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.

目前尚未开发出任何方法来对抗摄入乙醇的影响 在人身上。我们之前的研究表明，外源衍生的 将多酶系统注入犬的胃肠道中 能够将乙醇从体内总水转化为乙酸盐， 从而降低血液中的乙醇浓度。拟议的研究 将继续当前的工作并扩大使用的研究范围 体内外源酶系统可降低乙醇水平 实验动物。拟议的研究基于以下假设： “降低人体乙醇含量可以对抗不良健康 乙醇的影响。动物体内的乙醇可以通过以下方法消除： 胃肠道中的外源酶系统 将乙醇转化为乙酸盐。基于这一假设，长期目标 这项研究的目的是开发一种基于酶的生物制药 临床上可用于急剧降低乙醇的制剂 人的水平。研究的直接目标和方法 实现这些目标分为四个具体目标。 具体目标 1. 研究的最初目标是开发 乙醇剂量方案，为乙醇降低实验做准备。 具体目标 1 将 (1) 详细阐述前面的意义 实验药代动力学，并且（2）提供了完善的机会 使用顶空气相色谱法进行代谢物分析。 具体目标 2. 该目标将建立剂量-反应关系 酶制剂和狗体内乙醇降低之间的关系。的影响 酶制剂的乙醇达到峰值浓度、时间 峰值，血液乙醇-时间曲线下面积 (AUC) 将为 研究过。多酶制剂的用途还有待研究。这 使用酶制剂降低饲喂乙醇的效果 - 与禁食的狗也将成为该特定研究的一个主题 目标。 具体目标 3. 目标 3 的目标是优化酶 关于乙醇降低功效的制剂。拟进行的研究 完成的中心是评估对多方活动的影响 乙烯醋酸乙烯酯微胶囊中含有的酶系统。 具体目标 4. 摄入乙醇可导致酒精性肝病 （ALD）在人类中，以及在人类和人类中 IgA 沉积的连续模式 兔子有酗酒的特征。具体目标 4 将探索 通过多酶制剂每日降低乙醇的效果， 乙醇喂养的兔子肝脏中 IgA 沉积的模式。这 IgA 沉积的连续模式已被证明是一个指标 酒精性肝病。