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，与严重的 发病率和死亡率。此外，澳元在退伍军人中的直接和间接成本很大。 几种FDA批准的药物可用于治疗AUD，并被认为 通过抑制性和兴奋性神经通路起作用，包括γ-氨基丁酸 （GABA）、谷氨酸和阿片途径。然而，效应量通常很小， 用于少数患者。因此，具有新的作用机制的新药物正在开发中。 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， γ（过氧化物酶体增殖物激活受体）激动剂，已被证明可以减少成瘾行为，在几个前， 在一项小型可卡因临床研究中， 依赖的对象。吡格列酮被认为可以调节炎症反应， 重复的酒精使用周期，可能会减少酒精渴望并改善行为 灵活性.尚无针对AUD的吡格列酮临床研究。拟议工作 将建立在临床前数据，一个小的研究可卡因使用者和回顾性 明尼阿波利斯VA的评价显示吡格列酮与降低 酒精在退伍军人中的应用因此，我们建议进行一项随机对照双盲试验， 吡格列酮与安慰剂在患有至少中度严重程度的AUD且 目前正在喝酒。主要结果是饮酒行为（过去一年中的重度饮酒天数） 8周的研究，每周大量饮酒天数和每周总饮酒量）， 次要结果包括酒精使用的生物学指标（乙基葡萄糖醛酸苷、硫酸乙酯 和γ-谷氨酰转移酶）、渴望和安全措施。如果这项研究提供 吡格列酮治疗AUD的疗效和安全性证据，我们将建议进行更大规模的临床试验 通过合作研究项目。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使用“标签外”，以直接受益， 有AUD的人。最后，由于吡格列酮的作用机制独特，显示出疗效 可能会为AUD的药物发现开辟一条新的途径。具体地说， 可能会寻求解决免疫信号传导的药物，如其他PPAR激动剂， 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.