Metadoxine as a novel pharmacotherapy for older adults with alcohol use disorder

美他多辛作为治疗患有酒精使用障碍的老年人的新型药物疗法

• 批准号: 10591037
• 负责人: Samantha Portis
• 金额: $ 13.18万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591037
• 关键词: Abstinence; Acute; Adverse event; Age; Aging; Alcohol consumption; Alcoholic Intoxication; Alcohols; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Attenuated; Biometry; Brain-Derived Neurotrophic Factor; Carboxylic Acids; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cognition; Complement; Data; Dose; Double-Blind Method; Drug Interactions; Drug usage; Elderly; Enrollment; Ethanol; Europe; Excretory function; FDA approved; Frequencies; Future; Gerontology; Goals; Health; Heavy Drinking; Hepatocyte; Human; Impaired cognition; Individual; Inflammation; Inflammation Mediators; Interleukin-1 beta; Intoxication; Laboratories; Laboratory Study; Liver diseases; Mediating; Memory; Mentorship; Methods; National Institute on Alcohol Abuse and Alcoholism; Nerve Degeneration; Neurosciences; Nuclear; Participant; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebo Control; Placebos; Population; Prevalence; Production; Public Health; Public Health Schools; Pyridoxal; Pyrrolidinones; Randomized; Randomized Controlled Trials; Research; Research Support; Research Training; Risk; Safety; Sedation procedure; TNF gene; Testing; Training; Universities; Vitamin B Complex; Vitamin B6; Withdrawal; acceptability and feasibility; addiction; age related; alcohol abuse therapy; alcohol craving; alcohol cue; alcohol related consequences; alcohol research; alcohol use disorder; career; chronic alcohol ingestion; cognitive function; cognitive performance; cognitive testing; comorbidity; craving; cue reactivity; cytokine; drinking; effective therapy; fatty liver disease; human old age (65+); improved; mouse model; novel; pre-clinical; public health research; safety testing; satisfaction; tissue repair; urinary

PROJECT SUMMARY This K99/R00 proposal examines a novel pharmacotherapy for alcohol use disorder (AUD) in older adults (aged ≥65). As the population is aging at an unprecedented rate and alcohol is the most commonly used drug among older adults, AUD in the older adult population is becoming an increasing area of importance in public health and clinical research. Chronic alcohol consumption leads to accelerated aging and exacerbation of age-related sequelae, including chronic inflammation and cognitive decline. Therefore, identifying a safe and effective treatment option for older adults with AUD is critical. As older adults tend to have co-morbid health conditions which necessitate being prescribed multiple medications, adding a medication with few drug-drug interactions is paramount. Metadoxine is a medication approved in Europe for the treatment of acute alcohol intoxication as it is able to induce urinary excretion of ethanol from the body. Metadoxine is formed by the salification of pyridoxal (vitamin B6) and pyrrolidone carboxylic acid and has an excellent safety profile. Moreover, metadoxine has been shown to be associated with reduced alcohol craving, improvement on cognitive tests, and decreased inflammation. Preliminary data also suggest that metadoxine may reduce alcohol consumption. However, no studies have evaluated metadoxine safety or efficacy in older adults nor used a cue reactivity paradigm to assess craving. During the K99 phase, we propose a within-subjects, crossover, double-blind, placebo-controlled human laboratory safety and tolerability study in older adults (aged ≥65) with AUD. For the R00, we propose a pilot double-blind, between-subjects, placebo-controlled randomized controlled trial (RCT) in older adults (aged ≥ 65) with AUD. For the pilot RCT we will assess acceptability and feasibility of metadoxine for older adults, evaluate the effect on alcohol craving using an established cue reactivity paradigm, and assess the effect on coginitive function relative to placebo. Additionally, we will obtain data on the efficacy of metadoxine for reducing alcohol consumption and inflammation. The research plan is complemented by an exceptional mentorship team and training plan at the Center for Alcohol and Addiction Studies, School of Public Health, Brown University. The application builds on the applicant’s extensive background in aging and neuroscience and clinical alcohol research by proposing new, focused mentorship in specific methods related to human laboratory studies, clinical trials, gerontological research, and biostatistics with clinical data. The combined research and training plans will prepare the applicant for a successful independent career in clinical alcohol research focused on identifying novel treatments for older adults. This research is aligned with NIAAA’s strategic goals to develop and improve treatments for AUD and alcohol-related consequences and to enhance the public health impact of NIAAA- supported research. This research is urgently needed as the older adult population continues to grow exponentially and prevalence of AUD continues to increase.

项目摘要 这项K99/R00提案检查老年人的新型酒精使用障碍药物治疗（AUD） ≥65）。由于人口以前所未有的速度衰老，酒精是最常用的药物 老年人，老年人口中的AUD正在成为公共卫生和 临床研究。长期饮酒导致与年龄有关的加速衰老和加剧 后遗症，包括慢性炎症和认知能力下降。因此，确定安全有效 老年人使用AUD的治疗选择至关重要。由于老年人倾向于合并健康状况 需要使用多种药物处方，添加几乎没有药物相互作用的药物是 最重要的。元毒素是一种在欧洲批准的药物，用于治疗急性酒精中毒 能够诱导体内乙醇的尿液排泄。元毒素是通过吡啶毒素的盐度形成的 （维生素B6）和吡咯酮羧酸，具有出色的安全性。而且，元毒素已经 证明与降低酒精的渴望，认知测试的改善以及改进有关 炎。初步数据还表明，元毒素可以减少饮酒量。但是，不 研究已经评估了老年人的元毒素安全性或效率，也没有使用提示反应性范式评估 渴望。在K99阶段，我们提出了一个受试者，跨界，双盲，安慰剂对照的人 老年人的实验室安全性和耐受性研究（年龄≥65岁）。对于R00，我们提出了一名飞行员 老年人的双盲，受试者之间，安慰剂对照的随机对照试验（RCT）（≥65岁） 与aud。对于试点RCT，我们将评估老年人元毒素的可接受性和可行性，评估 使用已建立的提示反应性范式对酒精渴望的影响，并评估对coginative的影响 功能相对于安慰剂。此外，我们将获得有关元毒素降低酒精效率的数据 消费和炎症。该研究计划由一个杰出的Mentalship团队完成， 布朗大学公共卫生学院酒精与成瘾研究中心的培训计划。 应用程序建立在该应用程序的广泛衰老，神经科学和临床酒精的背景下 通过在与人类实验室研究有关的特定方法中提出新的，重点的心态，临床 临床数据的试验，老年学研究和生物统计学。联合研究和培训计划将 为申请人准备成功的临床酒精研究独立职业，专注于识别 老年人的新型治疗方法。这项研究与NIAAA的战略目标保持一致，以发展和改进 与AUD和酒精相关后果的治疗方法，并增强NIAAA-的公共卫生影响 支持研究。迫切需要这项研究，因为老年人群体继续增长 AUD的指数和流行率不断增加。