Interdisciplinary Study of Two Novel Anticonvulants in Alcoholism

描述(申请人提供)：这项研究的主要目标是在我们的抗惊厥有效性和毒性的临床前和临床筛选实验结果的基础上，指导开发更安全、更有效的治疗酒精依赖的药物。这项研究将考察来自三种化学类别的代表性抗惊厥药物：糖磺酸盐托吡酯、杂环磺酰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，与调节人类的乙醇消耗、耐受性和安全性有关。这项建议的主要目的是对酒精依赖受试者进行一项双盲安慰剂对照平行小组设计研究，其中4个治疗组(每组40人)被分配接受一种积极研究药物或安慰剂，为期14周。我们假设：在预期的最大稳态血浆浓度期间(治疗10-12周)，每个主动治疗组的平均每天饮酒量将显著低于安慰剂组。此外，我们假设，与安慰剂组相比，每个积极治疗组的酒精消耗量和积极临床结果的二级测量将显示出显着更好的疗效。我们还假设，与其他活性药物或安慰剂组相比，托吡酯组的受试者在神经毒性的综合测量以及语言流畅性和注意力测试中表现出更大的损害。这项研究的直接好处将是帮助确定新型抗惊厥药物是否提供了比目前被批准用于治疗酒精中毒的药物更安全和更有效的替代品。这项研究的更广泛的影响是根据研究药物的化学类别指导现有化合物的选择和治疗酒精中毒的新药物的合成。反过来，这将推动酒精依赖创新药物疗法的发展。 与公共卫生相关：目前批准的治疗酒精中毒的药物疗效有限，在临床实践中采用缓慢。目前这项研究的目标是通过研究化学结构和药理作用与现有药物不同的药物来寻找更有效、更安全的酒精中毒药物。

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.