Method of treating ischemia/reperfusion injury with nitroxyl donors

Abstract

Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

We claim:  
     
         1 . A method of reducing ischemia/reperfusion injury comprising; 
 selecting a subject at risk for an ischemic event; and    administering to a subject a therapeutically effective dose of at least one nitroxyl anion donating compound wherein the compound is administered prior to the onset of ischemia.    
     
     
         2 . The method of  claim 1 , wherein the nitroxyl anion donating compound is a nitroxyl-donating diazeniumdiolate.  
     
     
         3 . The method of  claim 2 , wherein the nitroxyl-donating diazeniumdiolate has the formula  
       
         
           
           
               
               
           
         
       
       wherein J is oxide, sulfite (SO 3   − ), amine, an NSAID, an aliphatic, aryl, or aryl-aliphatic substituted or unsubstituted hydrocarbon, or a biomolecule and M c   +x  is a pharmaceutically acceptable cation, wherein x is the valence of the cation, and c is the smallest integer that results in a neutral compound.  
     
     
         4 . The method of  claim 3 , wherein J is oxide.  
     
     
         5 . The method of  claim 3 , wherein J is lower alkyl.  
     
     
         6 . The method of  claim 3 , wherein J is amine.  
     
     
         7 . The method of  claim 6 , wherein J is primary amine.  
     
     
         8 . The method of  claim 7 , wherein the nitroxyl-donating diazeniumdiolate has the formula  
       
         
           
           
               
               
           
         
       
       where R is an aliphatic, aryl, or aryl-aliphatic substituted or unsubstituted hydrocarbon, an NSAID, or a biomolecule and M c   +x  is a pharmaceutically acceptable cation, wherein x is the valence of the cation, and c is the smallest integer that results in a neutral compound.  
     
     
         9 . The method of  claim 8 , wherein R is alkyl.  
     
     
         10 . The method of  claim 9 , wherein R is lower alkyl.  
     
     
         11 . The method of  claim 10 , wherein R is isopropyl.  
     
     
         12 . The method of  claim 1 , wherein the ischemia/reperfusion injury is an injury of the myocardium or brain.  
     
     
         13 . The method of  claim 12 , wherein the ischemia/reperfusion injury is an injury of the myocardium.  
     
     
         14 . The method of  claim 13 , wherein the size of infarction is reduced by about 35% or more.  
     
     
         15 . The method of  claim 14 , wherein the size of infarction is reduced by about 35% to about 55%.  
     
     
         16 . The method of  claim 1 , wherein selecting a subject at risk of an ischemic event comprises selecting a subject with no evidence of current ischemia.  
     
     
         17 . A method of reducing ischemia/reperfusion injury comprising, administering a dose of at least one nitroxyl donating compound to an organ that is to be transplanted, wherein the dose is effective to reduce ischemia/reperfusion injury upon reperfusion of the organ in a recipient.  
     
     
         18 . The method of  claim 17 , wherein the nitroxyl anion donating compound is a nitroxyl-donating diazeniumdiolate.  
     
     
         19 . The method of  claim 18 , wherein the nitroxyl-donating diazeniumdiolate has the formula  
       
         
           
           
               
               
           
         
       
       wherein J is oxide, sulfite, amine, an NSAID, an aliphatic, aryl, or aryl-aliphatic substituted or unsubstituted hydrocarbon, or a biomolecule and M c   +x  is a pharmaceutically acceptable cation, wherein x is the valence of the cation, and c is the smallest integer that results in a neutral compound.  
     
     
         20 . The method of  claim 19 , wherein J is oxide.  
     
     
         21 . The method of  claim 19 , wherein J is lower alkyl.  
     
     
         22 . The method of  claim 19 , wherein J is amine.  
     
     
         23 . The method of  claim 22 , wherein J is primary amine.  
     
     
         24 . The method of  claim 23 , wherein the nitroxyl-donating diazeniumdiolate has the formula  
       
         
           
           
               
               
           
         
       
       where R is an aliphatic, aryl, or aryl-aliphatic substituted or unsubstituted hydrocarbon, an NSAID, or a biomolecule and M c   +x  is a pharmaceutically acceptable cation, wherein x is the valence of the cation, and c is the smallest integer that results in a neutral compound.  
     
     
         25 . The method of  claim 24 , wherein R is alkyl.  
     
     
         26 . The method of  claim 25 , wherein R is lower alkyl.  
     
     
         27 . The method of  claim 26 , wherein R is isopropyl.