Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health & Science University, and VA Portland Health Care System, Portland, Oregon, USA.
Waggoner Center for Alcohol and Addiction Research, Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA.
J Clin Invest. 2023 Mar 15;133(6):e159103. doi: 10.1172/JCI159103.
Treatment options for alcohol use disorders (AUDs) have minimally advanced since 2004, while the annual deaths and economic toll have increased alarmingly. Phosphodiesterase type 4 (PDE4) is associated with alcohol and nicotine dependence. PDE4 inhibitors were identified as a potential AUD treatment using a bioinformatics approach. We prioritized a newer PDE4 inhibitor, apremilast, as ideal for repurposing (i.e., FDA approved for psoriasis, low incidence of adverse events, excellent safety profile) and tested it using multiple animal strains and models, as well as in a human phase IIa study. We found that apremilast reduced binge-like alcohol intake and behavioral measures of alcohol motivation in mouse models of genetic risk for drinking to intoxication. Apremilast also reduced excessive alcohol drinking in models of stress-facilitated drinking and alcohol dependence. Using site-directed drug infusions and electrophysiology, we uncovered that apremilast may act to lessen drinking in mice by increasing neural activity in the nucleus accumbens, a key brain region in the regulation of alcohol intake. Importantly, apremilast (90 mg/d) reduced excessive drinking in non-treatment-seeking individuals with AUD in a double-blind, placebo-controlled study. These results demonstrate that apremilast suppresses excessive alcohol drinking across the spectrum of AUD severity.
自 2004 年以来，治疗酒精使用障碍（AUD）的选择方案几乎没有进展，而每年的死亡人数和经济损失却惊人地增加。磷酸二酯酶 4（PDE4）与酒精和尼古丁依赖有关。使用生物信息学方法，发现 PDE4 抑制剂是一种有潜力的 AUD 治疗药物。我们将一种新型 PDE4 抑制剂阿普米司特（apremilast）作为重新定位（即，FDA 批准用于银屑病，不良反应发生率低，安全性良好）的理想选择，并使用多种动物品系和模型以及一项人类 IIa 期研究进行了测试。我们发现，阿普米司特可减少具有遗传易感性的小鼠模型中 binge-like 酒精摄入和酒精动机的行为测量。阿普米司特还可减少应激促进的饮酒和酒精依赖模型中的过度饮酒。通过使用靶向药物输注和电生理学，我们发现阿普米司特可能通过增加伏隔核（调节酒精摄入的关键大脑区域）中的神经活动，来减少小鼠的饮酒量。重要的是，在一项双盲、安慰剂对照研究中，阿普米司特（90mg/d）减少了非寻求治疗的 AUD 患者的过度饮酒。这些结果表明，阿普米司特可抑制 AUD 严重程度谱中的过度饮酒。
