Method of using pyruvate and/or its derivatives for the treatment of cytokine-mediated inflammatory conditions

Abstract

This invention is directed to a method of using a therapeutic composition comprising an ester of an alpha-ketoalkanoic acid for the treatment of cytokine-mediated inflammatory conditions. The cytokine-mediated inflammatory conditions are mediated by, for example, Tumor Necrosis Factor (TNF), interleukin-1β (IL-1β)) or High Mobility Group B-1 (HMGB-1) mediator of inflammation. Exemplary cytokine-mediated inflammatory conditions include, but are not limited to, rheumatoid spondylitis, osteoarthritis, gouty arthritis, endotoxic shock, cerebral malaria, silicosis, pulmonary sarcoidosis, bone resorption disease, graft versus host disease, allograft rejections, fever and myalgia due to infection, AIDS related complex (ARC), Crohn's disease, rheumatoid arthritis, cachexia and septic shock.

1 . A method for treating a cytokine-mediated inflammatory condition in a patient suffering therefrom, comprising: 
 administering to said patient an effective amount of a composition comprising an ester of an alpha-ketoalkanoic acid in a pharmaceutically acceptable inert carrier substance,    wherein the condition is selected from the group consisting of rheumatoid spondylitis, osteoarthritis, gouty arthritis, endotoxic shock, cerebral malaria, silicosis, pulmonary sarcoidosis, bone resorption disease, graft versus host disease, allograft rejections, fever and myalgia due to infection, AIDS related complex (ARC), Crohn's disease, rheumatoid arthritis, cachexia and septic shock.    
   
   
       2 . The method of  claim 1 , wherein said ester is an ester of a C3 to C8, straight chained or branched alpha-ketoalkanoic acid.  
   
   
       3 . The method of  claim 1 , wherein said ester of an alpha-ketoalkanoic acid is an alkyl, aralkyl, carboxyalkyl, glyceryl or dihydroxy acetone ester.  
   
   
       4 . The method of  claim 1 , wherein said ester of an alpha-ketoalkanoic acid is an ester of an acid selected from the group consisting of 2-keto-butyric acid, 2-ketopentanoic acid, 2-keto-3-methyl-butyric acid, 2-keto-4-methyl-pentanoic acid and 2-keto-hexanoic acid.  
   
   
       5 . The method of  claim 2 , wherein said ester of alpha-ketoalkanoic acid compound is an ethyl, propyl, butyl, carboxymethyl, acetoxymethyl, carbethoxymethyl and ethoxymethyl ester.  
   
   
       6 . The method of  claim 1 , wherein said alpha-ketoalkanoic acid portion of the ester is alpha-ketopropionic acid.  
   
   
       7 . The method of  claim 1 , wherein the inert carrier further includes a biologically safe component for inducing and stabilizing enolization of the alpha-keto functionality of the ester at physiological pH values.  
   
   
       8 . The method of  claim 7 , wherein the component for inducing and stabilizing enolization of the alpha-keto functionality of the ester is an inorganic, divalent cation.  
   
   
       9 . The method of  claim 8 , wherein the inorganic divalent cation is calcium or magnesium.  
   
   
       10 . The method of  claim 8 , wherein the divalent cation is calcium and said inert carrier substance is Ringer's solution in a pH range of 7-8.  
   
   
       11 . The method of  claim 1 , wherein the inert carrier is a Ringer's solution of isotonic saline supplemented with potassium ion.  
   
   
       12 . The method of  claim 1 , wherein said ester of an alpha-ketoalkanoic acid compound is admixed in a saline solution, said solution containing a cation selected from the group consisting of calcium and magnesium.  
   
   
       13 . A method for treating a cytokine-mediated inflammatory condition in a patient suffering therefrom said method comprising: 
 administering to said patient an effective amount of a composition comprising a compound of Formula (I) in a pharmaceutically acceptable inert carrier:                          wherein    R 1  is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 4-methylpentyl, 3-methylpentyl, hexyl, heptyl, octyl, 1-phenylmethyl or 2-phenyl-ethyl;    R 2  is ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 4-methylpentyl, ethoxymethyl, 2-ethoxyethyl, carboxymethyl or ethoxycarbonylmethyl.    
   
   
       14 . The method of  claim 13  wherein the patient is administered a composition consisting essentially of the compound of Formula (I) in a pharmaceutically acceptable inert carrier.  
   
   
       15 . The method of  claim 13  wherein R 2  is ethyl.  
   
   
       16 . The method of  claim 13  wherein the compound is ethyl pyruvate, propyl pyruvate, carboxymethyl pyruvate, ethoxymethyl pyruvate, ethyl alpha-keto-butyrate, ethyl alpha-keto-pentanoate, ethyl alpha-keto-3-methyl-butyrate, ethyl alpha-keto-4-methyl-pentanoate, or ethyl alpha-keto-hexanoate.  
   
   
       17 . The method of  claim 13  wherein the composition comprising a compound of Formula (I) is administered orally, intranasally, subcutaneously, intramuscularly, intravenously, intralumenally, intra-arterially, intravaginally, transurethrally or rectally.  
   
   
       18 . The method of  claim 17  wherein the composition comprising a compound of Formula (I) is administered orally, intranasally, subcutaneously, intramuscularly, intravenously, intralumenally or intra-arterially.  
   
   
       19 . The method of  claim 13 , wherein said composition is administered 24 hours after onset of said inflammatory condition.  
   
   
       20 . The method of  claim 13 , wherein the inert carrier further comprises a biologically safe component for inducing and stabilizing enolization of the alpha-keto functionality of the compound of Formula (I) at physiological pH values.  
   
   
       21 . The method of  claim 20 , wherein said component for inducing and stabilizing enolization of the alpha-keto functionality of said ester is an inorganic, divalent cation.  
   
   
       22 . The method of  claim 21 , wherein said divalent cation is calcium or magnesium.  
   
   
       23 . The method of  claim 13 , wherein said inert carrier is Ringer's solution in a pH range of 7-8.  
   
   
       24 . The method of  claim 13 , wherein said inert carrier is a Ringer's solution of isotonic saline supplemented with potassium ion.  
   
   
       25 . The method of  claim 13 , wherein the compound of Formula (I) is admixed in a saline solution, said solution containing a cation selected from the group consisting of calcium and magnesium.  
   
   
       26 . The method of  claim 13 , wherein said inflammatory condition is inflammatory bowel disease, rheumatoid arthritis, asthma, sepsis or septic shock.