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.
|Whitmire, David; Tedder, James; Craig, Seth et al. (2008) The effect of an amethystic product on ethanol in humans. Drug Metabol Drug Interact 23:283-90|
|Whitmire, David; Cornelius, Larry; Whitmire, Paula (2005) Short-term metabolic ethanol tolerance in dogs. Drug Metabol Drug Interact 21:87-98|
|Whitmire, David; Cornelius, Larry; Whitmire, Paula (2002) Effects of food on ethanol metabolism. Drug Metabol Drug Interact 19:83-96|
|Whitmire, David; Cornelius, Larry; Whitmire, Paula (2002) Monte Carlo simulation of an ethanol pharmacokinetic model. Alcohol Clin Exp Res 26:1484-93|
|Whitmire, D; Cornelius, L M; Whitmire, P S (1996) Pharmacodynamic response to Ro15-4513 in ethanol intoxicated dogs. Drug Metabol Drug Interact 13:99-109|
|Whitmire, D; Whitmire, P S (1995) Analysis of ethanol and acetaldehyde recovery from perchloric acid-treated blood. Alcohol Alcohol 30:623-8|
|Whitmire, D; Bowen, J P; Shim, J Y et al. (1995) Computational modeling of a putative fetal alcohol syndrome mechanism. Alcohol Clin Exp Res 19:1587-93|
|Whitmire, D R; Chambers, R P; Dillon, A R (1991) Multi-enzyme catalyzed rapid ethanol lowering in vitro. Alcohol Clin Exp Res 15:804-7|