US2007037860A1PendingUtilityA1

Synergistic effects of amlodipine and atorvastatin metabolite as a basis for combination therapy

57
Individually held — no corporate assignee on recordPriority: Apr 23, 1999Filed: Oct 11, 2006Published: Feb 15, 2007
Est. expiryApr 23, 2019(expired)· nominal 20-yr term from priority
Inventors:R. Preston Mason
A61K 31/455A61K 31/401A61K 31/4015A61K 31/44
57
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Claims

Abstract

The combination of amlodipine with atorvastatin metabolite shows a synergistic antioxidant effect on lipid peroxidation in human low-density lipoproteins and membrane vesicles enriched with polyunsaturated fatty acids. Inhibition of oxy-radical damage by this drug combination was observed at therapeutic levels in a manner that could not be reproduced by the combination of amlodipine with other statins or the natural antioxidant, vitamin E. The basis for the potent activity is attributed to the chemical structures of these compounds and their molecular interactions with phospholipids molecules, as determined by x-ray diffraction analyses. This combination therapy can be used to treat cardiovascular disorders, especially coronary artery disease, by increasing the resistance of low-density lipoproteins and vascular cell membranes against oxidative modification.

Claims

exact text as granted — not AI-modified
1 . A method of treating arterial and related heart disease and substantially inhibiting lipid peroxide in LDL and lipid membranes comprising administering a therapeutically effective amount of a combination of amlodipine and hydroxylated atorvastatin metabolite, wherein said hydroxylated atorvastatin metabolite is selected from the group consisting of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(4-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethy]1-1H-pyrrole-3-carboxamide, (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-( 3 -hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-( 2 -hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl]-1H-pyrrole-3-carboxamide.  
     
     
         2 . (canceled)  
     
     
         3 . The method of  claim 21  wherein the therapeutically effective amlodipine comprises amlodipine besylate.  
     
     
         4 . The method of  claim 1  wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipidemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         5 . The method of  claim 1  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered in the same therapeutic.  
     
     
         6 . The method of  claim 1  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered as separate therapeutics.  
     
     
         7 . The method of  claim 1  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered at the same time.  
     
     
         8 . The method of  claim 1  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered at different times.  
     
     
         9 . A method of substantially inhibiting lipid oxidation and lowering blood pressure and systemic lipid concentrations comprising administering a therapeutically effective amount of a combination of amlodipine and hydroxylated atorvastatin metabolite, wherein said hydroxylated atorvastatin metabolite is selected from the group consisting of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(4-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro- 4 -hydroxy- 6 -oxo- 2 H-pyran- 2 -yl)ethyl]-1H-pyrrole-3-carboxamide, (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(3-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-( 2 -hydroxyphenyl)- 4 -phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.  
     
     
         10 . (canceled)  
     
     
         11 . The method of  claim 9  wherein the therapeutically effective amlodipine comprises amlodipine besylate.  
     
     
         12 . The method of  claim 9  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered in the same therapeutic.  
     
     
         13 . The method of  claim 9  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered as separate therapeutics.  
     
     
         14 . The method of  claim 9  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered at the same time.  
     
     
         15 . The method of  claim 9  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered at different times.  
     
     
         16 . The method of  claim 9  wherein said combination of amlodipine and hydroxylated atorvastatin metabolite lowers blood pressure and systemic lipid concentrations to a level consistent with a reduced risk of arterial and related heart disease.  
     
     
         17 . The method of  claim 16  wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipidemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         18 . The method of  claim 9  wherein said combination of amlodipine and hydroxylated atorvastatin metabolite lowers blood pressure and systemic lipid concentrations to a level statistically equivalent to normal.  
     
     
         19 . The method of any of claims  9 - 18  wherein the lowering of blood pressure and systemic lipid concentrations results at least partially from reduced lipid oxidation.  
     
     
         20 . A method of synergistically inhibiting lipid oxidation comprising administering a therapeutically effective amount of a combination of amlodipine and hydroxylated atorvastatin metabolite, wherein said hydroxylated atorvastatin metabolite is selected from the group consisting of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(4-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(3-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, and (2R-trans)- 5 -( 4 -fluorophenyl)-2-(1-methylethyl)-N-(2-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.  
     
     
         21 . (canceled)  
     
     
         22 . The method of claim  2420  wherein the therapeutically effective amlodipine comprises amlodipine besylate.  
     
     
         23 . The method of  claim 20  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered in the same therapeutic.  
     
     
         24 . The method of  claim 20  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered as separate therapeutics.  
     
     
         25 . The method of  claim 20  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered at the same time.  
     
     
         26 . The method of  claim 20  wherein amlodipine and the hydroxylated atorvastatin metabolite are administered at different times.  
     
     
         27 . The method of  claim 20  wherein said combination of amlodipine and hydroxylated atorvastatin metabolite inhibits lipid oxidation to an extent consistent with a reduced risk of arterial and related heart disease.  
     
     
         28 . The method of  claim 27  wherein said arterial and related heart disease is selected from the group consisting of hypertension, hyperlipidemia, atherosclerosis, arteriosclerosis, coronary artery disease, myocardial infarction, congestive heart failure, stroke, and angina pectoris.  
     
     
         29 . A method of lowering blood pressure and systemic lipid concentrations comprising administering a therapeutically effective amount of a combination of amlodipine and hydroxylated atorvastatin metabolite, wherein said hydroxylated atorvastatin metabolite is selected from the group consisting of (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(4-hydroxyphenyl)-4-phenyl-1-2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(3-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy- 6 -oxo- 2 H-pyran- 2 -yl)ethyl]-1H-pyrrole-3-carboxamide, and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N-(2-hydroxyphenyl)-4-phenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethvll-1H-pyrrole-3-carboxamide.  
     
     
         30 . The method of  claim 29  wherein said combination of amlodipine and hydroxylated atorvastatin metabolite synergistically lowers blood pressure and systemic lipid concentrations to a level statistically equivalent to normal.  
     
     
         31 . The method of  claim 30  wherein the synergistic lowering of blood pressure and systemic lipid concentrations results at least partially from reduced lipid oxidation.  
     
     
         32 . The method of  claim 1  further comprising administering an effective amount of a lipophilic antioxidant.  
     
     
         33 . The method of  claim 9  further comprising administering an effective amount of a lipophilic antioxidant.  
     
     
         34 . The method of  claim 20  further comprising administering an effective amount of a lipophilic antioxidant.  
     
     
         35 . The method of  claim 29  further comprising administering an effective amount of a lipophilic antioxidant.

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