Ketone ester intervention in alcohol use disorder

酮酯干预酒精使用障碍

• 批准号: 10267748
• 负责人: Corinde E Wiers
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-25 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10267748
• 关键词: Abstinence; Acetates; Acetoacetates; Acetone; Acute; Affect; Agitation; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; American; American diet; Biometry; Blood; Body measure procedure; Brain; Brain Diseases; Carbohydrates; Cessation of life; Chronic; Clinical Trials; Cognition; Competence; Consumption; Crossover Design; Delirium; Desire for food; Diagnosis; Dietary Intervention; Distress; Dose; Drug Metabolic Detoxication; Educational process of instructing; Electroencephalography; Epilepsy; Esters; Fatty acid glycerol esters; Fellowship; Glucose; Goals; Hour; Human; Impairment; Individual; Inpatients; Intervention; Intervention Studies; Intoxication; Ketone Bodies; Ketones; Ketosis; Knowledge; Leadership; Life; Magnetic Resonance Spectroscopy; Maryland; Measures; Mediating; Mentors; Metabolic; Metabolism; Methods; Mission; Motivation; National Institute on Alcohol Abuse and Alcoholism; Nutritional; Outpatients; Participant; Patients; Peripheral; Phase; Plasma; Polysomnography; Positioning Attribute; Positron-Emission Tomography; Public Health; Randomized; Rattus; Recovery; Relapse; Reporting; Research; Research Training; Risk Factors; Rodent; Role; Scanning; Scientist; Seizures; Self Administration; Serum; Sleep; Sleep disturbances; Sleeplessness; Symptoms; Taste Perception; Testing; Therapeutic; Therapeutic Intervention; Training; Tremor; United States National Institutes of Health; Universities; Urine; Withdrawal; Withdrawal Symptom; alcohol craving; alcohol cue; alcohol seeking behavior; alcohol use disorder; alcoholism prevention; beta-Hydroxybutyrate; chronic alcohol ingestion; clinical effect; craving; deter alcohol use; drinking behavior; ghrelin; glucose metabolism; healthy volunteer; improved; ketogenic diet; lectures; neurotoxicity; novel; peripheral blood; preclinical study; recruit; side effect; skills; sleep quality; sleep regulation; sobriety; soft drink; standard measure; success; symposium; tenure track

07. PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is a chronic relapsing brain disorder that involves impairments in cognition, motivation and sleep. Globally, 5% of deaths can be attributed to alcohol consumption. There is an urgent need to test interventions that can promote long-term abstinence, reduce alcohol craving, and minimize withdrawal symptoms such as tremor, delirium and insomnia. Recent observations on brain energetics suggest a shift from brain glucose to acetate metabolism in AUD that persists beyond the acute intoxication state. During alcohol detoxification, brain acetate levels decrease, potentially leading to an energy-deficit state that contributes to neurotoxicity and withdrawal in AUD. A ketogenic diet (KD; high fat, low carbohydrate), increases ketone bodies including acetoacetate in plasma and brain (i.e., state of metabolic ketosis), which was shown to improve withdrawal in alcohol-drinking rodents during detoxification. For the K99 phase we propose a KD intervention study in AUD inpatients to test Aim 1: whether metabolic ketosis increases ketone bodies in the brain using 1H Magnetic Resonance Spectroscopy (MRS); Aim 2: the potential beneficial effects of metabolic ketosis on withdrawal symptoms, alcohol craving, sleep quality during alcohol detoxification. To this end, we randomize 50 AUD inpatients into a KD (n=25) or Standard American diet (n=25) for 3 weeks. Patients will undergo weekly MRS scans to quantify brain ketone bodies; and polysomnography to measure sleep quality. We hypothesize that: (1) we will be able to quantify ketone bodies in the brains of AUD patients on KD with MRS; (2) KD reduces withdrawal and craving in AUD patients, and improves sleep quality. For the R00 phase, we propose a 1-dose nutritional ketone ester (KE) intervention with a random 2-way crossover design in non-treatment seeking AUD outpatients (n=15) to test Aim 3: whether metabolic ketosis decreases alcohol consumption. KE is a safe, non-invasive method that increases ketone levels within 1 hr to concentrations similar to KD, and levels remain for 4 hrs. AUD outpatients consume a drink with either KE or isocaloric dextrose. Ketone bodies are measured in blood and brain (MRS), after which. participants perform a drink “taste test” including alcohol and soft drinks to measure alcohol self- administration. KE is expected to decrease alcohol intake, craving, and increase brain ketone bodies. If beneficial clinical effects of metabolic ketosis can be documented in human AUD patients, e.g., on withdrawal, alcohol craving, sleep or alcohol consumption, then KD or KE could be targeted as a therapeutic intervention to enhance success in recovery from AUD. The K99 training proposal further aims to provide the PI Dr. Corinde Wiers with adequate research training and skills to transition from a mentored postdoctoral fellowship to an independent tenure-track research position. Dr. Wiers will gain technical competence on MRS, sleep polysomnography and biostatistics. She will further enhance her leadership and teaching skills via courses at the OITE and by giving lectures and talks at NIH, at universities and conferences. To accomplish these goals, Dr. Wiers has proposed a mentoring team with expert scientists from NIAAA and US universities: Dr. Nora Volkow (NIAAA), Dr. Thomas Ernst (University of Maryland), and Dr. Peter Morgan (Yale).

07. 项目概要/摘要 酒精使用障碍 (AUD) 是一种慢性复发性脑部疾病，涉及认知障碍、 在全球范围内，5% 的死亡可归因于饮酒。 需要测试能够促进长期戒酒、减少对酒精的渴望并最大限度地减少饮酒的干预措施 戒断症状如震颤、谵妄和失眠等最近对大脑能量学的观察。 表明 AUD 中的脑葡萄糖代谢转变为醋酸盐代谢，这种转变在急性中毒后仍持续存在 在酒精解毒过程中，大脑醋酸盐水平下降，可能导致能量不足。 导致 AUD 中神经毒性和戒断的状态 生酮饮食（KD；高脂肪、低脂肪） 碳水化合物），增加血浆和大脑中的酮体，包括乙酰乙酸（即代谢状态 酮症），这被证明可以改善饮酒啮齿动物在解毒过程中的戒断反应。 对于 K99 阶段，我们建议对 AUD 住院患者进行 KD 干预研究，以测试目标 1：是否 代谢酮症使用 1H 磁共振波谱 (MRS) 增加大脑中的酮体； 目标 2：代谢酮症对戒断症状、酒精渴望、睡眠的潜在有益影响 为此，我们将 50 名澳元住院患者随机分为 KD（n=25）或 标准美国饮食 (n=25) 持续 3 周，患者将每周接受 MRS 扫描以量化大脑。 我们发现：（1）我们将能够测量睡眠质量。 使用 MRS 量化接受 KD 的 AUD 患者大脑中的酮体 (2) KD 减少戒断症状； 减少 AUD 患者的渴望，并改善睡眠质量。 对于 R00 阶段，我们建议采用 1 剂营养酮酯 (KE) 干预，并采用随机 2 路 在寻求 AUD 的非治疗门诊患者 (n=15) 中进行交叉设计，以测试目标 3：是否代谢 酮症可减少饮酒量，是一种安全、非侵入性的方法，可增加酮水平。 澳元门诊病人喝一杯 然后用 KE 或等热量葡萄糖测量血液和脑中的酮体。 参与者进行饮料“味觉测试”，包括酒精和软饮料，以测量酒精自我 KE 有望减少酒精摄入量、渴望并增加脑酮体。 如果可以在人类 AUD 患者中记录代谢酮症的有益临床效果，例如， 戒断、对酒精的渴望、睡眠或饮酒，那么 KD 或 KE 可以作为目标 治疗干预以提高 AUD 康复的成功率。 K99 培训计划进一步旨在为 PI 博士 Corinde Wiers 提供充分的研究 从指导博士后奖学金过渡到独立终身教授的培训和技能 Wiers 博士将获得 MRS、睡眠多导睡眠图和睡眠监测方面的技术能力。 她将通过 OITE 的课程和通过生物统计学进一步提高她的领导能力和教学技能。 为了实现这些目标，Wiers 博士在 NIH、大学和会议上发表演讲和演讲。 提议组建一个由 NIAAA 和美国大学的专家科学家组成的指导团队：Nora Volkow 博士 （NIAAA）、Thomas Ernst 博士（马里兰大学）和 Peter Morgan 博士（耶鲁大学）。