Interdisciplinary Study of Two Novel Anticonvulants in Alcoholism

本研究的总体目标是建立在我们的临床前和临床研究结果的基础上。 抗惊厥药物的疗效和毒性筛选实验，以指导开发更安全的 以及更有效的治疗酒精依赖的药物。这次调查将 检查三种化学类别的代表性抗惊厥药的作用： 氨基磺酸盐，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酒精消耗和神经毒性的影响。这些药物 有一些共同的药理作用，但也有不同的作用， 调节人类的乙醇消耗、耐受性和安全性。其主要目的是 建议进行一项双盲安慰剂对照平行组设计研究， 在酒精依赖受试者中分配接受一种治疗组（每组N=40） 活性研究药物或安慰剂治疗14周。我们假设： 最大稳态血药浓度的预期时间段（治疗第10-12周）， 每个活性治疗组的平均每日饮酒次数将显著低于 此外，我们假设酒精消耗的次要指标 每个活性治疗组的阳性临床结局将显示出显著更高的疗效 与安慰剂组相比。我们还假设托吡酯组的受试者 在神经毒性的综合测量和语言流畅性测试中显示出更大的损害 和注意力比其他活性药物或安慰剂组。这样做的直接好处是 研究将有助于确定新的抗惊厥药物是否提供更安全，更有效的 目前批准用于治疗酒精中毒的药物的替代品。更广泛的 该研究的意义是指导现有化合物的选择和合成， 根据研究药物的化学类别，开发新的酒精中毒治疗药物。在 反过来，这将促进酒精创新药物疗法的发展 依赖

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.