Interdisciplinary Study of Two Novel Anticonvulants in Alcoholism

描述（由申请人提供）：本研究的总体目标是建立在我们抗惊厥疗效和毒性的临床前和临床筛选实验的结果基础上，以指导开发更安全，更有效的药物治疗酒精依赖。本研究将检查三种化学类别的代表性抗惊厥药的影响：氨基磺酸糖，托吡酯;杂环磺酰胺，唑尼沙胺;和吡咯烷，左乙拉西坦对酒精依赖受试者的乙醇消耗和神经毒性。这些药物具有一些共同的药理学作用，但也具有不同的作用，这些作用与人类的乙醇消耗，耐受性和安全性有关。本提案的主要目的是在酒精依赖受试者中进行一项双盲安慰剂对照平行组设计研究，其中包括4个治疗组（每组N=40），这些受试者被分配接受一种活性研究药物或安慰剂治疗14周。我们假设：在最大稳态血浆浓度的预期期间（治疗第10-12周），每个活性治疗组中每天的平均饮酒次数将显著低于安慰剂组。此外，我们假设每个活性治疗组中酒精消耗和阳性临床结果的次要测量将显示出与安慰剂组相比显著更大的功效。我们还假设托吡酯组的受试者在神经毒性综合指标、语言流畅性和注意力测试中的损害程度比其他活性药物组或安慰剂组更大。这项研究的直接好处将有助于确定新的抗惊厥药物是否能提供更安全、更有效的替代药物，以治疗目前批准的酒精中毒。这项研究的更广泛意义是指导现有化合物的选择和基于研究药物的化学类别合成用于酒精中毒治疗的新药物。反过来，这将推动酒精依赖创新药物疗法的发展。 公共卫生相关性：目前批准用于治疗酒精中毒的药物与有限的有效性相关，并且它们在临床实践中的采用一直很缓慢。目前研究的目标是通过研究与现有药物在化学结构和药理作用上不同的药物，找到更有效、更安全的治疗酒精中毒的药物。

DESCRIPTION (provided by applicant): The overarching goal of this study is to build on the results of our pre-clinical and clinical screening experiments of anticonvulsant efficacy and toxicity to guide the development of safer and more effective medications for the treatment of alcohol dependence. This investigation will examine the effects of representative anticonvulsants from three chemical classes: a sugar sulfamate, topiramate; a heterocyclic sulfonamide, zonisamide; and a pyrrolidine, levetiracetam on ethanol consumption and neurotoxicity in alcohol dependent subjects. These medications share some common pharmacologic effects, but also have different actions that are relevant to regulation of ethanol consumption, tolerability, and safety in humans. The primary aim of this proposal is to conduct a double blind placebo controlled parallel group design study with 4 treatment groups (N=40 in each group) in alcohol dependent subjects assigned to receive one of the active study medications or placebo for 14 weeks. We hypothesize that: during the expected period of maximal steady state plasma concentrations, (treatment weeks 10-12), the mean number of drinks per day in each active treatment arm will be significantly lower than in the placebo arm. Furthermore we hypothesize that secondary measures of alcohol consumption and positive clinical outcome in each active treatment arm will show significantly greater efficacy compared to the placebo group. We also hypothesize that subjects in the topiramate group will show greater impairment on a composite measure of neurotoxicity, and tests of verbal fluency and attention than do the other active drug or placebo groups. The immediate benefits of this study will be to help determine if novel anticonvulsants offer safer and more effective alternatives to agents currently approved for the treatment of alcoholism. The broader implications of the study are to guide the selection of existing compounds and the synthesis of new agents for alcoholism treatment based on the chemical classes of the study medications. In turn, this will advance the development of innovative pharmacotherapies for alcohol dependence. PUBLIC HEALTH RELEVANCE: Currently approved medications for the treatment of alcoholism are associated with limited effectiveness and their adoption in clinical practice has been slow. The goal of the current study is to find more effective and safer medications for alcoholism by studying agents that differ in chemical structure and pharmacologic actions from those currently available.