Method of treating arrhythmias

Abstract

Methods are provided for treating arrhythmia in a manner that minimizes undesirable side effects, comprising administration of a therapeutically effective minimal dose of an A 1 adenosine receptor agonist with a therapeutically effective minimal dose of a beta blocker, calcium channel blocker, or a cardiac glycoside.

1 . A method of treating arrhythmias in a mammal, comprising administration of a therapeutically effective minimal dose of an A 1  adenosine receptor agonist in conjunction with a therapeutically effective minimal dose of a beta blocker, calcium channel blocker, or cardiac glycoside, to a mammal in need thereof. 
   
   
       2 . The method of  claim 1 , wherein the A 1  adenosine receptor agonist is a compound of compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is an optionally substituted heterocyclic group. 
   
   
       3 . The method of  claim 2 , wherein the compound of Formula I is administered in conjunction with a therapeutically effective minimal dose of a beta blocker. 
   
   
       4 . The method of  claim 3 , wherein in Formula I R 1  is 3-tetrahydrofuranyl, 3-tetrahydrothiofuranyl, 4-pyranyl, or 4-thiopyranyl. 
   
   
       5 . The method of  claim 4 , wherein the beta blocker is atenolol, esmolol, sotalol, or propranolol. 
   
   
       6 . The method of  claim 5 , wherein the compound of Formula I R 1  is 6-(3-(R)—N-aminotetrahydrofuranyl)purine riboside, namely CVT-510. 
   
   
       7 . The method of  claim 6 , wherein CVT-510 is present in an amount from about 0.0001-0.05 mg/kg. 
   
   
       8 . The method of  claim 6 , wherein the beta blocker is present in an amount from about 0.01 to 200 mg/kg. 
   
   
       9 . The method of  claim 8 , wherein the beta blocker is esmolol. 
   
   
       10 . The method of  claim 9 , wherein CVT-510 is present in an amount from about 0.0005-0.020 mg/kg and esmolol is present in an amount from about 0.1 to 10 mg/kg. 
   
   
       11 . The method of  claim 1 , wherein the A 1  adenosine receptor agonist is a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 2  is hydrogen, halo, trifluoromethyl, optionally substituted acyl, or cyano; 
 R 3  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heteroaryl, or optionally substituted heterocyclyl, 
 R 4  and R 5  are independently hydrogen or optionally substituted acyl; and 
 X and Y are independently a covalent bond or optionally substituted alkylene. 
 
   
   
       12 . The method of  claim 11 , wherein the compound of Formula II is administered in conjunction with a therapeutically effective minimal dose of a beta blocker. 
   
   
       13 . The method of  claim 12 , wherein the beta blocker is atenolol, esmolol, sotalol, or propranolol. 
   
   
       14 . The method of  claim 13 , wherein R 1  is (R)-2-hydroxycyclopentyl, X and Y are covalent bonds, R 2 , R 3 , and R 4  are hydrogen, and R 5  is 2-fluorophenyl, namely 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl} (4S,5S,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol (CVT-3619). 
   
   
       15 . The method of  claim 14 , wherein CVT-3619 is present in an amount from about 0.1 to 200 mg/kg. 
   
   
       16 . The method of  claim 14 , wherein the beta blocker is present in an amount from about 0.01 to 100 mg/kg. 
   
   
       17 . The method of  claim 16 , wherein the beta blocker is esmolol. 
   
   
       18 . The method of  claim 17 , wherein CVT-3619 is present in an amount from about 0.5 to 50 mg/kg and esmolol is present in an amount from about 0.1 to 10 mg/kg. 
   
   
       19 . A pharmaceutical composition comprising a therapeutically effective minimal dose of an A 1  adenosine receptor agonist and a therapeutically effective minimal dose of a beta blocker, and at least one pharmaceutically acceptable excipient. 
   
   
       20 . The pharmaceutical composition of  claim 19 , wherein the A 1  adenosine receptor agonist is a compound of compound of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is an optionally substituted heterocyclic group. 
   
   
       21 . The pharmaceutical composition of  claim 20 , wherein the compound of Formula I is administered in conjunction with a therapeutically effective minimal dose of a beta blocker. 
   
   
       22 . The pharmaceutical composition of  claim 21 , wherein in Formula I R 1  is 3-tetrahydrofuranyl, 3-tetrahydrothiofuranyl, 4-pyranyl, or 4-thiopyranyl. 
   
   
       23 . The pharmaceutical composition of  claim 22 , wherein the beta blocker is atenolol, esmolol, sotalol, or propranolol. 
   
   
       24 . The pharmaceutical composition of  claim 23 , wherein the compound of Formula I R 1  is 6-(3-(R)—N-aminotetrahydrofuranyl)purine riboside, namely CVT-510. 
   
   
       25 . The pharmaceutical composition of  claim 24 , wherein CVT-510 is present in an amount from about 0.0001-0.05 mg/kg. 
   
   
       26 . The pharmaceutical composition of  claim 24 , wherein the beta blocker is present in an amount from about 0.01 to 100 mg/kg. 
   
   
       27 . The pharmaceutical composition of  claim 26 , wherein the beta blocker is esmolol. 
   
   
       28 . The pharmaceutical composition of  claim 27 , wherein CVT-510 is present in an amount from about 0.0005-0.02 mg/kg and esmolol is present in an amount from about 0.1 to 10 mg/kg. 
   
   
       29 . The pharmaceutical composition of  claim 19 , wherein the A 1  adenosine receptor agonist is a compound of Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 R 1  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 2  is hydrogen, halo, trifluoromethyl, optionally substituted acyl, or cyano; 
 R 3  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl; optionally substituted heteroaryl, or optionally substituted heterocyclyl, 
 R 4  and R 5  are independently hydrogen or optionally substituted acyl; and 
 X and Y are independently a covalent bond or optionally substituted alkylene. 
 
   
   
       30 . The pharmaceutical composition of  claim 29 , wherein the compound of Formula II is administered in conjunction with a therapeutically effective minimal dose of a beta blocker. 
   
   
       31 . The pharmaceutical composition of  claim 30 , wherein the beta blocker is atenolol, esmolol, sotalol, or propranolol. 
   
   
       32 . The pharmaceutical composition of  claim 31 , wherein R 1  is (R)-2-hydroxycyclopentyl, X and Y are covalent bonds, R 2 , R 3 , and R 4  are hydrogen, and R 5  is 2-fluorophenyl, namely 2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]purin-9-yl}(4S,5S,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol (CVT-3619). 
   
   
       33 . The pharmaceutical composition of  claim 32 , wherein CVT-3619 is present in an amount from about 0.1 to 200 mg/kg. 
   
   
       34 . The pharmaceutical composition of  claim 32 , wherein the beta blocker is present in an amount from about 0.01 to 100 mg/kg. 
   
   
       35 . The pharmaceutical composition of  claim 34 , wherein the beta blocker is esmolol. 
   
   
       36 . The pharmaceutical composition of  claim 35 , wherein CVT-3619 is present in an amount from about 0.5 to 25 mg/kg and esmolol is present in an amount from about 0.1 to 10 mg/kg.