Methods for treatment of disorders of cardiac contractility

Abstract

The present invention relates to methods for modulating calcium sensitivity of cardiac muscle. In preferred aspects, the invention provides methods for enhancing myocardial contractility and cardiac performance, and methods for treatment of heart failure and other disorders associated with cardiac contractility by administration of one or more xanthine oxidase inhibitor compounds.

What is claimed is:  
     
         1 . A method for treating heart failure in a mammal suffering from or susceptible to heart failure, comprising administering to the mammal a therapeutically effective amount of a compound that provides increased cardiac contractile force as measured in a standard in vitro calcium-sensitizing assay.  
     
     
         2 . A method for enhancing efficiency of cardiac contraction in a mammal, comprising administering to a mammal in need of such treatment an effective amount of a xanthine oxidase inhibitor compound.  
     
     
         3 . The method of  claim 2  wherein the mammal has been identified and selected for treatment to increase myocardial contractility with reduced energy requirements, and the compound is then administered to the identified and selected mammal.  
     
     
         4 . The method of any one of claims  1 - 3  wherein the compound is administered to the mammal within about 6 hours after the mammal has suffered heart failure.  
     
     
         5 . The method of any one of claims  1 - 3  wherein the compound is administered to the mammal within about 18 hours after the mammal has suffered heart failure.  
     
     
         6 . The method of any one of claims  1 - 3  wherein the compound is administered to the mammal for at least about 1 week after the mammal has suffered heart failure.  
     
     
         7 . The method of any one of claims  1 - 3  wherein the compound is administered to the mammal for at least about 4 weeks after the mammal has suffered heart failure.  
     
     
         8 . The method of any one of claims  1 - 7  wherein the mammal is suffering from or susceptible to congestive heart failure.  
     
     
         9 . The method of any one of claims  1 - 7  wherein the mammal is suffering from or susceptible to cardiogenic shock.  
     
     
         10 . A method for treatment of a disorder of cardiac contractility in a mammal suffering from or susceptible to the disorder, comprising administering to the mammal a therapeutically effective amount of a xanthine oxidase inhibitor compound.  
     
     
         11 . A method of increasing calcium sensitivity of cardiac muscle, comprising administering to mammalian cardiac muscle an effective amount of a xanthine oxidase inhibitor compound.  
     
     
         12 . A method of  claim 1  wherein the administered compound is a xanthine oxidase inhibitor.  
     
     
         13 . A method of any one of claims  1  through  11  wherein the compound is allopurinol.  
     
     
         14 . A method of any one of claims  1  through  11  wherein the compound is oxypurinol.  
     
     
         15 . A method of any one of claims  1  through  11  wherein the compound is of any one of Formulae I through XXIII as those formulae are set forth above.  
     
     
         16 . A method of any one of claims  1  through  11  or  15  wherein the compound induces at least about a 10 percent increase in cardiac contractile force in a standard in vitro calcium-sensitizing assay.  
     
     
         17 . A method of any one of claims  1  through  11  or  15  wherein the compound induces at least about a 20 percent increase in cardiac contractile force in a standard in vitro calcium-sensitizing assay.  
     
     
         18 . A method of any one of claims  1  through  11  or  15  through  17  wherein the compound induces at least about a 3 percent decrease in intracellular calcium concentration as measured in a standard in vitro calcium-sensitizing assay.  
     
     
         19 . A method of any one of claims  1  through  11  or  15  through  17  wherein the compound induces at least about a 5 percent decrease in intracellular calcium concentration as measured in a standard in vitro calcium-sensitizing assay.  
     
     
         20 . The method of any one of claims  1  through  19  wherein the compound is administered to a primate.  
     
     
         21 . The method of any one of claims  1  through  19  wherein the compound is administered to a human.  
     
     
         22 . The method of any one of claims  1  through  21  wherein a mammal that is suffering from heart failure is selected for treatment for heart failure, and the compound is then administered to the selected mammal.  
     
     
         23 . The method of  claim 11  wherein a mammal suffering from a disorder of cardiac contractility is selected for treatment for the disorder, and the compound is then administered to the selected mammal.  
     
     
         24 . A method for treating heart failure in a mammal suffering from or susceptible to heart failure, comprising administering to the mammal a therapeutically effective amount of a compound that inhibits xanthine oxidase.  
     
     
         25 . The method of  claim 21  wherein the compound is administered to the mammal within about 6 hours after the mammal has suffered heart failure.  
     
     
         26 . The method of  claim 21  wherein the compound is administered to the mammal within about 18 hours after the mammal has suffered heart failure.  
     
     
         27 . The method of  claim 21  wherein the compound is administered to the mammal for at least about 1 week after the mammal has suffered heart failure.  
     
     
         28 . The method of  claim 21  wherein the compound is administered to the mammal for at least about 4 weeks after the mammal has suffered heart failure.  
     
     
         29 . The method of any one of claims  21 - 28  wherein the mammal is suffering from or susceptible to congestive heart failure.  
     
     
         30 . The method of any one of claims  21 - 28  wherein the mammal is suffering from or susceptible to cardiogenic shock.  
     
     
         31 . A method for treatment method for a disorder of cardiac contractility in a mammal suffering from or susceptible to the disorder, comprising administering to the mammal a therapeutically effective amount of a compound that inhibits xanthine oxidase.  
     
     
         32 . A method of increasing calcium sensitivity of cardiac muscle, comprising administering to mammalian cardiac muscle an effective amount of a compound that inhibits xanthine oxidase.  
     
     
         33 . A method of any one of claims  21  through  32  wherein the compound is allopurinol.  
     
     
         34 . A method of any one of claims  21  through  32  wherein the compound is oxypurinol.  
     
     
         35 . A method of any one of claims  21  through  32  wherein the compound exhibits an IC 50  of at least about 1 mM in a standard in vitro xanthine oxidase assay.  
     
     
         36 . A method of any one of claims  21  through  32  or  35  wherein the compound is of any one of Formulae I through XXIII as those formulae are set forth above.  
     
     
         37 . A method of any one of claims  21  through  32  or  36  wherein the compound induces at least about a 10 percent increase in cardiac contractile force in a standard in vitro calcium-sensitizing assay.  
     
     
         38 . A method of any one of claims  21  through  32  or  36  wherein the compound induces at least about a 20 percent increase in cardiac contractile force in a standard in vitro calcium-sensitizing assay.  
     
     
         39 . A method of any one of claims  21  through  32  or  36  through  38  wherein the compound induces at least about a 3 percent decrease in intracellular calcium concentration as measured in a standard in vitro calcium-sensitizing assay.  
     
     
         40 . A method of any one of claims  21  through  32  or  36  through  38  wherein the compound induces at least about a 5 percent decrease in intracellular calcium concentration as measured in a standard in vitro calcium-sensitizing assay.  
     
     
         41 . The method of any one of claims  21  through  40  wherein the compound is administered to a primate.  
     
     
         42 . The method of any one of claims  21  through  40  wherein the compound is administered to a human.  
     
     
         43 . The method of any one of claims  21  through  42  wherein a mammal that is suffering from heart failure is selected for treatment for heart failure, and the compound is then administered to the selected mammal.  
     
     
         44 . The method of  claim 31  wherein a mammal suffering from a disorder of cardiac contractility is selected for treatment for the disorder, and the compound is then administered to the selected mammal.