RCT targeting noradrenergic stress mechanisms in alcoholism with doxazosin

 描述(由申请人提供)：目前的药物治疗或酒精和药物成瘾导致获得长期康复的可能性相对较低。制药业最近大幅减少了用于治疗精神疾病，特别是物质使用障碍的新药的研发，这有力地推动了对现有化合物的“重新定位”，这些化合物可能是有效的治疗替代品。口服α1-去甲肾上腺素(NE)受体拮抗剂被广泛用于治疗高血压。此外，α1-NE拮抗剂越来越多地被用于治疗创伤后应激障碍，这与NE在调节应激的多个行为和生理过程中的作用是一致的。压力是导致酒精/毒品复发的一个重要因素。应激相关的恢复是一种有效的成瘾动物模型，而α-1-NE拮抗剂在该动物模型中可减少复发。NIAAA主任George Koob强烈呼吁对人类的压力机制进行转化性研究。在动物身上的临床前证据表明，使用α1-NE拮抗剂可能有助于预防复发，包括与应激相关的复发。为了验证这一假设，我们提出了两个互补的人类临床前和临床目标：1.将动物的临床前证据转化为 α1-NE阻滞剂多沙唑嗪对戒酒患者NE系统的直接药理拮抗作用在人类应激诱导复发的模型。2.筛选多沙唑嗪针对戒酒患者应激相关复发机制的有效性，作为重新利用α1-NE拮抗剂预防成瘾复发的成本效益的第一步。这两个目标将通过对最近戒酒的人进行的随机对照试验(RCT)来实现，以检验8毫克多沙唑嗪(与安慰剂相比，受试者之间)在8周治疗期间对应激反应和临床结果指标(例如，每周饮酒、饮酒欲望)的疗效。我们在基线(治疗前)以及治疗4周和8周后，使用经过良好验证的应激源反应性人体模型(NPU任务)来评估多沙唑嗪对应激相关复发机制的影响。NPU任务与动物临床前文献中的方法和措施都有很强的翻译联系。这项任务已经证明了吸毒和药物剥夺对药物依赖者的可靠和强有力的影响。因此，它可以作为一个有吸引力的治疗后早期替代终点，以评估治疗效果和检查应激机制。NIH主任弗朗西斯·柯林斯最近将改变现有药剂的用途作为研究重点。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。这个项目与NIMH RDoC非常一致，专注于精神病理学研究中可观察的行为和神经生物学测量的维度。该项目还预测NIMH的变化，以利用对随机对照试验的机制和结果的同时检查。

 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.