Details for Patent: 6,410,524

Title:	Combination therapy of angiotensin converting enzyme inhibitor and aldosterone antagonist for reducing morbidity and mortality from cardiovascular disease
Abstract:	Combinations of an ACE inhibitor, an aldosterone antagonist, and a loop diuretic are described for use in treatment of circulatory disorders. Of particular interest are therapies using captopril, enalapril or lisinopril co-administered with spironolactone. This co-therapy would be particularly useful to reduce the death rate or the number of non-fatal hospitalizations or prevent the progression of congestive heart failure in patients with cardiovascular disease.
Inventor(s):	Perez; Alfonzo T. (Lake Forest, IL), Asner; Debra J. (Morton Grove, IL), LaChapelle; Richard J. (Wilmette, IL), Alexander; John C. (Princeton, NJ), Roniker; Barbara (Chicago, IL)
Assignee:	G. D. Searle & Co. (Chicago, IL)
Filing Date:	Nov 05, 1999
Application Number:	09/434,685
Claims:	1. A co-therapy method for treating a cardiovascular disorder in a subject comprising administering a first amount of an angiotensin converting enzyme inhibitor and a second amount of eplerenone to the subject, wherein the first amount and second amount together comprise a therapeutically effective amount of the inhibitor and eplerenone. 2. The method of claim 1 wherein the 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. 3. The method of claim 2 wherein the 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. 4. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is benazepril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 5. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is moexipril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 6. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is perindopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 7. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is quinapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 8. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is ramipril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 9. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is trandolapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 10. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is cilazapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 11. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is fosinopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 12. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is spirapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 13. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is enalapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 14. The method of claim 13 wherein the angiotensin converting enzyme inhibitor is administered in a daily dose range of about 5 mg to about 40 mg. 15. The method of claim 1 wherein the angiotensin converting enzyme inhibitor is lisinopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 16. The method of claim 15 wherein the angiotensin converting enzyme inhibitor is administered in a daily dose range of about 5 mg to about 20 mg. 17. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered in a weight ratio range from about 0.1-to-one to about twenty-five-to-one of the angiotensin converting enzyme inhibitor to eplerenone. 18. The method of claim 17 wherein the weight ratio range is from about 0.5-to-one to about fifteen-to-one. 19. The method of claim 17 wherein the weight ratio range is from about 0.5-to-one to about five-to-one. 20. The method of claim 1 wherein eplerenone is administered in a daily dose range from about 0.5 mg to about 500 mg. 21. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered in a sequential manner. 22. The method of claim 1 wherein angiotensin converting enzyme inhibitor and eplerenone are administered in a substantially simultaneous manner. 23. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths as compared to monotherapy with an angiotensin converting enzyme inhibitor. 24. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the number of non-fatal hospitalizations as compared to monotherapy with an angiotensin converting enzyme inhibitor. 25. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths resulting from sudden death in subjects afflicted with or susceptible to elevated heart rate variability as compared to monotherapy with an angiotensin converting enzyme inhibitor. 26. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths resulting from progression of heart failure as compared to monotherapy with an angiotensin converting enzyme inhibitor. 27. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths or the number of non-fatal hospitalizations in subjects having a left ventricular ejection fraction greater than about 26% as compared to monotherapy with an angiotensin converting enzyme inhibitor. 28. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths or the number of non-fatal hospitalizations in subjects having a left ventricular ejection fraction less than about 26% as compared to monotherapy with an angiotensin converting enzyme inhibitor. 29. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination suppress clinically significant cough due to a respiratory tract disorder selected from the group consisting of elevated pulmonary arterial fibrosis, pulmonary edema and pleural effusion as compared to monotherapy with an angiotensin converting enzyme inhibitor. 30. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the blood level of N-terminal atrial natriuretic factor in the subject. 31. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in a reduction in the blood level of procollagen type III aminoterminal propeptide in the subject. 32. The method of claim 1 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered at doses that in combination result in an increase in the left ventricular ejection fraction in the subject as compared to monotherapy with an angiotensin converting enzyme inhibitor. 33. The method of claim 1 wherein the subject is a human. 34. The method of claim 1 wherein the subject is susceptible to sudden death. 35. The method of claim 1 wherein the subject is classified in New York Heart Association class III or class IV prior to combination therapy. 36. The method of claim 1 wherein the subject has a left ventricular ejection fraction greater than about 26%. 37. The method of claim 1 wherein the subject has a left ventricular ejection fraction less than about 26%. 38. The method of claim 1 wherein the subject is susceptible to or suffering from clinically significant cough due to a respiratory tract disorder selected from the group consisting of elevated pulmonary arterial fibrosis, pulmonary edema and pleural effusion. 39. A co-therapy method for treating a cardiovascular disorder in a subject comprising administering a first amount of an angiotensin converting enzyme inhibitor, a second amount of a diuretic, and a third amount of eplerenone to the subject, wherein the first, second and third amounts together comprise a therapeutically effective amount of the inhibitor, diuretic and eplerenone; and wherein the diuretic has no substantial aldosterone antagonist effect. 40. The method of claim 39 wherein the 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. 41. The method of claim 40 wherein the 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. 42. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is benazepril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 43. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is moexipril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 44. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is perindopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 45. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is quinapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 46. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is ramipril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 47. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is trandolapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 48. The method of claim 39 to wherein the angiotensin converting enzyme inhibitor is cilazapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 49. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is fosinopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 50. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is spirapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 51. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is enalapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 52. The method of claim 51 wherein the angiotensin converting enzyme inhibitor is administered in a daily dose range of about 5 mg to about 40 mg. 53. The method of claim 39 wherein the angiotensin converting enzyme inhibitor is lisinopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 54. The method of claim 53 wherein the angiotensin converting enzyme inhibitor is administered in a daily dose range of about 5 mg to about 20 mg. 55. The method of claim 39 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered in a weight ratio range from about 0.1-to-one to about twenty-five-to-one of the angiotensin converting enzyme inhibitor to eplerenone. 56. The method of claim 55 wherein the weight ratio range is from about 0.5-to-one to about fifteen-to-one. 57. The method of claim 55 wherein the weight ratio range is from about 0.5-to-one to about five-to-one. 58. The method of claim 39 wherein eplerenone is administered in a daily dose range from about 0.5 mg to about 500 mg. 59. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered in a sequential manner. 60. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered in a substantially simultaneous manner. 61. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths as compared to monotherapy with an angiotensin converting enzyme inhibitor. 62. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the number of non-fatal hospitalizations as compared to monotherapy with an angiotensin converting enzyme inhibitor. 63. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths resulting from sudden death in subjects afflicted with or susceptible to elevated heart rate variability as compared to monotherapy with an angiotensin converting enzyme inhibitor. 64. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths resulting from progression of heart failure as compared to monotherapy with an angiotensin converting enzyme inhibitor. 65. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths or the number of non-fatal hospitalizations in subjects having a left ventricular ejection fraction greater than about 26% as compared to monotherapy with an angiotensin converting enzyme inhibitor. 66. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the rate of deaths or the number of non-fatal hospitalizations in subjects having a left ventricular ejection fraction less than about 26% as compared to monotherapy with an angiotensin converting enzyme inhibitor. 67. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination suppress clinically significant cough due to a respiratory tract disorder selected from the group consisting of elevated pulmonary arterial fibrosis, pulmonary edema and pleural effusion as compared to monotherapy with an angiotensin converting enzyme inhibitor. 68. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the blood level of N-terminal atrial natriuretic factor in the subject. 69. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in a reduction in the blood level of procollagen type III aminoterminal propeptide in the subject. 70. The method of claim 39 wherein the angiotensin converting enzyme inhibitor, diuretic and eplerenone are administered at doses that in combination result in an increase in the left ventricular ejection fraction in the subject as compared to monotherapy with an angiotensin converting enzyme inhibitor. 71. The method of claim 39 wherein the subject is a human. 72. The method of claim 39 wherein the subject is susceptible to sudden death. 73. The method of claim 39 wherein the subject is classified in New York Heart Association class III or class IV prior to combination therapy. 74. The method of claim 39 wherein the subject has a left ventricular ejection fraction greater than about 26%. 75. The method of claim 39 wherein the subject has a left ventricular ejection fraction less than about 26%. 76. The method of claim 39 wherein the subject is susceptible to or suffering from clinically significant cough due to a respiratory tract disorder selected from the group consisting of elevated pulmonary arterial fibrosis, pulmonary edema and pleural effusion. 77. The method of claim 39 comprising administering a fourth amount of digoxin, wherein the first, second, third and fourth amounts together comprise a therapeutically effective amount of the angiotensin converting enzyme inhibitor, eplerenone, diuretic and digoxin. 78. The method of claim 71 wherein the angiotensin converting enzyme inhibitor, eplerenone, diuretic, and digoxin are administered at doses that in combination result in a reduction in the rate of deaths as compared to monotherapy with an angiotensin converting enzyme inhibitor. 79. The method of claim 77 wherein the angiotensin converting enzyme inhibitor, eplerenone, diuretic, and digoxin are administered at doses that in combination result in a reduction in the number of non-fatal hospitalizations as compared to monotherapy with an angiotensin converting enzyme inhibitor. 80. The method of claim 77 wherein the angiotensin converting enzyme inhibitor, eplerenone, diuretic, and digoxin are administered at doses that in combination result in a reduction in the blood level of N-terminal atrial natriuretic factor in the subject. 81. The method of claim 77 wherein the angiotensin converting enzyme inhibitor, eplerenone, diuretic, and digoxin are administered at doses that in combination result in a reduction in the blood level of procollagen type III aminoterminal propeptide in the subject. 82. The method of claim 77 wherein the angiotensin converting enzyme inhibitor, eplerenone, diuretic, and digoxin are administered at doses that in combination result in an increase in the left ventricular ejection fraction in the subject as compared to monotherapy with an angiotensin converting enzyme inhibitor. 83. A composition comprising an angiotensin converting enzyme inhibitor and eplerenone. 84. The composition of claim 83 comprising: a first amount of an angiotensin converting enzyme inhibitor; a second amount of eplerenone; and a pharmaceutically acceptable carrier. 85. The composition of claim 84 wherein the 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. 86. The composition of claim 85 wherein the 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. 87. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is benazepril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 88. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is moexipril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 89. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is perindopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 90. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is quinapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 91. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is ramipril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 92. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is trandolapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 93. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is cilazapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 94. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is fosinopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 95. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is spirapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 96. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is enalapril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 97. The composition of claim 96 wherein the angiotensin converting enzyme inhibitor is administered in a daily dose range of about 5 mg to about 40 mg. 98. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor is lisinopril, or a pharmaceutically acceptable salt, ester or prodrug thereof. 99. The composition of claim 98 wherein the angiotensin converting enzyme inhibitor is administered in a daily dose range of about 5 mg to about 20 mg. 100. The composition of claim 84 wherein the angiotensin converting enzyme inhibitor and eplerenone are administered in a weight ratio range from about 0.1-to-one to about twenty-five-to-one of the angiotensin converting enzyme inhibitor to eplerenone. 101. The composition of claim 100 wherein the weight ratio range is from about 0.5-to-one to about fifteen-to-one. 102. The composition of claim 101 wherein the weight ratio range is from about 0.5-to-one to about five-to-one. 103. The composition of claim 84 wherein eplerenone is administered in a daily dose range from about 0.5 mg to about 500 mg. 104. The composition of claim 84 further comprising a third amount of a diuretic. 105. The composition of claim 104 further comprising a fourth amount of digoxin.