RAPID ETHANOL LOWERING: A BIOENGINEERING APPROACH

快速降低乙醇：生物工程方法

• 批准号: 3452848
• 负责人: DAVID R WHITMIRE
• 金额: $ 10.29万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-29 至 1994-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3452848
• 关键词: acetaldehyde; acetates; alcoholic fatty liver; alcoholic hepatitis; alcoholic liver cirrhosis; alcoholism /alcohol abuse; alcoholism antagonist; bioengineering /biomedical engineering; blood chemistry; chromatography; computer simulation; dogs; drug metabolism; drug vehicle; enzyme mechanism; immunoglobulin A; implant; laboratory rabbit; lactates; mathematical model; methanol poisoning; model design /development; pharmacokinetics; protein engineering; synthetic enzyme

No method has been developed to counter the effects of ingested ethanol in man. Our previous studies have shown that an exogenously derived multi-enzyme system instilled into the gastrointestinal tract of dogs is capable of converting ethanol from the total body water to acetate, thereby lowering the blood ethanol concentration. The proposed studies will continue the current work and expand the scope of research on using exogenously derived enzyme systems in vivo to lower ethanol levels in experimental animals. the proposed research is based on the hypothesis: "Reduction of ethanol levels in man can counter the untoward health effects of ethanol. Ethanol can be eliminated in animals by using exogenously derived enzyme systems in the gastrointestinal tract to convert ethanol to acetate. Based on this hypothesis, the long term goal of this research is to develop an enzyme based biopharmaceutical preparation that will be clinically useful for acutely lowering ethanol levels in man. The immediate goals of the research and he methods to achieve these goals are dived into four specific aims. Specific Aim 1. The initial objective of the research is to develop ethanol dosing protocols to prepare for the ethanol lowering experiments. Specific Aim 1 will (1) elaborate the significance of the previous experimental pharmacokinetics, and (2) provide an opportunity to refine metabolite analysis capabilities using head-space gas chromatography. Specific Aim 2. This aim will establish a dose-response relationship between the enzyme preparation and ethanol lowering in dogs. Effects of the enzyme preparation of the ethanol peak concentration, time of the peak, and the Area Under the Blood Ethanol-Time curve (AUC) will be studied. Also to be studied use of the multi-enzyme preparation. The effects of using the enzyme preparation for ethanol lowering with fed - vs- fasted dogs will also be a subject of study within this specific aims. Specific Aim 3. The objective of Aim 3 is to optimize the enzyme preparation with respect to ethanol lowering efficacy. The studies to be done center about evaluation of the effect on the activity of the multi- enzyme system contained in ethylene vinyl acetate microcapsules. Specific Aim 4. Ethanol ingestion can lead to alcoholic liver disease (ALD) in man, and a continuous pattern of IgA deposition in man and rabbits characteristic of alcohol abuse. Specific Aim 4 will explore the effects of daily ethanol lowering by the multi-enzyme preparation, on the pattern of IgA deposition in the livers of ethanol fed rabbits. The continuous patterns of IgA deposition has been shown to be an indicator of ALD.

尚未开发任何方法来应对摄入的乙醇的影响 在男人。我们以前的研究表明，外源得出 灌输到狗的胃肠道中的多酶系统是 能够将乙醇从总体水转换为乙酸盐， 从而降低血液乙醇浓度。提出的研究 将继续进行当前的工作，并扩大有关使用的研究范围 体内的外源衍生的酶系统降低乙醇水平 实验动物。拟议的研究基于以下假设： “人类中乙醇水平的降低可以抵抗不利的健康 乙醇的作用。可以通过使用动物消除乙醇 胃肠道中的外源衍生的酶系统 将乙醇转换为乙酸。基于这个假设，长期目标 这项研究的是开发基于酶的生物药物 在临床上可用于急性降低乙醇的准备工作 人的水平。研究的直接目标和他的方法 实现这些目标将跳入四个特定目标。 具体目的1。研究的最初目的是开发 乙醇给药方案以准备降低乙醇的实验。 特定目标1将（1）阐述以前的意义 实验性药代动力学，（2）提供了完善的机会 使用头空气相色谱法代谢物分析能力。 具体目标2。此目标将建立剂量反应关系 在狗的酶制剂和狗的降低之间。效果 乙醇峰浓度的酶制备， 峰值，血液乙醇时曲线（AUC）下的面积将为 研究。还可以研究多酶制剂的使用。这 使用酶制剂来降低乙醇的影响 - VS禁食的狗也将是该特定的研究主题 目标。 特定目标3。目标3的目的是优化酶 在降低乙醇方面的准备。研究是 关于评估对多种活动的影响的中心 乙酸乙烯酯微胶囊中包含的酶系统。 特定目的4。乙醇摄入会导致酒精性肝病 （ALD）人类，以及人类和 兔子滥用酒精的特征。特定目标4将探索 通过多酶制剂降低乙醇的影响，对 乙醇喂养兔子的IgA沉积模式。这 IGA沉积的连续模式已被证明是一个指标 Ald。