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（由申请人提供）：目前的药物治疗或酒精和药物成瘾产生相对较低的概率实现长期恢复。最近制药业对治疗精神疾病，特别是药物使用障碍的新型药物的研发急剧减少，这为“重新利用”目前可用的可能是有效治疗替代品的化合物提供了强大的动力。口服脑渗透性α1-去甲肾上腺素能（NE）受体拮抗剂广泛用于治疗高血压。此外，α1-NE拮抗剂越来越多地用于治疗创伤后应激障碍（PTSD），这与NE在介导应激中的多种行为和生理过程中的充分记录的作用一致。压力是酒精/药物复发的重要因素。应激相关复发是一种经过充分验证的成瘾动物模型，α1-NE拮抗剂可减少该动物模型的复发。NIAAA主任乔治库布强烈呼吁对人类的压力机制进行转化研究。动物临床前证据表明，使用α1-NE拮抗剂可能有助于预防复发，包括应激相关复发。为了验证这一假设，我们提出了两个互补的临床前和临床目标：1。将动物实验的临床前证据 通过α1-NE阻滞剂多沙唑嗪对戒酒者NE系统的直接药理学拮抗作用，建立了人类应激诱导复发模型。2.筛选多沙唑嗪靶向戒酒者的应激相关复发机制的疗效，作为重新利用α1-NE拮抗剂预防成瘾复发的具有成本效益的第一步。 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 mg多沙唑嗪（与安慰剂相比，受试者之间）对应激反应和临床结局指标（例如，饮酒/周，酒精渴望）。我们评估多沙唑嗪的影响，压力相关的复发机制，使用一个良好的验证人类模型的应激反应（NPU任务）在基线（治疗前），治疗4周和8周后。NPU任务与动物临床前文献中的方法和措施有很强的翻译联系。这项任务已经证明了可靠的，强大的药物管理和药物依赖者的药物剥夺的影响。因此，它作为一个有吸引力的早期替代终点治疗后评估治疗疗效和检查应激机制。NIH主任弗朗西斯柯林斯最近将重新利用现有的药物制剂作为研究重点。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对精神病理学研究中可观察行为和神经生物学测量维度的关注保持一致。该项目还预计NIMH的变化，以利用随机对照试验中的机制和结果的同时检查。