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抗惊厥药物疗效和毒性的临床前和临床筛选实验结果的基础上，以指导开发更安全、更有效的治疗酒精依赖的药物。本研究将检查来自三种化学类别的代表性抗惊厥药物的作用：磺胺酸糖，托吡酯；杂环磺胺；吡咯烷和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，这些作用与调节乙醇的消耗、耐受性和人体安全性有关。本提案的主要目的是开展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，有4个治疗组（每组N=40）被分配接受一种有效研究药物或安慰剂，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），每个积极治疗组每天的平均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阳性临床结果的二次测量将显示出更大的疗效。我们还假设托吡酯组的受试者在神经毒性的综合测量、语言流畅性和注意力测试中比其他活性药物组或安慰剂组表现出更大的损伤。这项研究的直接好处将是帮助确定新的抗惊厥药是否能提供更安全、更有效的替代目前批准用于治疗酒精中毒的药物。这项研究的更广泛的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新的酒精中毒治疗药物。反过来，这将推动创新药物治疗酒精依赖的发展。

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.