Catherine Bomont

Post-Ischemic Treatment with Dipyruvyl-Acetyl-Glycerol Decreases Myocardial Infarct Size in the Pig

The beneficial effects of pyruvate in organ reperfusion injury have been documented, however the therapeutic use of pyruvate has been hindered by the lack of an appropriate delivery method. Pyruvic acid is unstable and high rates of sodium pyruvate infusion are toxic. Dipyruvyl-acetyl-glycerol (DPAG) ester was developed as a novel method for intravenous pyruvate delivery at a high rate without sodium overload. We tested the ability of DPAG to reduce myocardial infarct size when administered after severe myocardial ischemia in an anesthetized open-chest pig model of ischemia-reperfusion injury. Ischemia was induced by total occlusion of the distal 2/3 of the left anterior descending coronary artery for one hour, followed by two hours of reperfusion. Animals were either untreated (n = 7), or treated with intravenous DPAG (8.0 mg/kg−1 · min−1, n = 8) during the two hours of reperfusion. Infarct size was measured on blinded samples using tetrazolium staining. The DPAG treated group had elevated pyruvate levels (0.82 ± 0.07 mM) and reduced infarct size (20.1 ± 4.2% of the volume at risk, compared to 30.8 ± 4.6% in the untreated animals (p < 0.05)), with no difference in blood pressure or heart rate between groups. In conclusion, an intravenous infusion of DPAG safely increases arterial pyruvate concentration and reduces myocardial infarct size following myocardial ischemia.

Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate.

A high-fat, almost carbohydrate-free diet is used in children with intractable epilepsy to help control seizures by inducing a permanent state of ketosis. Esters of ketone bodies have been previously studied for their potential as parenteral and enteral nutrients. We tested in conscious dogs whether ketosis could be induced by repeated ingestion of R,S-1,3-butanediol diacetoacetate with or without carbohydrates. This ester is a water-soluble precursor of ketone bodies. Two constraints were imposed on this preclinical study: The rate of ester administration was limited to one half of the daily caloric requirement and to one half of the capacity of the liver to oxidize butanediol derived from ester hydrolysis. Under these conditions, the level of ketosis achieved in this dog model (0.8 mM) was lower than the level measured in children whose seizures were controlled by the ketogenic diet (1-3 mM). However, because humans may have a lower capacity for ketone body utilization than dogs, the doses of R,S-butanediol diacetoacetate used in the present study might induce higher average ketone body concentrations in humans than in dogs.

R,S-1,3-butanediol acetoacetate esters, potential alternates to lipid emulsions for total parenteral nutrition

Abstract We present the preparation and characterization of totally and partially water-soluble forms of fat which could replace emulsions of long-chain triacylglycerols for total parenteral nutrition. R,S-1,3-butanediol acetoacetate monoesters and diester represent pH-neutral, sodium-free, diffusible precursors of ketone bodies. The latter are water-soluble forms of fat that are well used by peripheral tissues except in prolonged starvation and diabetic ketoacidosis. The esters are rapidly hydrolyzed by plasma and tissue esterases. R,S-1,3-butanediol liberated is oxidized in liver to R,S-β-hydroxybutyrate. Reducing equivalents generated during this oxidation are trapped in the conversion of acetoacetate to R-β-hydroxybutyrate. So both the carbon and the hydrogen of the esters are exported from the liver to peripheral tissues in the form of R- + S-β-hydroxybutyrate. Thus, contrary to what occurs after administration of ethanol or R,S-1,3-butanediol alone, administration of the R,S-1,3-butanediol acetoacetate esters does not lead to major shifts in the livers [NADH] [NAD + ] ratio. Such shifts are responsible for the toxic effects of ethanol on the liver. It is therefore likely that long-term administration of the R,S-1,3-butanediol acetoacetate esters will not lead to liver toxicity.