A Randomized Trial of Pioglitazone for the Treatment of Alcohol Use Disorder

酒精使用障碍(AUD)在退伍军人中很常见，与显著的 发病率和死亡率。此外，退伍军人的澳门氏症的直接和间接成本是显著的。 FDA批准的几种药物可用于治疗AUD，据信 通过包括γ-氨基丁酸在内的抑制性和兴奋性神经元通路起作用 (GABA)、谷氨酸和阿片途径。然而，效果大小通常很小，而且它们 在少数患者中使用。因此，具有新作用机制的新药是 需要改善结果。吡格列酮是一种过氧化物酶体增殖物激活受体- 伽玛(PPAR)激动剂，已被证明在几个前 临床研究和减少可卡因和酒精使用的一项小型可卡因临床研究 从属对象。吡格列酮被认为可以调节与以下相关的炎症反应 反复饮酒，潜在地减少饮酒欲望和改善行为 灵活性。目前还没有关于吡格列酮治疗AUD的临床研究。拟议中的工作 将建立在临床前数据、一项针对可卡因使用者的小型研究和一项回顾研究的基础上 明尼阿波利斯退伍军人管理局的评估显示，吡格列酮和降压药之间存在关联 退伍军人的酒精使用情况。因此，我们提出了一项随机对照双盲试验。 吡格列酮与安慰剂在至少中度AUD和世卫组织退伍军人中的比较 目前正在饮酒。主要结果是饮酒行为(最后几天大量饮酒 研究的8周，每周大量饮酒天数和每周总饮酒量)和 次要结果包括酒精使用的生物学措施(乙基葡萄糖醛酸乙酯、乙基硫酸乙酯 和γ-谷氨酰转移酶)、渴求和安全措施。这项研究是否应该提供 吡格列酮治疗AUD的有效性和安全性的证据，我们建议进行更大规模的临床试验 通过合作学习计划。此外，由于吡格列酮目前是FDA 批准的药物它可以在临床实践中“非标签”使用，以直接受益于 患有澳元的退伍军人。最后，由于吡格列酮的作用机制独特，显示出疗效 这可能会为澳大利亚糖尿病的药物发现开辟一条新的途径。具体来说， 针对免疫信号的药物，如其他PPAR激动剂，可能会被寻求 解决AUD和其他物质使用障碍。

Alcohol use Disorder (AUD) is common among Veterans and is associated with significant morbidity and mortality. In addition, the direct and indirect cost of AUD in Veterans is significant. Several FDA approved medications are available for the treatment of AUD and are thought to act through inhibitory and excitatory neuronal pathways including gamma-aminobutyric acid (GABA), glutamate and opioid pathways. However, effect sizes are generally small and they are used in a minority of patients. Thus, new medications with novel mechanisms of action are needed to improve outcomes. Pioglitazone is a peroxisome proliferator-activated receptor- gamma (PPAR) agonist that has been shown to reduce addictive behaviors in several pre- clinical studies and reduce cocaine and alcohol use in one small clinical study of cocaine dependent subjects. Pioglitazone is thought to modulate the inflammatory response related to repeated cycles of alcohol use, potentially reducing alcohol craving and improving behavioral flexibility. No clinical studies of pioglitazone focused on AUD are available. The proposed work would build on the pre-clinical data, one small study in cocaine users and a retrospective evaluation at the Minneapolis VA showing an association between pioglitazone and reduced alcohol use in Veterans. Therefore, we propose a randomized controlled double-blind trial of pioglitazone compared to placebo in Veterans with AUD of at least moderate severity and who are currently drinking. The primary outcome is drinking behavior (heavy drinking days in the last 8 weeks of the study, number of heavy drinking days per week and total drinks per week) and secondary outcomes include biological measures of alcohol use (ethyl glucuronide, ethyl sulfate and gamma-glutamyl transferase), craving and safety measures. Should this study provide evidence of efficacy and safety for pioglitazone in AUD, we would propose a larger clinical trial through the cooperative studies program. In addition, as pioglitazone is currently an FDA approved drug it could be used "off-label" in clinical practice to the immediate benefit of Veterans with AUD. Finally, as pioglitazone's mechanisms of action is unique, showing efficacy would potentially lead to a new avenue of medication discovery for AUD. Specifically, medications that address immune signaling such as other PPAR agonists might be pursued to address AUD and other substance use disorders.