Methods for prevention and treatment of gastrointestinal disorders

Abstract

Disclosed are methods for preventing or treating a gastrointestinal (GI) disorder in a mammal such as a human patient. In one embodiment, the methods include administering to the mammal a therapeutically effective amount of a compound that modulates a nitric oxide (NO) signaling pathway, particularly in GI neurons. Methods of the invention are particularly useful for the treatment (including prophylactic treatment) of diabetic gastropathies and other GI disorders.

1 . A method for treating a gastrointestinal disorder in a mammal suffering from or susceptible to the disorder, the method comprising administering to the mammal a therapeutically effective amount of a compound that increases nitric oxide (NO) activity as measured in a standard gastric emptying assay, wherein the compound is not sildenafil.  
     
     
         2 . A method for treating a gastrointestinal disorder in a mammal suffering from or susceptible to the disorder, the method comprising administering to the mammal a therapeutically effective amount of at least one compound that provides increased nitric oxide synthase (nNOS) as measured in a standard nNOS protein expression assay.  
     
     
         3 . The method of  claim 1  or  2  wherein the mammal has been identified and selected for treatment to increase at least one of the NO activity and the nNOS level, and the compound is then administered to the identified and selected mammal.  
     
     
         4 . The method of  claim 1  or  2  wherein the amount of the administered compound is sufficient to increase neuronal cyclic guanosine 3′-monophosphate (cGMP) levels as measured by a standard cGMP assay.  
     
     
         5 . The method of  claim 1  or  2  wherein the gastrointestinal disorder is characterized by motility disturbances in at least one of the small intestine, large intestine, colon, esophagus or stomach.  
     
     
         6 . The method of  claim 1  or  2  wherein the gastrointestinal disorder is further characterized by at least one of nausea, vomiting, heartburn, postprandial discomfort, diarrhea, constipation, and indigestion.  
     
     
         7 . The method of  claim 1  or  2  wherein the disorder is associated with at least one of diabetes, anorexia nervosa, bulimia, achlorhydria, achalasia, anal fissure, irritable bowel syndrome, intestinal pseudoobstruction, scleroderma and gastrointestinal damage.  
     
     
         8 . The method of  claim 1  or  2  wherein the mammal is suffering from or susceptible to Crohn's disease or ulcerative colitis.  
     
     
         9 . The method of  claim 1  or  2  wherein a PDE inhibitor compound is administered.  
     
     
         10 . The method of  claim 1  or  2  wherein insulin, a biologically active variant of insulin, or a compound that boosts insulin effects or levels is administered.  
     
     
         11 . The method of  claim 10  wherein the compound that boosts insulin effects or levels is a sulfonylurea or a thiazolidinedione.  
     
     
         12 . A method for treating a gastrointestinal disorder in a mammal suffering from or susceptible to the disorder, comprising administering to the mammal a therapeutically effective amount of a phosphodiesterase (PDE) inhibitor in an amount sufficient to augment nitric oxide (NO) production as measure in a gastric emptying assay.  
     
     
         13 . A method for treating a gastrointestinal disorder in a mammal suffering from or susceptible to the disorder, comprising administering to the mammal a therapeutically effective amount of insulin, a biologically active variant thereof, or other compound that can boost insulin effects or levels in an amount sufficient to provide increased nitric oxide synthase (nNOS) levels as measured in a standard nNOS protein expression assay.  
     
     
         14 . The method of  claim 12  wherein the PDE inhibitor decreases activity of a cyclic guanosine monophosphate (cGMP) specific PDE as determined by at least one of a standard PDE or PDE5 assay.  
     
     
         15 . The method of  claim 12  wherein the inhibitor decreases activity of a type 5 PDE (PDE5).  
     
     
         16 . The method of  claim 13  wherein the compound that can boost insulin effects or levels is administered in conjunction with a PDE inhibitor compound.  
     
     
         17 . A method for preventing or treating a diabetic gastropathy in a mammal comprising administering to the mammal a therapeutic amount of one or more of the compounds represented above by formulae I through XIII as those formulae are set forth above, or a pharmaceutically acceptable salt thereof, wherein the compound is not sildenafil.  
     
     
         18 . A method for preventing or treating a diabetic gastropathy in a mammal comprising administering to the mammal a therapeutic amount of one or more insulin(s) or a biologically active variant thereof, or a compound that can boost insulin effects or levels in the mammal.  
     
     
         19 . The method of  claim 18  wherein the mammal has been identified as suffering from diabetic gastropathy and selected for treatment for diabetic gastropathy.  
     
     
         20 . A method for treating a mammal suffering or susceptible to diabetes, anorexia nervosa, bulimia, achlorhydria, achalasia, anal fissure, irritable bowel syndrome, intestinal pseudoobstruction, scleroderma, gastrointestinal damage, Crohn's disease or ulcerative colitis, comprising administering to the mammal an effective amount of one or more of the compounds represented above by Formulae I through XIII as those formulae are set forth above, or a pharmaceutically acceptable salt thereof, wherein the compound is not sildenafil.  
     
     
         21 . A method for treating diabetes comprising administering to the mammal an effective amount of one or more of the compounds represented above by Formulae I through XIII as those formulae are set forth above, or a pharmaceutically acceptable salt thereof, wherein the compound is not sildenafil.  
     
     
         22 . The method of  claim 20  wherein insulin, a biologically active variant of insulin, or a compound that boosts insulin effects or levels is administered to the mammal.  
     
     
         23 . The method of  claim 21  wherein the mammal has been identified as suffering from diabetes, anorexia nervosa, bulimia, achlorhydria, achalasia, anal fissure, irritable bowel syndrome, intestinal pseudoobstruction, scleroderma, gastrointestinal damage, Crohn's disease or ulcerative colitis, and the mammal has been selected for treatment for diabetes, anorexia nervosa, bulimia, achlorhydria, achalasia, anal fissure, irritable bowel syndrome, intestinal pseudoobstruction, scleroderma, gastrointestinal damage, Crohn's disease or ulcerative colitis.  
     
     
         24 . The method of  claim 22 , wherein the mammal has been identified as suffering from diabetes.  
     
     
         25 . The method of any one of claims  1  or  2  wherein the mammal is a human patient.  
     
     
         26 . The method of any one of claims  1  or  2  wherein the mammal has been subjected to or will be subjected to treatment with at least one prokinetic agent.  
     
     
         27 . The method of any one of claims  1  or  2  wherein the method further comprises administering to the mammal a therapeutically effective amount of at least one prokinetic agent.  
     
     
         28 . The method of  claim 26  or  27  wherein the prokinetic agent is metoclopramide, domperidone, erytthromycin or cisapride.