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

基本信息

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
项目类别：
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

项目摘要

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）：目前的药物疗法或酒精和药物成瘾实现长期康复的可能性相对较低。制药行业最近大幅减少了治疗精神疾病（特别是物质使用障碍）的新药物的研发。强烈推动“重新利用”现有的化合物，这些化合物可能是有效的治疗替代品，口服的脑渗透性α1-去甲肾上腺素（NE）受体拮抗剂也广泛用于治疗高血压。越来越多地用于治疗创伤后应激障碍 (PTSD)，这与 NE 在调节压力中的多种行为和生理过程中的作用一致，是导致酒精/药物复发的重要因素。经充分验证的成瘾动物模型和 α1-NE 拮抗剂可减少该动物模型中的复发，NIAAA 主任 George Koob 强烈呼吁对人类应激机制进行转化研究。 α1-NE 拮抗剂可能有助于预防复发，包括与压力相关的复发。为了检验这一假设，我们提出了两个互补的人类临床前和临床目标： 1. 转化来自动物的临床前证据。通过使用多沙唑嗪（一种 α1-NE 阻滞剂）对戒酒者的 NE 系统进行直接药理学拮抗作用，建立人类压力诱发的复发模型。 2. 筛选多沙唑嗪针对戒酒者压力相关复发机制的功效，作为成本。重新利用这种α1-NE拮抗剂预防成瘾复发的有效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。在 8 周的治疗期间检查 8 毫克多沙唑嗪（与安慰剂相比，受试者之间）对应激性和临床结果测量（例如每周饮酒、酒精渴望）的功效，我们使用评估多沙唑嗪对压力相关复发机制的影响。在基线（治疗前）和治疗 4 周和 8 周后，经过充分验证的压力源反应性（NPU 任务）人类模型具有很强的转化联系。这项任务已经证明了药物依赖性使用者的药物给药和药物剥夺的可靠、稳健的效果，因此，它可以作为治疗后评估治疗效果和治疗效果的一个有吸引力的早期替代终点。美国国立卫生研究院 (NIH) 主任弗朗西斯·柯林斯 (Francis Collins) 最近提倡重新利用现有药物，并将其作为研究重点，提倡在临床研究中开发和使用早期替代终点。 NIMH RDoC 重点关注精神病理学研究中可观察行为和神经生物学测量的维度，该项目还预计 NIMH 会发生变化，以利用随机对照试验的机制和结果的同时检查。