Patent EA-003782-B1 (EA)
Title: Combination therapy of angiotensin converting enzyme inhibitor and aldosterone antagonist for reducing and morbidity and mortality from cardiovascular disease
Inventor: PEREZ ALFONSO T
IPC: A61K31/401
Filed: 1999-11-05
Abstract: 1. A method for preventing or treating a cardiovascular disorder in a subject, comprising a co-therapy characterized by administering the subject both eplerenone and an angiotensin converting enzyme inhibitor. 2. The method of claim 1 further characterized by administering diuretic to a subject which exhibits no such substantial effect as an aldosterone antagonist. 3. The method of claim 1 or 2 wherein said cardiovascular disorder is heart failure. 4. The method of claim 1 or 2 wherein said cardiovascular disorder is congestive heart failure. 5. The method of claim 1 or 2 wherein said cardiovascular disorder is hypertension. 6. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat, spirapril, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590. 7. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril. 8. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of benazepril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 9. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of moexipril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 10. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of perindopril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 11. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of quinapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 12. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of ramipril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 13. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of trandolapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 14. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of cilazapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 15. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of fosinopril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 16. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of spirapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 17. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of enalapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 18. The method of claim 17 wherein the daily dose of said of enalapril or a pharmaceutically acceptable salt thereof, ester or a prodrug is from 5 mg to 40 mg. 19. The method of any one of claims 1 to 5 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of lisinopril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 20. The method of claim 19 wherein the daily dose of said of lisinopril or a pharmaceutically acceptable salt thereof, ester or a prodrug is from 5 mg to 20 mg. 21. The method of claim 1 or 2 wherein weight ratio of angiotensin converting enzyme inhibitor to eplerenone in a daily dosage is from about 0.1:1 to about 25:1. 22. The method of claim 21 wherein said weight ratio is from about 0.5:1 to about 15:1. 23. The method of claim 21 wherein said weight ratio is from about 0.5:1 to about 5:1. 24. The method of any one of claims 1 to 5 wherein eplerenone amount is from about 1 mg to about 400 mg. 25. The method of any one of claims 1 to 5 wherein eplerenone amount is from about 2 mg to about 150 mg. 26. The method of claim 1 or 2 wherein administering said agents are administered in a sequential manner. 27. The method of claim 1 or 2 wherein administering said agents are administered in a substantially simultaneous manner. 28. The method of claim 1 or 2 wherein the amount of eplerenone administered to a patient is a therapeutically effective amount for reducing death rate or the number of non-fatal hospitalizations among a plurality of patients as compared to the mono-therapy by angiotensin converting enzyme inhibitor. 29. A pharmaceutical composition comprising an angiotensin converting enzyme inhibitor and eplerenone. 30. The composition of claim 29 comprising: a first amount of the angiotensin converting enzyme inhibitor, a second amount of the eplerenone, and a pharmaceutically acceptable carrier, wherein said first amount and the second amount comprise in combination a therapeutically effective amount of said angiotensin converting enzyme inhibitor and eplerenone. 31. The method of claim 29 or 30 further comprising a diuretic which exhibits no such substantial effect as an aldosterone antagonist. 32. The composition of any one of claims 29 to 31 further comprising digoxin. 33. The composition method of any one of claims 29 to 31 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat, spirapril, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590. 34. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril. 35. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of benazepril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 36. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of moexipril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 37. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of perindopril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 38. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of quinapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 39. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of ramipril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 40. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of trandolapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 41. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of cilazapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 42. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of fosinopril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 43. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of spirapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 44. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of enalapril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 45. The composition of claim 44 wherein the daily dose of said of enalapril or a pharmaceutically acceptable salt thereof, ester or a prodrug is from 5 mg to 40 mg. 46. The composition of any one of claims 29 to 32 wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of lisinopril or a pharmaceutically acceptable salt thereof, ester or a prodrug. 47. The composition of claim 46 wherein the daily dose of said of lisinopril or a pharmaceutically acceptable salt thereof, ester or a prodrug is from 5 mg to 20 mg. 48. The composition of any one of claims 29 to 32 wherein weight ratio of angiotensin converting enzyme inhibitor to eplerenone in a daily dosage is from about 0.1:1 to about 25:1. 49. The composition of claim 48 wherein said weight ratio is from about 0.5:1 to about 15:1. 50. The composition of claim 48 wherein