Development of Guanfacine to decrease drug craving, anxiety and cocaine relapse r

开发胍法辛以减少药物渴望、焦虑和可卡因复吸

• 批准号: 7714868
• 负责人: Rajita Sinha
• 金额: $ 35.17万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714868
• 关键词: Abstinence; Address; Adrenergic Agonists; Adverse effects; Affect; Anxiety; Arousal; Attenuated; Behavior; Behavior Therapy; Blood Pressure; Brain; Cardiovascular system; Catecholamines; Clinical; Cocaine; Cocaine Dependence; Corticotropin-Releasing Hormone; Cues; Data; Dependence; Development; Distress; Dose; Double-Blind Method; Epinephrine; Exposure to; Extinction (Psychology); FDA approved; Foxes; Guanfacine; Guided imagery; Heart Rate; Individual; Inpatients; Laboratories; Laboratory Animals; Laboratory Study; Light; Measures; Moods; Naltrexone; Nicotine; Norepinephrine; Opiates; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Pilot Projects; Placebo Control; Placebos; Predisposition; Public Health; Randomized; Recruitment Activity; Relapse; Reporting; Research; Rewards; Risk; Safety; Smoking; Stimulus; Stress; Symptoms; System; Testing; Therapeutic; Treatment Protocols; Treatment outcome; Work; base; cocaine relapse prevention; craving; depressive symptoms; drug craving; experience; high risk; hypothalamic-pituitary-adrenal axis; improved; lofexidine; meetings; negative mood; neuroadaptation; new therapeutic target; nicotine craving; noradrenergic; novel; pre-clinical; pre-clinical research; prevent; public health relevance; response; social

DESCRIPTION (provided by applicant): This application proposes to conduct a randomized, double blind, placebo-controlled laboratory study to examine whether guanfacine (GUA) decreases cocaine and nicotine craving, anxiety and stress related arousal in cocaine dependent, nicotine smoking (CD) individuals. In previous research we've shown that laboratory exposure to stress and drug cues increases drug craving and stress related arousal and both measures predict cocaine relapse outcomes. Alpha-2-adrenergic agonists such as lofexidine and guanfacine attenuate stress-induced reinstatement of cocaine-seeking behavior in cocaine experienced laboratory animals. In previous pilot studies, we've shown that lofexidine decreases stress and cue-induced opiate and cocaine craving and reduces negative affect and physiological arousal in opiate dependent individuals treated with naltrexone. It was also found to improve opiate abstinence rates and compliance with daily naltrexone regimen. Preliminary work with GUA 2 mg and 3 mg daily dosing versus placebo (PLA) showed positive results with respect to drug cue-induced and stress- induced drug craving, anxiety and stress-related arousal. Thus, in light of previous preclinical research and our clinical findings, we propose a 3-year study that will recruit 60 CD individuals to participate in a randomized, double blind, placebo-controlled 4-week inpatient laboratory study. The following specific aims will be addressed: (1) to evaluate the safety/tolerability of 2mg and 3mg daily of guanfacine in CD individuals; (2) to determine the dose-dependent effects of guanfacine on basal cocaine and nicotine craving, depressive symptoms and perceived stress scores in weekly assessments during the inpatient stay; (3) To determine the dose-dependent effects of guanfacine on cocaine craving, nicotine craving and mood following guided imagery exposure to stress, drug cue and combined stress+drug cue scenarios; and (4) to determine the dose-dependent effects of guanfacine on cardiovascular and catecholamine (norepinephrine and epinephrine) response following exposure to stress, drug cue and combined stress+drug cue scenarios. Findings from this study will provide important information on whether alpha-2adrenergic compounds such as guanfacine show promise in decreasing drug craving, anxiety and stress, factors shown to predict high cocaine relapse outcomes. If the proposed hypotheses are supported, it will also provide evidence for further development of guanfacine as a medication for cocaine relapse prevention. PUBLIC HEALTH RELEVANCE: Drug craving and associated high cocaine relapse rates are major clinical challenges in the treatment of cocaine dependence, and drug craving, anxiety and stress-related arousal are significant factors that increase cocaine relapse risk. The proposed study will test guanfacine as a potential therapeutic strategy to decrease these symptoms of drug craving, anxiety and distress and cocaine relapse risk and the results will have significant clinical implications for the development of new medications to decrease cocaine craving and prevent relapse in cocaine dependence.

描述（由申请人提供）：本申请提议进行一项随机，双盲，安慰剂对照实验室研究，以检查鸟雀（GUA）是否减少可卡因和尼古丁的渴望，焦虑和压力相关的可卡因依赖性尼古丁吸烟（CD）个体。在先前的研究中，我们已经表明，实验室承受压力和药物提示会增加药物的渴望和与压力相关的唤醒，并且两种措施都可以预测可卡因复发结果。 α-2-肾上腺素能激动剂，例如洛己胺和鸟汀，减轻了应激诱导的可卡因经验丰富的实验室动物的可卡因寻求可卡因行为。在先前的初步研究中，我们表明洛芬丁胺会降低压力并诱发的鸦片和可卡因的渴望，并降低了用纳曲酮治疗的鸦片依赖的个体的负面影响和生理唤醒。还发现它可以提高鸦片戒酒率和遵守每日纳曲酮方案。与安慰剂（PLA）的GUA 2 mg和3 mg剂量的初步工作有关药物提示诱导的和应激诱导的药物渴望，焦虑和与压力相关的唤醒显示了积极的结果。因此，鉴于先前的临床前研究和我们的临床发现，我们提出了一项为期3年的研究，该研究将招募60个CD个人参加一项随机，双盲，安慰剂对照的4周住院实验室研究。将解决以下具体目标：（1）评估CD个体中2mg和3mg每天的2mg和3mg的安全性； （2）确定鸟汀对基底可卡因和尼古丁渴望的剂量依赖性作用，抑郁症状以及在住院期间每周评估中的压力评分； （3）确定胍法汀对可卡因渴望，尼古丁渴望和情绪的剂量依赖性作用，导致图像暴露于压力，药物提示和综合压力+药物提示方案； （4）在暴露于压力，药物提示和综合压力+药物提示方案后，确定胍法汀对心血管和儿茶酚胺（去甲肾上腺素和肾上腺素）反应的剂量依赖性作用。这项研究的结果将提供有关α-2肾上腺素能化合物（如鸟汀）是否在减少药物渴望，焦虑和压力的有望的重要信息，这表明可以预测可卡因高可卡因复发结果。如果支持所提出的假设，它还将为进一步开发鸟法汀作为可卡因复发预防的药物提供证据。 公共卫生相关性：渴望和相关的可卡因复发率是可卡因依赖性治疗的主要临床挑战，而渴望药物，焦虑和与压力相关的唤醒是增加可卡因复发风险的重要因素。拟议的研究将测试鸟明作为一种潜在的治疗策略，以减轻这些渴望，焦虑和困扰的症状以及可卡因复发风险，结果将对新药物的开发产生重大临床意义，以减少可卡因的渴望并防止可卡因依赖性中可卡因的复发。