阿普米司特改变了小鼠对乙醇的行为反应：I. 减少了消耗和偏好。
Apremilast Alters Behavioral Responses to Ethanol in Mice: I. Reduced Consumption and Preference.
机构信息
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas.
Drug Dynamics Institute, College of Pharmacy, The University of Texas at Austin, Austin, Texas.
出版信息
Alcohol Clin Exp Res. 2018 May;42(5):926-938. doi: 10.1111/acer.13616. Epub 2018 Mar 24.
BACKGROUND
Phosphodiesterase type 4 (PDE4) inhibitors produce widespread anti-inflammatory effects and reduce ethanol (EtOH) consumption in several rodent models. These drugs are potential treatments for several diseases, including central nervous system disorders, but clinical use is limited by their emetic activity. Apremilast is a selective PDE4 inhibitor with fewer gastrointestinal side effects that is FDA-approved for the treatment of psoriasis.
METHODS
We measured the acute and chronic effects of apremilast on EtOH consumption in male and female C57BL/6J mice using the continuous and intermittent 24-hour 2-bottle choice drinking models. We also studied the effects of apremilast on preference for sucrose or saccharin, spontaneous locomotor activity, and blood EtOH clearance. Finally, apremilast levels in plasma, liver, and brain were measured 1 or 2 hours after injection.
RESULTS
In the continuous and intermittent drinking tests, apremilast (15 to 50 mg/kg, p.o.) dose dependently reduced EtOH intake and preference in male and female mice. Higher doses of apremilast (30 to 50 mg/kg) also reduced total fluid intake in these mice. Chronic administration of apremilast (20 mg/kg) produced a stable reduction in EtOH consumption in both drinking tests with no effect on total fluid intake. The drinking effects were reversible after drug treatment was replaced with vehicle administration (saline) for 2 to 4 days. Six daily apremilast injections did not alter preference for saccharin or sucrose in male or female mice. Apremilast (20 mg/kg) transiently decreased spontaneous locomotor activity and did not alter blood EtOH clearance. The highest levels of apremilast were found in liver followed by plasma and brain.
CONCLUSIONS
Apremilast produced stable reductions in voluntary EtOH consumption and was rapidly distributed to plasma and tissues (including the brain), suggesting that it may be an improved PDE4 inhibitor for medication development and repurposing efforts to treat alcohol abuse.
背景
磷酸二酯酶 4 型（PDE4）抑制剂在几种啮齿动物模型中产生广泛的抗炎作用，并减少乙醇（EtOH）的消耗。这些药物是几种疾病的潜在治疗方法，包括中枢神经系统疾病，但由于其催吐作用，临床应用受到限制。阿普米司特是一种选择性 PDE4 抑制剂，胃肠道副作用较少，已被 FDA 批准用于治疗银屑病。
方法
我们使用连续和间歇性 24 小时 2 瓶选择饮用模型，测量了阿普米司特对雄性和雌性 C57BL/6J 小鼠乙醇消耗的急性和慢性影响。我们还研究了阿普米司特对蔗糖或糖精偏好、自发运动活动和血液乙醇清除率的影响。最后，在注射后 1 或 2 小时测量了血浆、肝脏和大脑中的阿普米司特水平。
结果
在连续和间歇性饮用测试中，阿普米司特（15 至 50mg/kg，po）剂量依赖性地降低了雄性和雌性小鼠的乙醇摄入量和偏好。较高剂量的阿普米司特（30 至 50mg/kg）也降低了这些小鼠的总液体摄入量。阿普米司特（20mg/kg）的慢性给药在两种饮用测试中均产生了稳定的乙醇消耗减少，而对总液体摄入量没有影响。在药物治疗用生理盐水代替 2 至 4 天后，饮用效果是可逆的。阿普米司特（20mg/kg）每日 6 次注射不会改变雄性或雌性小鼠对糖精或蔗糖的偏好。阿普米司特（20mg/kg）短暂降低自发运动活动，不改变血液乙醇清除率。阿普米司特的最高水平存在于肝脏中，其次是血浆和大脑。
结论
阿普米司特可稳定减少自愿性乙醇消耗，且迅速分布到血浆和组织（包括大脑），表明它可能是一种改进的 PDE4 抑制剂，可用于药物开发和重新利用努力，以治疗酒精滥用。
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