Synergistic effect of amlodipine and atorvastatin on cholesterol crystal formation inhibition and aortic endothelial cell nitric oxide release

Abstract

The combination of the antihypertensive calcium channel blocker amlodipine and lipid-lowering agent atorvastatin inhibits free cholesterol crystallization in atherosclerotic-like membranes. In addition, treatment with a combination of amlodipine and atorvastatin results in a synergistic effect on the release of NO from aorta endothelial cells.

1 . A method of synergistically inhibiting cholesterol crystal formation comprising administering a therapeutically effective amount of a combination of amlodipine and an atorvastatin compound selected from the group consisting of atorvastatin and hydroxylated atorvastatin metabolite.  
     
     
         2 . The method of  claim 1 , wherein the amlodipine comprises a therapeutically effective derivative of amlodipine.  
     
     
         3 . The method of  claim 2 , wherein the therapeutically effective derivative of amlodipine comprises amlodipine besylate.  
     
     
         4 . The method of  claim 1 , wherein the atorvastatin compound comprises a therapeutically effective derivative of atorvastatin.  
     
     
         5 . The method of  claim 4 , wherein the therapeutically effective derivative of the atorvastatin compound is a hemicalcium salt.  
     
     
         6 . The method of  claim 1 , wherein amlodipine and the atorvastatin compound are administered in the same therapeutic.  
     
     
         7 . The method of  claim 1 , wherein amlodipine and the atorvastatin compound are administered as separate therapeutics.  
     
     
         8 . The method of  claim 1 , wherein amlodipine and the atorvastatin compound are administered at the same time.  
     
     
         9 . The method of  claim 1 , wherein amlodipine and the atorvastatin compound are administered at different times.  
     
     
         10 . The method of  claim 1 , wherein said pharmaceutical composition synergistically inhibits cholesterol crystal formation to an extent consistent with a reduced risk of arterial and related heart disease.  
     
     
         11 . The method of  claim 10 , wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipdemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         12 . A method of synergistically increasing nitric oxide production by endothelial cells comprising administering a therapeutically effective amount of a combination of amlodipine and an atorvastatin compound selected from the group consisting of atorvastatin and hydroxylated atorvastatin metabolite.  
     
     
         13 . The method of  claim 12 , wherein amlodipine comprises a therapeutically effective derivative of amlodipine.  
     
     
         14 . The method of  claim 13 , wherein the therapeutically effective derivative of amlodipine comprises amlodipine besylate.  
     
     
         15 . The method of  claim 12 , wherein the atorvastatin compound comprises a therapeutically effective derivative of the atorvastatin compound.  
     
     
         16 . The method of  claim 15 , wherein the therapeutically effective derivative of the atorvastatin compound is a hemicalcium salt.  
     
     
         17 . The method of  claim 12 , wherein amlodipine and the atorvastatin compound are administered in the same therapeutic.  
     
     
         18 . The method of  claim 12 , wherein amlodipine and the atorvastatin compound are administered as separate therapeutics.  
     
     
         19 . The method of  claim 12 , wherein amlodipine and the atorvastatin compound are administered at the same time.  
     
     
         20 . The method of  claim 12 , wherein amlodipine and the atorvastatin compound are administered at different times.  
     
     
         21 . The method of  claim 12 , wherein said pharmaceutical composition synergistically increases nitric oxide production by endothelial cells to an extent consistent with a reduced risk of arterial and related heart disease.  
     
     
         22 . The method of  claim 21 , wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipdemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         23 . A method of treating arterial and related heart disease comprising administering a therapeutically effective amount of a combination of amlodipine and an atorvastatin compound selected from the group consisting of atovastatin and hydroxylated atorvastatin metabolite.  
     
     
         24 . The method of  claim 23 , wherein the amlodipine comprises a therapeutically effective derivative of amlodipine.  
     
     
         25 . The method of  claim 24 , wherein the therapeutically effective derivative of amlodipine comprises amlodipine besylate.  
     
     
         26 . The method of  claim 25 , wherein the atorvastatin compound comprises a therapeutically effective derivative of atorvastatin.  
     
     
         27 . The method of  claim 26 , wherein the therapeutically effective derivative of the atorvastatin compound is a hemicalcium salt.  
     
     
         28 . The method of  claim 23 , wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipdemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         29 . The method of  claim 23 , wherein amlodipine and the atorvastatin compound are administered in the same therapeutic.  
     
     
         30 . The method of  claim 23 , wherein amlodipine and the atorvastatin compound are administered as separate therapeutics.  
     
     
         31 . The method of  claim 23 , wherein amlodipine and the atorvastatin compound are administered at the same time.  
     
     
         32 . The method of  claim 23 , wherein amlodipine and the atorvastatin compound are administered at different times.  
     
     
         33 . The method of  claim 23 , wherein the treatment of arterial and related heart disease is at least partially a result of a process selected from the group consisting of reduced lipid oxidation, inhibited cholesterol crystal formation, and increased nitric oxide production from endothelial cells.  
     
     
         34 . A method of lowering blood pressure and systemic lipid concentrations comprising administering a therapeutically effective amount of a combination of amlodipine and an atorvastatin compound selected from the group consisting of atorvastatin and hydroxylated atorvastatin metabolite.  
     
     
         35 . The method of  claim 34 , wherein the amlodipine comprises a therapeutically effective derivative of amlodipine.  
     
     
         36 . The method of  claim 35 , wherein the therapeutically effective derivative of amlodipine comprises amlodipine besylate.  
     
     
         37 . The method of  claim 36 , wherein the atorvastatin compound comprises a therapeutically effective derivative of the atorvastatin compound.  
     
     
         38 . The method of  claim 37 , wherein the therapeutically effective derivative of the atorvastatin compound is a hemicalcium salt.  
     
     
         39 . The method of  claim 34 , wherein amlodipine and the atorvastatin compound are administered in the same therapeutic.  
     
     
         40 . The method of  claim 34 , wherein amlodipine and the atorvastatin compound are administered as separate therapeutics.  
     
     
         41 . The method of  claim 34 , wherein amlodipine and the atorvastatin compound are administered at the same time.  
     
     
         42 . The method of  claim 34 , wherein amlodipine and the atorvastatin compound are administered at different times.  
     
     
         43 . The method of  claim 34 , wherein said pharmaceutical composition lowers blood pressure and systemic lipid concentrations to a level consistent with a reduced risk of arterial and related heart disease.  
     
     
         44 . The method of  claim 43 , wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipidemia, atheroclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         45 . The method of  claim 34 , wherein said pharmaceutical composition lowers blood pressure and systemic lipid concentrations to a level statistically equivalent to normal.  
     
     
         46 . The method of  claim 34 , wherein the lowering of blood pressure and systemic lipid concentrations is at least partially a result of a process selected from the group consisting of reduced lipid oxidation, inhibited cholesterol crystal formation, and increased nitric oxide production from endothelial cells.  
     
     
         47 . A pharmaceutical composition comprising: 
 (a) a therapeutically effective amount of amlodipine;    (b) a therapeutically effective amount of a hydroxylated atorvastatin metabolite; and    (c) pharmaceutically acceptable formulation agents wherein said pharmaceutical composition synergistically lowers blood pressure and systemic lipid concentrations.    
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the therapeutically effective amount of amlodipine comprises a therapeutically effective derivative of amlodipine.  
     
     
         49 . The pharmaceutical composition of  claim 48 , wherein the therapeutically effective derivative of amlodipine comprises amlodipine besylate.  
     
     
         50 . The pharmaceutical composition of  claim 47 , wherein the hydroxylated atorvastatin compound comprises a therapeutically effective derivative of the hydroxylated atorvastatin compound.  
     
     
         51 . The pharmaceutical composition of  claim 50 , wherein the therapeutically effective derivative of the atorvastatin compound is a hemicalcium salt.  
     
     
         52 . The pharmaceutical composition of  claim 47 , wherein said pharmaceutical composition reduces the risk of arterial and related heart disease.  
     
     
         53 . The pharmaceutical composition of  claim 52 , wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipdemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         54 . The pharmaceutical composition of  claim 47 , wherein said pharmaceutical composition synergistically lowers blood pressure and systemic lipid concentrations to a level consistent with a reduced risk of arterial and related heart disease.  
     
     
         55 . The pharmaceutical composition of  claim 47 , wherein said pharmaceutical composition synergistically lowers blood pressure and systemic lipid concentrations to a level statistically equivalent to normal.  
     
     
         56 . The pharmaceutical composition of  claim 47 , wherein the synergistic lowering of blood pressure and systemic lipid concentrations results at least partially from a synergistic inhibition of cholesterol crystal formation.  
     
     
         57 . A pharmaceutical composition comprising: 
 (a) a therapeutically effective amount of a combination of amlodipine and a hydroxylated atorvastatin metabolite; and    (b) a one or more pharmaceutically acceptable formulation agents, 
 wherein said pharmaceutical composition synergistically lowers blood pressure and systemic lipid concentrations at least partially as a result of a synergistic inhibition of cholesterol crystal formation.  
   
     
     
         58 . A pharmaceutical composition comprising: 
 (a) a therapeutically effective amount of amlodipine;    (b) a therapeutically effective amount of a hydroxylated atorvastatin metabolite; and    (c) a one or more pharmaceutically acceptable formulation agents. 
 wherein said pharmaceutical composition synergistically lowers blood pressure and systemic lipid concentrations.  
   
     
     
         59 . A pharmaceutical composition comprising: 
 (a) a therapeutically effective amount of a combination of amlodipine and a hydroxylated atorvastatin metabolite; and    (b) a one ore more pharmaceutically acceptable formulation agents, 
 wherein said pharmaceutical composition synergistically lowers blood pressure and systemic lipid concentrations at least partially as a result of a synergistic increase in nitric oxide production by endothelial cells.