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: 10704742
• 负责人: Samantha Portis
• 金额: $ 11.93万
• 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/10704742
• 关键词: Abstinence; Acceleration; Acute; Adverse event; Age; Aging; Alcohol consumption; Alcoholic Intoxication; Alcoholic Liver Diseases; Alcohols; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; 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; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1 beta; Intoxication; Laboratories; Laboratory Study; 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; 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; efficacy evaluation; fatty liver disease; human old age (65+); improved; mouse model; novel; pre-clinical assessment; public health research; safety testing; satisfaction; tissue repair; urinary; verbal

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 本K99/R 00提案研究了一种治疗老年人酒精使用障碍（AUD）的新型药物疗法（年龄 ≥65）。随着人口以前所未有的速度老龄化，酒精是最常用的药物， 在老年人中，AUD在老年人人群中正成为公共卫生中越来越重要的领域， 临床研究长期饮酒会加速衰老，加剧与年龄相关的 后遗症，包括慢性炎症和认知能力下降。因此，确定一种安全有效的 患有AUD的老年人的治疗选择至关重要。由于老年人往往有共同的健康状况 这需要开多种药物，增加一种药物与药物之间的相互作用很少， 至高无上。二甲双胍是欧洲批准用于治疗急性酒精中毒的药物， 能够诱导体内乙醇的尿排泄。美托洛尔是由吡哆醛成盐形成的 （维生素B6）和吡咯烷酮羧酸，并且具有优异的安全性。此外，二甲双胍已被 显示与减少酒精渴望，改善认知测试， 炎症初步数据还表明，二甲双胍可能会减少饮酒量。但没有 已有研究评估了美托洛尔在老年人中的安全性或有效性， 渴望在K99阶段，我们提出了一个受试者内，交叉，双盲，安慰剂对照的人 在患有AUD的老年人（年龄≥65岁）中进行的实验室安全性和耐受性研究。对于R 00，我们提出了一个试点 在老年人（年龄≥ 65岁）中进行的双盲、受试者间、安慰剂对照、随机对照试验（RCT） 关于AUD对于试点RCT，我们将评估二甲双胍对老年人的可接受性和可行性， 使用已建立的线索反应范式对酒精渴求的影响，并评估对认知能力的影响。 相对于安慰剂的功能。此外，我们将获得关于二甲双胍减少酒精的疗效的数据。 消耗和炎症。该研究计划是由一个特殊的导师团队补充， 布朗大学公共卫生学院酒精和成瘾研究中心的培训计划。的 申请建立在申请人在老龄化和神经科学和临床酒精广泛的背景 通过提出新的，重点指导与人类实验室研究，临床 试验、老年学研究和具有临床数据的生物统计学。研究和培训计划将 准备申请人在临床酒精研究中成功的独立职业生涯，重点是识别 老年人的新疗法。这项研究与NIAAA的战略目标是一致的，以发展和改善 治疗AUD和酒精相关后果，并加强NIAAA的公共卫生影响- 支持研究。随着老年人口的持续增长，迫切需要进行这项研究 呈指数增长，AUD的患病率继续增加。