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.

项目概要 该 K99/R00 提案研究了一种针对老年人（老年）酒精使用障碍 (AUD) 的新型药物疗法 随着人口以前所未有的速度老龄化，酒精成为其中最常用的药物。 老年人口中的澳元在公共卫生和健康领域日益重要 临床研究表明，长期饮酒会加速衰老并加剧与年龄相关的症状。 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方法。 患有 AUD 的老年人的治疗选择至关重要，因为老年人往往患有共病。 需要开多种药物，添加一种药物相互作用很少的药物是 美他多辛是欧洲批准用于治疗急性酒精中毒的药物。 能够诱导体内乙醇从尿中排泄，由吡哆醛成盐形成。 （维生素 B6）和吡咯烷酮羧酸，而且美他多辛具有出色的安全性。 研究表明，与减少对酒精的渴望、改善认知测试以及减少酒精摄入有关。 初步数据还表明美他多辛可以减少饮酒量，但事实并非如此。 研究评估了美他多辛对老年人的安全性或有效性，也没有使用提示反应范式来评估 在 K99 阶段，我们提出了一个受试者内、交叉、双盲、安慰剂对照的人类。 对于 R00，我们建议开展一项针对老年人（≥65 岁）的实验室安全性和耐受性研究。 针对老年人（年龄 ≥ 65 岁）的双盲、受试者间安慰剂对照随机对照试验 (RCT) 对于试点随机对照试验，我们将评估美他多辛对老年人的可接受性和可行性，并评估 使用已建立的线索反应范式对酒精渴望的影响，并评估对认知的影响 相对于安慰剂的功能，我们还将获得有关美他多辛减少酒精功效的数据。 该研究计划得到了优秀的指导团队和 布朗大学公共卫生学院酒精和成瘾研究中心的培训计划。 申请建立在申请人在衰老、神经科学和临床酒精方面的广泛背景之上 通过在与人类实验室研究、临床研究相关的特定方法中提出新的、有针对性的指导来进行研究 试验、老年学研究以及临床数据的生物统计学将结合研究和培训计划。 为申请人在临床酒精研究领域取得成功的独立职业生涯做好准备，重点是识别 这项研究与 NIAAA 开发和改进的战略目标一致。 治疗 AUD 和酒精相关后果，并增强 NIAAA- 的公共卫生影响 随着老年人口的持续增长，迫切需要这项研究。 呈指数级增长，AUD 的患病率持续增加。