Gap junction-enhancing agents for treatment of necrotizing enterocolitis and inflammatory bowel disease

Abstract

The present invention relates to methods of reducing the risk of occurrence of, and/or treating, necrotizing enterocolitis (“NEC”) or inflammatory bowel disease (“IBD”) comprising administering, to a subject in need of such treatment, an effective amount of a gap junction enhancing agent (“GJEA”), for example a peptide (“GJP”) or peptide analog (“GJPA”). It is based, at least in part, on the discovery that greater functionality of gap junctions between enterocytes increases their rate of migration and reduces the severity of intestinal inflammation.

What is claimed is: 
     
         1 . A method of treating necrotizing enterocolitis in a subject in need of such treatment comprising administering to the subject one or more dose of a gap junction enhancing agent, wherein the gap junction enhancing agent is a quinoline derivative selected from the group consisting of
 primaquine,   mefloquine,   PQ2 having the structure   
       
         
           
           
               
               
           
         
         PQ3 having the structure 
       
       
         
           
           
               
               
           
         
         PQ4 having the structure 
       
       
         
           
           
               
               
           
         
         PQ5 having the structure 
       
       
         
           
           
               
               
           
         
         PQ6 having the structure 
       
       
         
           
           
               
               
           
         
         PQ7 having the structure, 
       
       
         
           
           
               
               
           
         
         PQ8 having the structure and 
       
       
         
           
           
               
               
           
         
          and 
         PQ1 having the structure 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 10 mg/kg. 
     
     
         3 . The method of  claim 2 , wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 5 mg/kg. 
     
     
         4 . The method of  claim 3 , wherein the one or more dose of the gap junction enhancing agent is between 0.1 mg/kg and 1 mg/kg. 
     
     
         5 . A method of reducing the risk of occurrence of necrotizing enterocolitis in a subject in need of such treatment comprising administering to the subject one or more dose of a gap junction enhancing agent, wherein the gap junction enhancing agent is a quinoline derivative selected from the group consisting of
 primaquine,   mefloquine,   PQ2 having the structure   
       
         
           
           
               
               
           
         
         PQ3 having the structure 
       
       
         
           
           
               
               
           
         
         PQ4 having the structure 
       
       
         
           
           
               
               
           
         
         PQ5 having the structure 
       
       
         
           
           
               
               
           
         
         PQ6 having the structure 
       
       
         
           
           
               
               
           
         
         PQ7 having the structure, 
       
       
         
           
           
               
               
           
         
         PQ8 having the structure and 
       
       
         
           
           
               
               
           
         
          and 
         PQ1 having the structure 
       
       
         
           
           
               
               
           
         
       
     
     
         6 . The method of  claim 5 , wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 10 mg/kg. 
     
     
         7 . The method of  claim 6 , wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 5 mg/kg. 
     
     
         8 . The method of  claim 7 , wherein the one or more dose of the gap junction enhancing agent is between 0.1 mg/kg and 1 mg/kg. 
     
     
         9 . A method of inducing increased migration of enterocytes in a subject diagnosed with necrotizing enterocolitis, the method comprising administering to the subject one or more dose of a gap junction enhancing agent, wherein the gap junction enhancing agent is a quinoline derivative selected from the group consisting of
 primaquine,   mefloquine,   PQ2 having the structure   
       
         
           
           
               
               
           
         
         PQ3 having the structure 
       
       
         
           
           
               
               
           
         
         PQ4 having the structure 
       
       
         
           
           
               
               
           
         
         PQ5 having the structure 
       
       
         
           
           
               
               
           
         
         PQ6 having the structure 
       
       
         
           
           
               
               
           
         
         PQ7 having the structure, 
       
       
         
           
           
               
               
           
         
         PQ8 having the structure and 
       
       
         
           
           
               
               
           
         
          and 
         PQ1 having the structure 
       
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 9 , wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 10 mg/kg. 
     
     
         11 . The method of  claim 10 , wherein the one or more dose of the gap junction enhancing agent is between 0.05 mg/kg and 5 mg/kg. 
     
     
         12 . The method of  claim 11 , wherein the one or more dose of the gap junction enhancing agent is between 0.1 mg/kg and 1 mg/kg.