A focus on alpha-1 blockade as a novel pharmacological treatment for alcohol use disorder

摘要 虽然压力在酒精使用障碍（AUD）中的作用已经得到了很好的确立，但目前FDA批准的 美国的药物治疗针对的是压力系统。应激成分的一个潜在药理学靶点 AUD是去甲肾上腺素。 该应用程序的目标是复制以前在试点试验中进行的发现，并了解， 从机制上讲，应激在靶向去甲肾上腺素能的AUD药物治疗开发中的作用 封锁为了实现这些目标，本研究提出了一项为期12周的受试者间双盲随机 多沙唑嗪（16 mg，或最大耐受剂量，MTD）与安慰剂相比的临床试验（RCT），184例 寻求治疗的AUD患者。我们将：（1）在基线检查饮酒和临床结果， 在整个治疗过程中和治疗后;（2）在酒吧中进行应激诱导的酒精线索反应， 实验室;和（3）测试多沙唑嗪反应的调节剂，以告知个性化的治疗方法。 本研究计划有三个目标。在目标1中，我们将测试多沙唑嗪是否会减少饮酒量 （主要结果）和酒精渴望（次要结果）在整个研究的自然条件。然后 在目标2中，在酒吧实验室中，我们将测量单次口服32.4 mg育亨宾（以 启动与应激诱导相关的神经内分泌过程并增强暴露疗法）， 与酒精线索反应性方案（以选择性地靶向酒精线索）结合。最后，在探索 旨在进一步阐明去甲肾上腺素能药物疗法的潜在个性化医学方法 对于AUD，我们将检验以下假设：基线酗酒家族史密度、血压和 rs 1611115多态性中度多沙唑嗪对AUD个体饮酒的影响

ABSTRACT While the role of stress in alcohol use disorder (AUD) is well established, none of the current FDA-approved medications in the U.S target the stress system. One potential pharmacological target for the stress component of AUD is norepinephrine. The goal of this application is to replicate findings previously conducted in a pilot trial and to understand, mechanistically, the role of stress in the development of AUD pharmacotherapies that target noradrenergic blockade. To achieve these goals, this study proposes a 12 week, between-subject, double-blind, randomized clinical trial (RCT) with doxazosin (16 mg, or maximum tolerated dose, MTD) compared to placebo in 184 treatment seeking individuals with AUD. We will: (1) examine alcohol drinking and clinical outcomes at baseline, throughout treatment, and at posttreatment; (2) conduct a stress-induced alcohol cue-reactivity in a bar- laboratory; and (3) test moderators of doxazosin response to inform a personalized treatment approach. There are three aims in this research plan. In Aim 1, we will test if doxazosin decreases alcohol consumption (primary outcome) and alcohol craving (secondary outcome) in naturalistic conditions throughout the study. Then in Aim 2, in the bar laboratory, we will measure acute craving after a single oral dose of 32.4 mg yohimbine (to initiate the neuroendocrine process associated with stress induction and to enhance exposure therapy), combined with an alcohol cue reactivity protocol (to selectively target alcohol cues). Finally, in the exploratory aims, to further shed light on potential personalized medicine approaches with noradrenergic pharmacotherapies for AUD, we will test the hypotheses that baseline family history density of alcoholism, blood pressure and rs1611115 polymorphism moderate doxazosin's effect on alcohol consumption in individuals with AUD.