Use of pyridone derivatives in the prevention or treatment of tissue or organ toxicity induced by cytotoxic agents and radiation

Abstract

The present invention is directed to a novel use of pyridone derivatives such as pirfenidone for the prevention and treatment of damages to tissues or organs induced by various cytotoxic agents, such as chemotherapeutic agents, biologics, immunosuppressants and radiation. Such prophylactic and/or therapeutic effects of the pyridone derivatives make it possible to increase therapeutic dosages of the cytotoxic agent, thereby enhancing the therapeutic efficacy of the cytotoxic agent and radiation therapy.

What is claimed is: 
     
         1 . A method for treating tissue damage associated with a cytotoxic agent, an immunosuppressant, and/or radiation in a mammal in need thereof, comprising:
 administering to the mammal a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof,   
       
         
           
           
               
               
           
         
       
       wherein R 1  is methyl, ethyl or trifluoromethyl at position 3, 4, 5 or 6; and R 2  is hydroxyl, sulfydryl, C 1-6  alkoxyl such as methoxyl and ethoxyl, or a C 1-6  alkylthio group such as a methylthio group or an ethylthio group at position 2, 3 or 4; or, R 2  is absent. 
     
     
         2 . The method of  claim 1 , wherein R 1  is methyl, and R 2  is absent. 
     
     
         3 . The method of  claim 1 , wherein R 1  is methyl, and R 2  is hydroxyl. 
     
     
         4 . The method of  claim 1 , wherein the compound is pirfenidone. 
     
     
         5 . The method of  claim 1 , wherein the compound is 5-methyl-1-(4-hydroxylphenyl)-2-(1H)-pyridone (F351). 
     
     
         6 . The method of  claim 1 , wherein the mammal is a human. 
     
     
         7 . The method of  claim 1 , wherein the compound or its pharmaceutically acceptable salt is administered simultaneously with or after the mammal is administered the cytotoxic agent, immunosuppressant, or radiation. 
     
     
         8 . The method of  claim 1 , wherein the tissue damage is fibrosis or inflammation of the kidney or lung. 
     
     
         9 . The method of  claim 1 , wherein the tissue damage is radiation pneumonitis, interstitial pneumonia, or pulmonary fibrosis. 
     
     
         10 . A method of administering an increased dosage (D 1 ) of radiotherapy or a chemotherapeutic agent to a mammal in need thereof, comprising:
 (a) administering to the mammal a therapeutically-effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof,   
       
         
           
           
               
               
           
         
       
       wherein R 1  is methyl, ethyl or trifluoromethyl at position 3, 4, 5 or 6; and R 2  is hydroxyl, sulfydryl, C 1-6  alkoxyl such as methoxyl and ethoxyl, or a C 1-6  alkylthio group such as a methylthio group or an ethylthio group at position 2, 3 or 4; or, R 2  is absent, and
 (b) administering to the mammal the increased dosage (D 1 ) of radiotherapy or the chemotherapeutic agent, 
 
       wherein the increased dosage (D 1 ) is greater than a dosage administered in the absence of a compound of Formula I (D 0 ). 
     
     
         11 . The method of  claim 10 , wherein the irradiation dose D 1  and D 0  fit the following equation:
   ( D   1   −D   0 )/ D   0 ≧20%.
   
     
     
         12 . The method of  claim 10 , wherein the chemotherapeutic dose D 1  and D 0  fit the following equation:
   ( D   1   −D   0 )/ D   0 ≧20%.
   
     
     
         13 . The method of  claim 10 , wherein R 1  is methyl, and R 2  is absent. 
     
     
         14 . The method of  claim 10 , wherein R 1  is methyl, and R 2  is hydroxyl. 
     
     
         15 . The method of  claim 10 , wherein the compound of Formula I is pirfenidone or 5-methyl-1-(4-hydroxylphenyl)-2-(1H)-pyridone (F351). 
     
     
         16 . A method for treating pulmonary fibrosis or kidney fibrosis associated with a cytotoxic agent, an immunosuppressant, and/or radiation in a mammal in need thereof, comprising:
 administering to the mammal a therapeutically-effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof,   
       
         
           
           
               
               
           
         
       
       wherein R 1  is methyl, ethyl or trifluoromethyl at position 3, 4, 5 or 6; and R 2  is hydroxyl, sulfydryl, C 1-6  alkoxyl such as methoxyl and ethoxyl, or a C 1-6  alkylthio group such as a methylthio group or an ethylthio group at position 2, 3 or 4; or, R 2  is absent. 
     
     
         17 . The method of  claim 16 , wherein the compound of Formula I is pirfenidone or 5-methyl-1-(4-hydroxylphenyl)-2-(1H)-pyridone (F351). 
     
     
         18 . A method for treating pneumonitis associated with a cytotoxic agent, an immunosuppressant, and/or radiation in a mammal in need thereof, comprising:
 administering to the mammal a therapeutically-effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof,   
       
         
           
           
               
               
           
         
       
       wherein R 1  is methyl, ethyl or trifluoromethyl at position 3, 4, 5 or 6; and 
       R 2  is hydroxyl, sulfydryl, C 1-6  alkoxyl such as methoxyl and ethoxyl, or a C 1-6  alkylthio group such as a methylthio group or an ethylthio group at position 2, 3 or 4; or, R 2  is absent. 
     
     
         19 . The method of  claim 18 , wherein the compound of Formula I is 5-methyl-1-(4-hydroxylphenyl)-2-(1H)-pyridone (F351).