Medication Development for Protracted Abstinence in Alcoholism

描述（由申请人提供）：酒精依赖（AD）是一个主要的公共卫生问题，缺乏可用的治疗方法。开发具有更大效应量的治疗AD的新药是NIAAA的优先事项。这种竞争性延续的目的是确定新的药物来治疗AD的长期禁欲，同时开发和验证一种转化方法来筛选潜在的药物，这将推动该领域的发展。酒精戒断涉及急性酒精戒断后复发脆弱性的增加，这是由CNS中的压力和奖励系统的失调驱动的。在上一个资助期间，在开发对药物作用敏感的长期戒断动物和人类模型方面取得了重大进展，这些模型在阿坎酸、度洛沙汀、加巴喷丁、纳洛酮和普瑞巴林的II期和III期临床试验中得到了疗效结果的验证。作为长期禁欲模型开发的下一步（具体目标1-临床前，具体目标3-人类），我们的人类线索反应模型将进一步开发，以包括压力诱导的渴望，以更全面地评估长期禁欲的药物疗效。将在依赖性和酗酒动物中完善线索和压力诱导的恢复的动物模型，以更接近地平行于AD的人类状况。作为药物开发的下一步（具体目标2-临床前，具体目标4-人类），我们已经确定了5种药物（阿瑞匹坦，左乙拉西坦，唑尼沙胺，奥卡西平，哌唑嗪），假设这些药物可以使与长期禁欲相关的负面情绪状态和渴望相关的失调脑系统正常化，这些药物将在我们的转化模型中评估潜在的药物疗效。选择用于临床前研究的其他药物代表了可能用于人类研究的理想靶点的管道。测试的总体假设是，所选择的动物和人类模型将为特定药物的治疗潜力提供有效，可靠和差异化的筛选，以降低长期禁欲的复发风险。来自动物和人体组件的动态反馈以及临床试验数据将促进这些模型的进一步发展。本提案的一个关键方面是来自动物部分和临床部分的拟议动态反馈，这两者都旨在简化信息并为最终临床使用提供汇聚证据。目前的提案提供了一个先进的筛选层，将允许识别AD的治疗和可能在临床试验中成功的终点。

DESCRIPTION (provided by applicant): Alcohol dependence (AD) is a major public health problem with a paucity of available treatments. The development of novel drugs with larger effect sizes to treat AD is a NIAAA priority. The purpose of this competing continuation is to identify new medications to treat protracted abstinence in AD while at the same time developing and validating a translational approach to screening potential medications that will move the field forward. Protracted abstinence involves a state of heightened relapse vulnerability following acute alcohol withdrawal that is driven by dysregulation in stress and reward systems in the CNS. In the previous funding period, significant progress was made in developing animal and human models of protracted abstinence with sensitivity to drug effects that were validated by efficacy outcomes in Phase II and III clinical trials of acamprosate, duloxetine, gabapentin, naltrexone and pregabalin. As next steps in model development for protracted abstinence (Specific Aim 1-preclinical, Specific Aim 3-human), our human cue reactivity model will be further developed to include stress-induced craving to more comprehensively assess medication efficacy for protracted abstinence. Animal models of cue- and stress- induced reinstatement will be refined in dependent and binge-drinking animals, to more closely parallel the human condition of AD. As next steps in medication development (Specific Aim 2-preclinical, Specific Aim 4-human) we have identified 5 drugs (aprepitant, levetiracetam, zonisamide, oxcarbazepine, prazosin) hypothesized to normalize the dysregulated brain systems related to the negative emotional states and craving associated with protracted abstinence that will be assessed for potential drug efficacy in our translational models. Additional drugs selected for preclinical studies represent a pipeline of desirable targets that may become available for human studies. The overall hypothesis under test is that animal and human models chosen will provide efficient, reliable and differential screens for the treatment potential of specific drugs for reducing relapse risk in protracted abstinence. Dynamic feedback from the animal and human components, and clinical trial data as it becomes available, will facilitate further development of these models. A critical aspect of the present proposal is the proposed dynamic feedback from the animal component and the clinical component, both of which are designed to streamline information and provide converging evidence for ultimate clinical use. The present proposal provides an advanced tier of screening that will allow identification of treatments for AD and endpoints likely to succeed in clinical trials.