RCT targeting noradrenergic stress mechanisms in alcoholism with doxazosin

多沙唑嗪针对酒精中毒中去甲肾上腺素能应激机制的随机对照试验

• 批准号: 8986543
• 负责人: John J. Curtin
• 金额: $ 43.81万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986543
• 关键词: Abstinence; Advocate; Affect; Aftercare; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Behavior; Behavioral; Blood Pressure; Brain; Chemosensitization; Clinical; Clinical Research; Cues; Development; Dimensions; Dose; Double-Blind Method; Doxazosin; Drug Addiction; Drug Industry; FDA approved; Human; Hypertension; Individual Differences; Laboratories; Link; Literature; Measures; Mediating; Mental Health; Methods; Modeling; National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; Neurobiology; Norepinephrine; Outcome; Outcome Measure; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Physiological; Physiological Processes; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Probability; Psychopathology; Randomized Controlled Trials; Recovery; Relapse; Research; Research Domain Criteria; Research Priority; Rodent; Role; Shock; Stress; Substance Use Disorder; Surrogate Endpoint; System; Testing; Therapeutic; Translating; Translational Research; Treatment Efficacy; United States; United States National Institutes of Health; addiction; alcohol craving; alcohol use disorder; alcoholism therapy; cost effective; craving; deprivation; disorder later incidence prevention; drinking; drinking behavior; drug relapse; effective therapy; indexing; neuropsychiatry; noradrenergic; novel; pre-clinical; problem drinker; public health relevance; receptor; research and development; response; stress reactivity; stressor; treatment duration

 DESCRIPTION (provided by applicant): Current pharmacotherapy or alcohol and drug addiction yields relatively low probability for attaining long- term recovery. The recent dramatic reduction in R&D by the pharmaceutical industry for novel medications to treat psychiatric conditions, particularly substance use disorders, provides a strong impetus to "repurpose" currently available compounds that may be effective treatment alternatives. Orally available, brain-penetrant α1-noradrenergic (NE) receptor antagonists are widely used to treat hypertension. Additionally, α1-NE antagonists are increasingly used to treat post-traumatic stress disorder (PTSD), consistent with the well- documented role of NE in mediating multiple behavioral and physiological processes in stress. Stress is a significant contributor to alcohol/drug relapse. Stress-related reinstatement is a well-validated animal model of addiction and α1-NE antagonists reduce relapse in this animal model. NIAAA Director George Koob has made strong calls for translational research on stress-mechanisms in humans. This preclinical evidence in animals suggests the use of α1-NE antagonists may be useful in relapse prevention including stress-related relapse. To test this hypothesis, we propose two complementary preclinical and clinical objectives in humans: 1. To translate the preclinical evidence from animal models to stress-induced relapse in humans via direct pharmacological antagonism of the NE system in abstinent alcoholics with doxazosin, an α1-NE blocker. 2. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in abstinent alcoholics as a cost-effective first step to repurpose this α1-NE antagonist for relapse prevention in addiction. Thes two objectives will be accomplished in a randomized controlled trial (RCT) of recently abstinent alcoholics, to examine the efficacy of 8 mg doxazosin (vs. placebo, between-subjects) on stress reactivity and clinical outcome measures (e.g., drinks/week, alcohol craving) during a 8 week treatment period. We assess doxazosin's impact on stress-related relapse mechanisms using a well-validated human model of stressor reactivity (NPU task) at baseline (pre-treatment), and after 4 weeks and 8 weeks of treatment. The NPU task has strong translational ties to both methods and measures from the preclinical literature in animals. This task has demonstrated reliable, robust effects of drug administration and drug deprivation in drug dependent users. As such, it serves as an attractive early surrogate endpoint post-treatment to assess treatment efficacy and examine stress mechanisms. Repurposing existing pharmaceutical agents has recently been promoted by NIH director, Francis Collins, as a research priority. Tom Insel and others have strongly advocated for the development and use of early surrogate endpoints in clinical research. This project aligns well with the NIMH RDoC focus on dimensions of observable behavior and neurobiological measures in psychopathology research. This project also anticipates changes at NIMH to capitalize on simultaneous examination of mechanism and outcome in RCTs.

 描述（由适用提供）：当前的药物治疗或酒精和药物成瘾产生的长期恢复的可能性相对较低。制药行业最近对治疗精神病疾病的新型药物（尤其是药物使用障碍）进行的研发急剧减少，为当前可用的化合物“重新利用”提供了强大的动力，这些化合物可能是有效的治疗方法。口服可用的脑渗透α1-甲状腺素能（NE）受体拮抗剂被广泛用于治疗高血压。另外，α1-NE拮抗剂越来越多地用于治疗创伤后应激障碍（PTSD），与NE在介导多种行为和物理过程中的作用相一致。压力是酒精/药物继电器的重要贡献者。与压力相关的恢复是成瘾的验证动物模型，而α1-NE拮抗剂减少了这种动物模型的缓解。 NIAAA董事乔治·科布（George Koob）强烈呼吁对人类的压力机理进行翻译研究。动物中的临床前证据表明，使用α1-NE拮抗剂可能有助于预防，包括与压力相关的继电器。为了检验这一假设，我们提出了人类的两个完整的临床前和临床目标：1。 通过与α1-ne阻滞剂多沙唑嗪的戒酒中，NE系统的直接药物拮抗作用导致压力诱导的人类释放的模型。 2。筛选毒sosin的有效性，以靶向戒酒中的与压力相关的继电器机制，这是复制这种α1-NE拮抗剂以预防成瘾中的α1-NE拮抗剂的第一步。这两个目标将在最近戒酒的随机对照试验（RCT）中实现，以检查8毫克多沙唑嗪（与安慰剂，受试者之间）在8周的治疗期间对压力反应性和临床结果指标（例如，饮料/周，饮酒）的有效性。我们使用在基线（预处理前）以及4周和8周的治疗后，使用验证良好的人体反应性（NPU任务）的人体模型来评估多克萨斯素对与压力相关的继电器机制的影响。 NPU任务与动物的临床前文献的方法和措施具有很强的翻译联系。这项任务表明药物给药和药物剥夺对药物依赖用户的可靠，强大的影响。因此，它是一种有吸引力的早期替代端点，以评估治疗有效性和检查压力机制。重新利用现有的药物代理最近已由NIH董事弗朗西斯·柯林斯（Francis Collins）晋升为研究优先。汤姆·因斯尔（Tom Insel）和其他人强烈主张在临床研究中开发和使用早期替代终点。该项目与NIMH RDOC的重点是可观察到的行为和心理病理学研究中神经生物学措施的维度相吻合。该项目还预计，NIMH的变化将利用RCT中的机制和结果的同时检查。