Medication Development for Protracted Abstinence in Alcoholism

长期戒酒的药物开发

• 批准号: 9110767
• 负责人: BARBARA J MASON
• 金额: $ 18.86万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-20 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110767
• 关键词: Abstinence; Acute; Affective; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Animal Model; Animals; Brain; Cessation of life; Chronic; Clinical; Clinical Trials; Cues; Data; Development; Disease; Disulfiram; Extinction (Psychology); Feedback; Funding; Heavy Drinking; Human; Laboratories; Laboratory Study; Levetiracetam; Medical; Modeling; Naltrexone; National Institute on Alcohol Abuse and Alcoholism; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Prazosin; Productivity; Public Health; Rattus; Relapse; Research Priority; Rewards; Risk; Risk Factors; Sleep disturbances; Societies; Stress; Symptoms; System; Testing; Therapeutic; Time; Withdrawal; acamprosate; aprepitant; binge drinking; cost; craving; cue reactivity; design; drinking; drug efficacy; duloxetine; expectation; gabapentin; model development; negative emotional state; non-compliance; novel; oxcarbazepine; pre-clinical; preclinical study; pregabalin; premature; reduced alcohol use; research clinical testing; research study; screening; theories; translational approach

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.

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，且可用的治疗方法很少。开发具有更大疗效的新药来治疗 AD 是 NIAAA 的首要任务。这一竞争性延续的目的是确定治疗 AD 长期禁欲的新药物，同时开发和验证一种转化方法来筛选将推动该领域向前发展的潜在药物。长期戒酒涉及急性酒精戒断后易复发的状态，这是由中枢神经系统压力和奖励系统失调引起的。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体模型方面取得了重大进展，这些模型已通过阿坎酸、度洛西汀、加巴喷丁、纳曲酮和普瑞巴林的 II 期和 III 期临床试验的疗效结果得到验证。作为长期禁欲模型开发的下一步（Specific Aim 1-临床前、Specific Aim 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。线索和压力诱导的恢复动物模型将在依赖性和酗酒动物中得到完善，以更接近人类的 AD 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（阿瑞吡坦、左乙拉西坦、唑尼沙胺、奥卡西平、哌唑嗪），这些药物假设可以使与负面情绪状态和渴望相关的失调的大脑系统正常化与长期禁欲相关，将在我们的转化模型中评估潜在的药物疗效。为临床前研究选择的其他药物代表了一系列可能可用于人类研究的理想靶标。正在测试的总体假设是，所选择的动物和人体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，以降低长期戒断的复发风险。来自动物和人体成分的动态反馈以及可用的临床试验数据将促进这些模型的进一步开发。本提案的一个关键方面是所提出的来自动物部分和临床部分的动态反馈，这两者都旨在简化信息并为最终临床使用提供一致的证据。目前的提案提供了高级筛选，可以确定 AD 的治疗方法和可能在临床试验中取得成功的终点。