Preclinical Evaluation of Medications to Treat Polydrug Addiction

治疗多药成瘾药物的临床前评价

基本信息

批准号：
8470143
负责人：
JACK BERGMAN
金额：
$ 52.37万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8470143
关键词：
AIDS/HIV problem Adverse effects Agonist Anti-Anxiety Agents Antidepressive Agents Antihypertensive Agents Antismoking Anxiety Behavioral Blood Chemical Analysis Blood drug level result Buprenorphine Bupropion Buspirone Cardiovascular Diseases Characteristics Chronic Clinical Research Clinical Treatment Clinical Trials Cocaine Complement Complex Development Dopamine Agonists Dopamine Antagonists Dose Effectiveness Ensure Evaluation FDA approved Food Goals Heroin Limb structure Lung diseases Malignant Neoplasms Modafinil Modeling Monitor Monkeys NIH Program Announcements Nalbuphine Narcotic Antagonists National Institute of Drug Abuse Neurobiology Nicotine Opioid Pharmaceutical Preparations Pharmacology Pre-Clinical Model Procedures Property Public Health Publishing Relative (related person)Research Schedule Self Administration Series Severities Stimulus Time Translations Treatment Effectiveness Withdrawal Withdrawal Symptom addiction base behavior observation clinical practice cocaine use drug discrimination effective therapy lofexidine multidrug abuse nicotine abuse nonhuman primate novel opioid withdrawal preclinical evaluation preclinical study public health relevance response smoking cessation stimulant/agonist treatment program varenicline

项目摘要

DESCRIPTION (provided by applicant): This is a new application in response to NIDA Program Announcement PAS-08-186 for Medications Development for Polydrug Addiction Treatment. The concurrent use of cocaine + heroin and cocaine + nicotine are prevalent forms of polydrug abuse, and are associated with significant public health problems, including cancer, pulmonary and cardiovascular disease and HIV/AIDS. We developed the first preclinical model of cocaine + heroin (speedball) addiction, and now we propose to develop a new polydrug model of cocaine + nicotine abuse. These two models will be used to identify and evaluate medications for the treatment of dual addiction to cocaine in combination with heroin or nicotine. Polydrug abuse involving two or more drugs is a complex treatment challenge, and often the effectiveness of a medication is not predictable from its known pharmacology. To facilitate translation of the most effective treatment approaches into clinical practice, we propose to evaluate a pharmacologically diverse series of medications that are FDA approved for other indications. These medications include anxiolytics, antidepressants, nicotinic partial agonists, stimulants, and an opioid mixed agonist antagonist. Each medication has been shown to reduce the abuse-related effects of cocaine, heroin, or nicotine alone in clinical or preclinical studies. We hypothesize that medications that effectively reduce cocaine self-administration may also be effective in reducing the abuse-related effects of cocaine in combination with nicotine or heroin. Well-validated behavioral procedures are proposed to evaluate the effects of these medications on the abuse-related effects of cocaine and polydrug combinations of cocaine + heroin or nicotine. Drug discrimination procedures will be used to characterize the potency, time-course and stimulus characteristics of polydrug combinations, and candidate treatment medications. In drug self-administration studies, medications will be administered chronically to model clinical treatment programs. Chronic treatment is necessary to determine the stability of medication effects, the severity and duration of any adverse side effects, and to monitor possible medication withdrawal signs when treatment is discontinued. The selectivity of medication effects will be determined with a second-order schedule of drug- and food-maintained responding. The abuse liability of the most effective medications will also be examined. A progressive-ratio procedure will be used to compare the relative effectiveness of treatment medications as well as the extent to which the reinforcing efficacy of polydrug combinations is altered. These multi-disciplinary studies will facilitate translation of novel polydrug abuse medications into clinical treatment.

描述（由申请人提供）：这是针对NIDA计划公告PAS-08-186的新应用程序，用于用于多药成瘾治疗的药物开发。可卡因 +海洛因和可卡因 +尼古丁的同时使用是普遍的滥用多药的形式，并且与包括癌症，肺和心血管疾病以及艾滋病毒/艾滋病在内的重大公共卫生问题有关。我们开发了可卡因 +海洛因（快球）成瘾的第一个临床前模型，现在我们建议开发一种可卡因 +尼古丁滥用的新的Polydrug模型。这两种模型将用于识别和评估与海洛因或尼古丁结合使用双重成瘾可卡因的药物。涉及两种或多种药物的多药滥用是一项复杂的治疗挑战，通常无法从已知的药理学中预测药物的有效性。为了促进将最有效的治疗方法转化为临床实践，我们建议评估一系列在药理学上多样的药物，这些药物已被FDA批准用于其他适应症。这些药物包括抗焦虑药，抗抑郁药，烟碱部分激动剂，兴奋剂和阿片类混合激动剂拮抗剂。已显示每种药物可减少可卡因，海洛因或尼古丁在临床或临床前研究中的滥用相关作用。我们假设有效地减少可卡因自我管理的药物也可能有效地减少可卡因与尼古丁或海洛因相结合的滥用相关作用。提出了精心验证的行为程序，以评估这些药物对可卡因 +海洛因或尼古丁的可卡因和多药物组合的滥用相关影响的影响。药物歧视程序将用于表征多药组合和候选治疗药物的效力，时间和刺激特征。在药物自我管理研究中，将长期服用药物以建模临床治疗计划。必须进行慢性治疗，以确定药物效应的稳定性，任何不良副作用的严重程度和持续时间，并在停用治疗时监测可能的药物戒断迹象。用药效应的选择性将通过二阶药物和维持食物的响应时间表确定。最有效的药物的虐待责任也将进行检查。将使用进行性比率的程序来比较治疗药物的相对有效性以及多药组合的增强功效的程度。这些多学科研究将有助于将新型多药物滥用药物转化为临床治疗。