Pyruvate ester composition and method of use for resuscitation after events of ischemia and reperfusion

Abstract

A therapeutic composition comprising an alkyl, aralkyl, alkoxyalkyl or carboxyalkyl ester of 2ketoalkanoic acid and a component for inducing and stabilizing the enol resonance form of the ester at physiological pH values is disclosed. The composition of the invention further comprises a pharmaceutically acceptable carier vehicle in which the enol resonance form of the ester is stabilized at physiological pH values. Formulations containing the compositions of the invention permit the successful use of 2-ketoalkanoic acid esters, e.g., pyruvic acid esters, to treat, e.g., is chemic events, shock, organ reanimation, resuscitation and other recognized pyruvate-effective treatments. The compositions of the inventions are also useful in a process for preserving organ parts, organs or limbs removed from a living mammal and in need of preservation, e.g., for later transplantation to an organ recipient.

1 . A method for treating a mammal suffering from a condition characterized by ischemia or reperfusion injury, comprising administering to said mammal a therapeutically effective amount of a composition comprising an ester of a 2-ketoalkanoic acid selected from the group consisting of alkyl, aralkyl, alkoxyalkyl and carboxyalkyl ester in a pharmaceutically-acceptable carrier, wherein said carrier further comprises a biologically safe component for inducing and stabilizing enolization of the 2-keto functionality of said ester at physiological pH values.  
     
     
         2 . The method of  claim 1 , wherein said pharmaceutically-acceptable carrier is a Ringer's solution of isotonic saline supplemented with potassium ion.  
     
     
         3 . The method of  claim 1 , wherein said 2-ketoalkanoic acid ester is selected from the group consisting of ethyl pyruvate, propyl pyruvate, butyl pyruvate, carboxymethylpyruvate, acetoxymethylpyruvate, carbethoxymethylpyruvate and ethoxymethylpyruvate.  
     
     
         4 . The method of  claim 1 , wherein said 2-ketoalkanoic acid ester is selected from the group consisting of ethyl 2-keto-buyrate, ethyl 2-ketopentanoate, ethyl 2-keto-3-methyl-butyrate, ethyl 2-keto-4-methyl-pentanoate and ethyl 2-keto-hexanoate.  
     
     
         5 . The method of  claim 3 , wherein said 2-ketoalkanoic acid ester is admixed in a saline solution, said solution containing a cation selected from the group consisting of calcium and magnesium.  
     
     
         6 . The method of  claim 4 , wherein said 2-ketoalkanoic acid ester is admixed in a saline solution, said solution containing a cation selected from the group consisting of calcium and magnesium.  
     
     
         7 . The method of  claim 1 , wherein the condition characterized by ischemia is selected from the group consisting of mesenteric ischemia, mesenteric thrombus, mesenteric venous occlusion, aortic aneurism repair, coronary artery bypass and surgical treatment of arterial occlusion of limbs.  
     
     
         8 . A process for preserving organ parts, organs or limbs removed from a living mammal, said process comprising perfusing said organ or limb with a solution containing an effective amount of a composition comprising an ester of a 2-ketoalkanoic acid selected from the group consisting of alkyl, aralkyl, alkoxyalkyl and carboxyalkyl ester in a pharmaceutically-acceptable carrier, said carrier further comprising a biologically safe component for inducing and stabilizing enolization of the 2-keto functionality of said ester at physiological pH values.  
     
     
         9 . The process of  claim 8 , wherein said 2-ketoalkanoic acid ester is selected from the group consisting of ethyl pyruvate, propyl pyruvate, butyl pyruvate, carboxymethylpyruvate, acetoxymethylpyruvate, carbethoxymethylpyruvate and ethoxymethylpyruvate.  
     
     
         10 . The process of  claim 8 , wherein said 2-ketoalkanoic acid ester is selected from the group consisting of ethyl 2-keto-butyrate, ethyl 2-ketopentanoate, ethyl 2-keto-3-methyl-butyrate, ethyl 2-keto-4-methyl-pentanoate and ethyl 2-keto-hexanoate.  
     
     
         11 . The process of  claim 9 , wherein said 2-ketoalkanoic acid ester is admixed in a saline solution, said solution containing a cation selected from the group consisting of calcium and magnesium  
     
     
         12 . The process of  claim 10 , wherein said 2-ketoalkanoic acid ester is admixed in a saline solution, said solution containing a cation selected from the group consisting of calcium and magnesium.  
     
     
         13 . The process of  claim 9 , wherein said 2-ketoalkanoic acid ester is ethyl pyruvate.  
     
     
         14 . The method of  claim 1 , wherein said 2-ketoalkanoic acid ester is an alkyl ester.  
     
     
         15 . The method of  claim 14 , wherein said alkyl ester is ethyl pyruvate.  
     
     
         16 . The method of  claim 1 , wherein said condition is characterized by ischemia.  
     
     
         17 . The method of  claim 16 , wherein said ischemia is due to an ischemic event selected from the group consisting myocardial infarction, cerebral infarction and intestinal infarction.  
     
     
         18 . The method of  claim 1 , wherein said condition is characterized by reperfusion injury.