Kufahl Peter R, Watterson Lucas R, Olive M Foster
Arizona State University, Behavioral Neuroscience Area, Department of Psychology , Tempe, AZ 85287 , USA.
Expert Opin Drug Discov. 2014 Nov;9(11):1355-69. doi: 10.1517/17460441.2014.960840. Epub 2014 Sep 26.
Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate (Campral), one of only three pharmacological treatments approved for the treatment of alcohol dependence, has shown mixed efficacy in clinical trials in maintaining abstinence of detoxified alcoholics since studies began in the 1980s. Yielding inconsistent results, these studies have prompted skepticism.
Herein, the authors review the preclinical studies which have assessed the efficacy of acamprosate in various animal models of alcohol dependence and discuss the disparate findings from the major clinical trials. Moreover, the authors discuss the major limitations of these preclinical and clinical studies and offer explanations for the often-contradictory findings. The article also looks at the importance of the calcium moiety that accompanies the salt form of acamprosate and its relevance to its activity.
The recent discovery that large doses of calcium largely duplicate the effects of acamprosate in animal models has introduced a serious challenge to the widely held functional association between this drug and the glutamate neurotransmission system. Future research on acamprosate or newer pharmacotherapeutics should consider assessing plasma and/or brain levels of calcium as a correlate or mediating factor in anti-relapse efficacy. Further, preclinical research on acamprosate has thus far lacked animal models of chemical dependence on alcohol, and the testing of rodents with histories of alcohol intoxication and withdrawal is suggested.
在全球范围内，酒精滥用和酒精依赖是导致慢性病和损伤的重要因素，每年造成近4%的死亡。阿坎酸（坎普拉尔）是仅有的三种被批准用于治疗酒精依赖的药物治疗方法之一，自20世纪80年代开始研究以来，在维持戒酒的酒精中毒者的临床试验中显示出了混合疗效。这些研究结果不一致，引发了人们的怀疑。
在此，作者回顾了评估阿坎酸在各种酒精依赖动物模型中的疗效的临床前研究，并讨论了主要临床试验中不同的研究结果。此外，作者讨论了这些临床前和临床研究的主要局限性，并对经常相互矛盾的研究结果做出了解释。文章还探讨了与阿坎酸盐形式相伴的钙部分的重要性及其与活性的相关性。
最近发现大剂量的钙在动物模型中很大程度上复制了阿坎酸的作用，这对该药物与谷氨酸神经传递系统之间广泛存在的功能关联提出了严峻挑战。未来对阿坎酸或更新的药物治疗方法的研究应考虑评估血浆和/或大脑中的钙水平，将其作为抗复发疗效的相关因素或介导因素。此外，迄今为止，对阿坎酸的临床前研究缺乏对酒精化学依赖的动物模型，建议对有酒精中毒和戒断史的啮齿动物进行测试。
