Pioglitazone for the Treatment of Opioid and of Nicotine Dependence

描述（由申请人提供）：目前，滥用海洛因和处方阿片类药物是美国普遍存在的社会问题。类似地，尽管为减少烟草使用做出了大量努力，但美国成年人的烟草使用率约为20%。我们建议测试吡格列酮（一种过氧化物酶体增殖物激活受体-γ（PPAR）激动剂，FDA批准用于治疗2型糖尿病）减少海洛因滥用（研究1）和吸烟（研究2）的能力。将对吡格列酮与丁丙诺啡/纳洛酮（研究1）和尼古丁贴剂（研究2）联合给药进行试验。这些研究基于一系列未发表的临床前数据，这些数据表明吡格列酮可能用于治疗阿片类药物和尼古丁依赖。所有研究的参与者将住在一个锁定的住院病房，并将在实验室进行测试。将评估吡格列酮改变药物自我给药、对药物线索的反应性和药物使用复发的能力。此外，还将评价主观反应，如药物喜好、渴望和再次服用药物的愿望的评级。将通过测量认知表现和生理反应来评估药物组合的潜在毒性。这些研究的结果将提供大量关于吡格列酮与激动剂替代疗法联合使用的作用的信息。如果拟定研究的结果支持吡格列酮的临床前数据，则可能揭示药物滥用药物开发的先前未确定的靶点。 公共卫生相关性：海洛因和处方阿片类药物滥用在美国很普遍，就像吸烟一样。本提案的目的是表征吡格列酮（目前用于治疗糖尿病的药物）改变海洛因（研究1）和吸烟（研究2）滥用倾向的能力。吡格列酮将与丁丙诺啡/纳洛酮（研究1）或尼古丁贴剂（研究2）联合给药。

DESCRIPTION (provided by applicant): Currently, the abuse of heroin and prescription opioid medications is a pervasive social problem in the U.S. Similarly, the prevalence of tobacco use among adults in the U.S. is approximately 20%, despite intensive efforts to reduce its use. We are proposing to test the ability of pioglitazone, a peroxisome proliferator-activated receptor- gamma (PPAR) agonist that is FDA-approved for use in the management of type 2 diabetes mellitus, to reduce abuse of heroin (Study 1), and cigarette smoking (Study 2). Pioglitazone will be tested in combination with buprenorphine/naloxone (Study 1) and with the nicotine patch (Study 2). These studies were based on a series of unpublished preclinical data showing that pioglitazone may have utility in treating opioid and nicotine dependence. Participants in all studies will live on a locked inpatient unit and will be tested in the laboratory. The ability of pioglitazone to alter drug self-administration, reactivity to drug cues, and relapse to drug use will be assessed. In addition, subjective responses, such as ratings of drug liking, craving, and desire to take the drug again will be evaluated. Potential toxicity of the medication combinations will be assessed by measuring cognitive performance and physiological responses. The results of these studies will provide a great deal of information about the effects of pioglitazone in combination with agonist replacement therapies. If the results of the proposed studies support the preclinical data with pioglitazone, they may reveal a previously unidentified target for medications development for substance abuse. PUBLIC HEALTH RELEVANCE: Heroin and prescription opioid abuse are prevalent in the U.S., as is cigarette smoking. The purpose of the present proposal is to characterize the ability of pioglitazone, a medication currently used to treat diabetes, to alter the abuse liability of heroin (Study 1) and of cigarette smoking (Study 2). Pioglitazone will be given in combination with buprenorphine/naloxone (Study 1) or the nicotine patch (Study 2).