Treating effects of excessive reactive oxygen species

Abstract

A method of treatment is disclosed whereby a nitroxide compound is administered to a patient in a therapeutically effective amount. The nitroxide compound is comprised of a first portion which comprises a nitrogen atom and an oxygen atom bound directly together and an unpaired electron (.NO), and a second portion which provides a negative charge. The first and second portions are connected directly or indirectly by a linking group positioned between and bound to the first portion and the second portion in a manner such that the negative charge of the second portion stabilizes the .NO of the first portion when the nitroxide is present in the patient. By stabilizing the .NO portion of the molecule the nitroxide is allowed to interact with reactive oxygen species in the patient for a longer period of time and modulate adverse effects of those reactive oxygen species.

What is claimed is:  
     
         1 . A method of treatment, comprising: 
 administering to a patient a therapeutically effective amount of a formulation, comprising a pharmaceutically acceptable carrier and a nitroxide comprised of a first portion comprising a nitrogen atom and an oxygen atom bound directly together and an unpaired electron (.NO), a second portion which provides a negative charge, and a linking group positioned between and bound to the first portion and the second portion in a manner such that the negative charge of the first portion stabilizes the .NO of the first portion when the nitroxide is present in the patient; and    allowing the nitroxide to interact with reactive oxygen species in the patient.    
     
     
         2 . The method of  claim 1 , wherein the second portion is comprised of two ester groups and wherein an alkyl moiety of the ester groups is removed in the patient and replaced with a moiety chosen from —H, Na, and K.  
     
     
         3 . The method of  claim 1 , wherein the linking group is chosen from a double bond between two carbon atoms and an —NH— group between two carbon atoms.  
     
     
         4 . The method of  claim 1 , wherein the formulation is applied topically to the patient.  
     
     
         5 . The method of  claim 4 , wherein the formulation is applied topically to the patient's skin.  
     
     
         6 . The method of  claim 4 , wherein the formulation is applied topically to a mucous membrane of the patient.  
     
     
         7 . The method of  claim 4 , wherein the formulation is applied topically to an ocular surface of the patient.  
     
     
         8 . The method of  claim 1 , wherein the formulation is applied by injection.  
     
     
         9 . The method of  claim 1 , wherein the formulation is administered orally.  
     
     
         10 . The method of  claim 1 , wherein the nitroxide has the general structural formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a nitroxide;  
 wherein R 2  and R 3  are each independently chosen from Na, K, hydrogen, alkyl, alkenyl, acyl, aralkyl, alkaryl and a nitroxide; and  
 wherein “n” is an integer of from 0 to 18.  
 
     
     
         11 . The method of  claim 1 , wherein the nitroxide has the general structural formula II.  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a nitroxide;  
 wherein R 2  and R 3  are each independently chosen from Na, K, hydrogen, alkyl, alkenyl, acyl, aralkyl, alkaryl and a nitroxide; and  
 wherein “n” is an integer of from 1 to 6.  
 
     
     
         12 . The method of  claim 1 , wherein the nitroxide has the general structural formula III:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a nitroxide;  
 wherein R 2  and R 3  are each independently chosen from Na, K, hydrogen, alkyl, alkenyl, acyl, aralkyl, alkaryl and a nitroxide; and  
 wherein “n” is an integer of from 1-6.  
 
     
     
         13 . The method of  claim 1 , wherein the nitroxide has the general structural formula IV.  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are each independently an alkyl and the circle is a cyclic moiety comprising carbon atoms.  
     
     
         14 . A formulation for modulating an effect of a reactive oxygen species, comprising: 
 a pharmaceutically acceptable carrier; and    a nitroxide comprised of a first portion comprising a nitrogen atom and an oxygen atom bound directly together and an unpaired electron (.NO), a second portion which provides a negative charge, and a linking group positioned between and bound to the first portion and the second portion in a manner such that the negative charge of the first portion stabilizes the .NO of the first portion when the nitroxide is present in vivo.    
     
     
         15 . The formulation of  claim 14 , wherein the nitroxide has the general structural formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a nitroxide;  
 wherein R 2  and R 3  are each independently chosen from Na, K, hydrogen, alkyl, alkenyl, acyl, aralkyl, alkaryl and a nitroxide; and  
 wherein “n” is an integer of from 0 to 18.  
 
     
     
         16 . The formulation of  claim 14 , wherein the nitroxide has the general structural formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a nitroxide;  
 wherein R 2  and R 3  are each independently chosen from Na, K, hydrogen, alkyl, alkenyl, acyl, aralkyl, alkaryl and a nitroxide; and  
 wherein “n” is an integer of from 1 to 6.  
 
     
     
         17 . The formulation of  claim 14 , wherein the nitroxide has the general structural formula III:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a nitroxide;  
 wherein R 2  and R 3  are each independently chosen from Na, K, hydrogen, alkyl, alkenyl, acyl, aralkyl, alkaryl and a nitroxide; and  
 wherein “n” is an integer of from 1-6.  
 
     
     
         18 . The formulation of  claim 14 , wherein the nitroxide has the general structural formula IV:  
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  are each independently an alkyl and the circle is a cyclic moiety comprising carbon atoms.  
     
     
         19 . A formulation, comprising: 
 a dermatologically acceptable carrier;    a UV absorber; and    a nitroxide.    
     
     
         20 . The formulation of  claim 19 , wherein the nitroxide has the general structural formula I:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is a nitroxide;  
 wherein R 2  and R 3  are each independently chosen from Na, K, hydrogen, alkyl, alkenyl, acyl, aralkyl, alkaryl and a nitroxide; and  
 wherein “n” is an integer of from 0 to 18.