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

众所周知，压力在酒精的产生和持续中起着重要作用- 相关行为。研究表明，患有酒精使用障碍（AUD）的人患上糖尿病的风险增加。 然而，压力调节失调，目前FDA批准的AUD药物中没有一种针对压力的 系统因此，靶向去甲肾上腺素能系统以调节应激的新的药理学干预 在患有AUD的个体中的反应提供了有希望的治疗机会。此外，它在 文献表明，AUD与慢性和长期免疫炎症有关。因此，赞成/反对- 炎性细胞因子可能代表了一种重要的生物学机制，有助于增强 研究表明，AUD具有抑制酒精作用的作用，可作为开发AUD药效团的新靶点。主要目标 本补充的目的是检查多沙唑嗪的抗炎作用， 受体阻滞剂对AUD患者血清细胞因子水平的影响，并评估 炎症细胞因子作为多沙唑嗪减少酒精消耗的机制。血清样品 将从184名寻求治疗的AUD患者中收集。将在7个时间点采集样本 12周研究中的时间点：基线时，最大耐受剂量（实验室阶段和 在第5-11周期间的自然阶段）和在研究结束时（第12周）。使用ELLA的细胞因子分析， 自动化酶联免疫分析系统将作为次要结局（目标1）和介体进行测试 多沙唑嗪对酒精相关结局的影响（目标2）。据我们所知，这项研究将是第一个 细胞因子作为多沙唑嗪调节酒精消耗的介质。此外，为了进一步 开发“个性化”药物干预方法，补充的探索性目标将 评估性别作为多沙唑嗪对酒精影响的生物学变量和种族群体 消费这一多样性补充将提供有价值的见解，进一步阐明机制 基础AUD和治疗AUD的新型药物疗法的机制作用。

It has been well established that stress plays an important role in the initiation and continuation of alcohol- related behaviors. Studies indicate that individuals with alcohol use disorder (AUD) are at increased risk for the dysregulation of stress, however, currently none of the FDA-approved medications for AUD target the stress system. As such, novel pharmacological interventions targeting the noradrenergic system to regulate the stress response in individuals with AUD provide a promising therapeutic opportunity. Further, it is well-described in the literature that AUD is associated with chronic and prolonged immune inflammation. Therefore, pro/anti- inflammatory cytokines may represent an important biological mechanism that contributes to the reinforcing effect of alcohol and can be utilized as novel targets to develop AUD pharmacophore. The primary objectives of this supplement are to examine the anti-inflammatory effect of doxazosin, an alpha 1 noradrenergic receptor blocker, on serum levels of cytokines in individuals with AUD, and to assess the mediating role of inflammatory cytokines as a mechanism by which doxazosin decreases alcohol consumption. Serum samples will be collected from 184 treatment seeking individuals with AUD. Samples will be obtained at seven time points over the 12-week study: at baseline, at the maximum tolerated dose (the laboratory phase and naturalistic phase during week 5-11), and at the end of the study (week 12). Cytokine analysis using ELLA, an automated enzyme-linked immunoassay system, will be tested as a secondary outcome (Aim 1) and mediator of doxazosin on alcohol-related outcomes (Aim 2). This study will be the first to our knowledge to examine cytokines as a mediator of doxazosin’s regulation of alcohol consumption. Additionally, to further develop the “personalized” pharmacological intervention approach the exploratory aim of the supplement will evaluate sex as a biological variable and racial group as moderators of doxazosin’s effect on alcohol consumption. This Diversity Supplement will provide valuable insight further elucidating the mechanisms underlying AUD and the mechanistic actions of novel pharmacological therapies for the treatment of AUD.