PHARMACOTHERAPY FOR MULTIPLE ETHANOL WITHDRAWALS

长期饮酒的严重后果之一是 身体上的依赖和体验生活的可能性- 威胁戒断综合症。各种药理制剂都有 用于乙醇(Etoh)戒断的医疗管理。 然而，尽管大量的努力集中在评估治疗上 在单一的戒断事件中，很少有人关注 多次Etoh戒断经历对 治疗效果，以及治疗的选择。这是特别的 考虑到酗酒者的高累犯率，以及 事实上，许多前来接受治疗的酒精中毒患者都有 之前的许多戒毒经验。因此，这项提案 专注于评估多次停用乙醇的药物治疗。 我们最近建立了一种乙醇戒断的动物模型 演示了先前的乙醇戒断经验的增强效果。 这与其他实验和临床证据一起提供了支持。 酒精戒断的引燃假说。虽然这项工作中的大部分 关注的是身体症状的进行性加重 戒断(癫痫)，看来有效的治疗还需要 瞄准心理(焦虑)和对乙醇线索的主观知觉) 戒断综合症的组成部分，考虑到 这些变量影响了人们恢复饮酒的动机。拟议中的工作 将使用已建立的多次提取乙醇的模型来评估 不同药物疗法治疗体力活动障碍的疗效比较 戒断综合征的心理和主观方面。 虽然阐明机制不是这项临床研究的主要目标- 以项目为导向，相关基础研究成果提供了指导 以及选择要评估的药物的理由。更多 具体地说，我们选择将最初的调查重点放在毒品上。 活跃于GABAA、谷氨酸(NMDA和非NMDA)，并由电压驱动 钙通道受体系统。非镇静剂的作用 抗惊厥药物也将接受检查。这些药物都是经过挑选的 因为它们以神经化学系统为目标，这些系统(A)表现出神经适应性 慢性乙醇暴露的变化可能是乙醇戒断的基础 症状和(B)涉及神经元可塑性事件(可能是 类似于点火过程)。因此，这些药物可能特别 适用于有以下病史的患者的治疗 多次提取乙醇。综上所述，拟议的工作可能会提供 关于更有效的重要临床相关信息 治疗急性乙醇戒断的药物治疗策略以及 酒精依赖和酒精中毒的长期管理。

One of the serious consequences of chronic alcohol use is the development of physical dependence and the possibility of experiencing a life- threatening withdrawal syndrome. A variety of pharmacologic agents have been used for the medical management of ethanol (EtOH) withdrawal. However, while a great deal of effort has focused on evaluating treatment of a single withdrawal episode, very little attention has been directed toward the potential impact of multiple EtOH withdrawal experiences on treatment efficacy, as well as choice of treatment. This is particularly relevant given the high rate of recidivism among alcoholics, along with the fact that many alcoholic patients presenting for treatment have a history of numerous prior detoxification experiences. Accordingly, this proposal is focused on evaluating pharmacotherapy for multiple EtOH withdrawals. We have recently established an animal model of EtOH withdrawal that demonstrates the potentiating effects of prior EtOH withdrawal experiences. This, along with other experimental and clinical evidence provide support for the kindling hypothesis of alcohol withdrawal. While much of this work has focused on the progressive intensification of physical symptoms of withdrawal (seizures), it would seem that effective treatment needs to also target the psychological (anxiety) and subjective perception of EtOH cues) components of the withdrawal syndrome, given the potential importance of these variables in the motivation to resume drinking. The proposed work will use an established model of multiple EtOH withdrawals to evaluate the efficacy of various pharmacotherapies in treating physical as well as psychological and subjective aspects of the withdrawal syndrome. While elucidation of mechanisms is not the primary goal of this clinically- oriented project, relevant basic research findings have provided guidance and a rationale for the selection of drugs to be evaluated. More specifically, we have chosen to initially focus our investigation on drugs active at the GABAa, glutamate (NMDA and non-NMDA), and voltage-operated calcium channel receptor systems. The effects of non-sedative anticonvulsants will be examined as well. These drugs have been selected because they target neurochemical systems that (a) exhibit neuroadaptive changes to chronic EtOH exposure which may underlie EtOH withdrawal symptoms and (b) are involved in neuronal plasticity events (which may be akin to the kindling process). Thus, these drugs may be particularly appropriate with regard to treatment for patients with a history of multiple EtOH withdrawals. Taken together, the proposed work may provide important clinically-relevant information regarding more effective pharmacotherapy strategies for treating acute EtOH withdrawal, as well as long-term management of EtOH dependence and alcoholism.