1(Rs6912029)；SLC6A3(Rs28363170)]。因此，这项研究使用了一种有重点的方法来评估其影响已被其他研究证实的基因多态的影响，以及一种探索性的方法来评估几个可能的遗传调节因素的个体和联合影响。这项建议中的两项研究结合在一起，将有助于评估NTX fr治疗精神刺激剂滥用的临床效用，并可能有助于识别有助于个人化治疗的x基因药理相互作用。