A Novel Pharmacotherapy for Alcoholism and Alcohol Liver Disease

治疗酒精中毒和酒精性肝病的新型药物疗法

• 批准号: 8277663
• 负责人: GEORGE A. KENNA
• 金额: $ 20.38万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277663
• 关键词: Abstinence; Accounting; Acetaldehyde; Acute; Adenosine Triphosphate; Adverse event; Albumins; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcoholism; Alcohols; Back; Bilirubin; Biological Markers; Cessation of life; Chronic; Cirrhosis; Clinical Trials Design; Commit; Country; Development; Diagnosis; Disulfiram; Double-Blind Method; Europe; European; Free Radicals; Frequencies; Glutathione; Goals; Grant; Health Care Costs; Hepatic; Hepatotoxicity; Histology; Hour; Individual; Institutes; Lead; Liver; Liver Cirrhosis; Liver diseases; Measures; Medical; Metabolism; Mission; Morbidity - disease rate; Naltrexone; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Public Health; Quality of life; Questionnaires; Randomized; Randomized Clinical Trials; Recovery; Recruitment Activity; Research Design; Risk; Role; Staging; Testing; Therapeutic Intervention; Time; TimeLine; United States; United States Food and Drug Administration; Work; alcohol abstinence; alcohol abuse therapy; alcohol craving; alcohol use disorder; alcoholism pharmacotherapy; alcoholism therapy; drinking; effective therapy; experience; follow-up; improved; innovation; liver function; mortality; novel; outcome forecast; placebo controlled study; problem drinker; psychosocial; satisfaction; success; trafficking

DESCRIPTION (provided by applicant): Alcohol use disorders in the United States (US) account for about 1 death every 5 minutes including 32% of all traffic fatalities, an average of one fatality related to alcohol every 39 minutes. Alcohol liver disease (ALD) is often present in alcohol dependent (AD) patients. Treatments for ALD have limited success when drinking continues. Cessation of alcohol consumption or a significant reduction in alcohol intake improves histology and survival of patients with any stage of ALD. While alcohol abstinence may not be sufficient to provide a total recovery of ALD, patients with uncomplicated ALD have a 5-year survival of almost 90% if they stop drinking. Consequently, abstinence is the most important therapeutic intervention for patients with ALD. When combined with psychosocial treatments, currently approved medications can improve outcomes for some AD individuals; however, these treatments are unsuccessful for many others. One of the limiting factors that must be taken into consideration when using currently approved medications such as disulfiram or naltrexone is liver function. Given their hepatic metabolism, disulfiram or naltrexone both increase the risk of hepatotoxicity in AD individuals. Therefore, a pharmacotherapy that is effective for AD, that is safe for the liver and able to recover alcohol-related liver damage thereby improving liver function, would be an ideal medication. However as of now, no drug has been found to provide all of these benefits to AD individuals. We propose therefore to test metadoxine (MTDX) that we hypothesize is significantly beneficial for the treatment of alcoholism and ALD. Metadoxine is currently approved in Europe for acute and chronic alcohol intoxication but has never been tested in the US. Furthermore, MTDX is used in Europe to treat ALD. Our group and others have shown preliminary evidence that MTDX reduces alcohol consumption in AD individuals. If the role of MTDX in reducing alcohol consumption and improve liver function is confirmed by a rigorous study design, then MTDX might represent a truly innovative pharmacotherapy for AD, given the potential to be used for AD individuals with ALD. However until this proposal, MTDX has never been investigated as a treatment for AD able to reduce both alcohol consumption and improve alcohol-related liver damage via a double-blind placebo- controlled study. This project therefore proposes to conduct a 12-week (followed by a 3-month follow-up), double-blind, placebo-controlled, between-subject randomized clinical trial with MTDX (500mg t.i.d.) in AD individuals. This project will randomize 83 AD individuals who also have a diagnosis of ALD. Given our previous experience in using MTDX, we propose this innovative R21 grant to explore MTDX's efficacy in reducing or stopping alcohol consumption in AD individuals with evidence of alcohol-related liver damage. Our long-term goal is to provide the first safe and effective treatment option for both AD and ALD. PUBLIC HEALTH RELEVANCE: Alcohol use disorders account for 100,000 excess deaths per year and causes serious morbidity and mortality, increased health care costs and lost work hours. Thus, there exists a substantial need for discovering new, more effective treatments for alcohol use disorders. Furthermore, alcohol liver disease (ALD) represents a significant medical problem often present in individuals with alcohol dependence (AD). This project proposes testing a novel pharmacotherapy, metadoxine, as a medication potentially effective in treating both AD and ALD. Better characterization of this pharmacological approach, by studying the medication metadoxine, may lead to a novel pharmacotherapy able to simultaneously treat AD and ALD.

描述（由申请人提供）：在美国，酒精使用障碍每 5 分钟约造成 1 人死亡，其中占所有交通死亡人数的 32%，平均每 39 分钟就有 1 人与酒精相关死亡。酒精性肝病 (ALD) 常见于酒精依赖 (AD) 患者。如果继续饮酒，酒精性肝病的治疗效果有限。停止饮酒或显着减少酒精摄入量可以改善任何阶段 ALD 患者的组织学和生存率。虽然戒酒可能不足以使 ALD 完全康复，但无并发症的 ALD 患者如果停止饮酒，其 5 年生存率接近 90%。因此，戒酒是 ALD 患者最重要的治疗干预措施。当与社会心理治疗相结合时，目前批准的药物可以改善某些 AD 患者的预后；然而，这些治疗对于许多其他人来说并不成功。使用目前批准的药物（例如双硫仑或纳曲酮）时必须考虑的限制因素之一是肝功能。鉴于其肝脏代谢，双硫仑或纳曲酮都会增加 AD 个体发生肝毒性的风险。因此，一种对AD有效、对肝脏安全、能够恢复酒精相关肝损伤从而改善肝功能的药物疗法将是一种理想的药物治疗。然而到目前为止，还没有发现任何药物可以为 AD 患者提供所有这些益处。因此，我们建议测试美他多辛 (MTDX)，我们假设它对治疗酒精中毒和 ALD 非常有益。美他多辛目前在欧洲被批准用于治疗急性和慢性酒精中毒，但从未在美国进行过测试。此外，MTDX 在欧洲用于治疗 ALD。我们的小组和其他人已经显示出初步证据表明 MTDX 可以减少 AD 个体的饮酒量。如果严格的研究设计证实了 MTDX 在减少饮酒和改善肝功能方面的作用，那么 MTDX 可能代表一种真正创新的 AD 药物疗法，因为它有可能用于患有 ALD 的 AD 个体。然而，在此提议之前，MTDX 从未被研究为 AD 治疗方法，能够通过双盲安慰剂对照研究减少饮酒量并改善酒精相关的肝损伤。因此，该项目建议在 AD 个体中进行为期 12 周（随后为期 3 个月的随访）、双盲、安慰剂对照、受试者间随机临床试验，使用 MTDX（500mg tid）。该项目将随机抽取 83 名同样诊断为 ALD 的 AD 个体。鉴于我们之前使用 MTDX 的经验，我们提出这项创新的 R21 资助，以探索 MTDX 在有酒精相关肝损伤证据的 AD 个体中减少或停止饮酒的功效。我们的长期目标是为 AD 和 ALD 提供第一个安全有效的治疗选择。 公共卫生相关性：酒精使用障碍每年导致 100,000 人超额死亡，并导致严重的发病率和死亡率、医疗保健费用增加和工作时间损失。因此，迫切需要发现新的、更有效的酒精使用障碍治疗方法。此外，酒精肝病（ALD）代表了酒精依赖（AD）个体中经常出现的严重医疗问题。该项目建议测试一种新的药物疗法——美他多辛，作为一种可能有效治疗 AD 和 ALD 的药物。通过研究美他多辛药物，更好地表征这种药理学方法，可能会产生一种能够同时治疗 AD 和 ALD 的新型药物疗法。