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。项目摘要/摘要 酒精使用障碍（AUD）是一种慢性复发脑疾病，涉及认知障碍， 动力和睡眠。在全球范围内，5％的死亡可归因于饮酒。有紧急 需要测试可以促进长期禁欲，减少酒精渴望并最小化的干预措施 tremor，del妄和失眠等戒断症状。关于大脑能量学的最新观察 建议从AUD中的脑葡萄糖转变为乙酸代谢，这持续超出了急性中毒 状态。在酒精排毒期间，乙酸脑含量降低，可能导致能量缺陷 声明在AUD中有助于神经毒性和退出。生酮饮食（KD；高脂肪，低脂肪 碳氢化物），增加酮体，包括血浆和大脑中的乙酸乙酸酯（即代谢状态 酮症），显示可以改善排毒过程中酒精饮用的啮齿动物的戒断。 对于K99阶段，我们建议在AUD住院患者中进行KD干预研究以测试目标1：是否是否 代谢酮症使用1H磁共振光谱（MRS）增加了大脑中的酮体； 目标2：代谢酮症对戒断症状，​​渴望，睡眠的潜在有益影响 酒精解毒期间的质量。为此，我们将50个AUD住所随机分为KD（n = 25）或 美国标准饮食（n = 25）3周。患者将每周进行扫描MRS扫描以量化大脑 酮体；和多个测量睡眠质量。我们假设：（1）我们将能够 用MRS量化KD的AUD患者的大脑中的酮体； （2）KD减少了退出和 渴望AUD患者，并提高睡眠质量。 对于R00阶段，我们提出了1剂营养酮酯（KE）干预，并随机2向 在非治疗中寻求AUD门诊患者（n = 15）测试目标3的跨界设计3：是否代谢 酮症减少饮酒。 KE是一种安全的，无创的方法，可提高酮水平 在1小时内，浓度类似于KD，并且水平保持4小时。奥德门诊患者喝酒 用KE或等量水力葡萄糖。酮体在血液和大脑（MRS）中测量，之后。 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 行政。预计KE将减少酒精摄入量，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作用，例如 提取，渴望酒精，睡眠或饮酒，然后KD或KE可以作为目标 治疗干预措施以增强AUD恢复的成功。 K99培训建议进一步旨在为PI Corinde Wiers博士提供足够的研究 培训和技能从受过指导的博士后奖学金过渡到独立的终身制 研究职位。 Wiers博士将获得夫人，睡眠多个术语和 生物统计学。她将通过OETE的课程和通过 在NIH，大学和会议上进行讲座和会谈。为了实现这些目标，威尔斯博士拥有 与NIAAA和美国大学的专家科学家提出了一个心理团队：Nora Volkow博士 （NIAAA），托马斯·恩斯特（Thomas Ernst）（马里兰大学）和彼得·摩根（Peter Morgan）博士（耶鲁大学）。