Methods and compositions for reducing ischemic injury of the heart by administering adenosine receptor agonists and antagonists

• US 20030092668A1
• Filed: 03/05/2001
• Published: 05/15/2003
• Est. Priority Date: 11/05/1999
• Status: Active Grant

• Current Assignee: The United States of America As Represented By The Secretary of Agriculture, Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Original Assignee: Trustees Of The University Of Pennsylvania (University of Pennsylvania)
• Inventors: Jacobson, Kenneth A., Liang, Bruce T.
• Granted Patent: US 6,586,413 B2
• Time in Patent Office: Days
• US Class Current: 514/46
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds

Abstract

Compositions and methods for reducing or preventing ischemic damage of the heart are disclosed. A preferred embodiment of the invention comprises the simultaneous administration of specific A3/A1 receptor agonists, to patients suffering from ischemic damage or at risk for the same. In yet another embodiment of the invention, a binary conjugate which acts as an agonist for the A3 receptor and an antagonist at the A2a receptor, is administered to reduce or prevent ischemic damage to the heart.

Claims

1. A method for preventing or reducing ischemic damage to the heart, in a patient in need thereof, comprising administering to said patient a partial agonist having affinity for the A1 adenosine receptors in an amount effective to activate the A1 receptors in the heart of said patient.

2. A method as claimed in claim 1, wherein said partial agonist is delivered using an administration means selected from the group consisting of intravenous administration, oral administration and cardiac perfusion.

3. A method as claimed in claim 1, wherein said partial agonist is 8-butylamino-N⁶-cyclopentyladenosine.

4. A method as claimed in claim 1 wherein said partial agonist is administered to said patient prior to a surgical procedure having potential to cause cardiac ischemic damage.

5. A method as claimed in claim 1, wherein said partial agonist is administered to said patient during a surgical procedure having potential to cause cardiac ischemic damage.

6. A method as claimed in claim 1, wherein said agonist is administered to said patient following a surgical procedure having potential to result in cardiac ischemic damage.

7. A method as claimed in claim 1, wherein said patient is in need of said treatment due to an anginal condition selected from the group consisting of chronic stable angina, unstable angina, post myocardial infarction angina.

8. A method as claimed in claim 1, wherein said patient is in need of such treatment due to acute myocardial infarction.

9. A method for preventing or reducing ischemic damage to the heart, in a patient in need thereof, comprising administering to said patient a partial agonist having affinity for the A3 adenosine receptors in an amount effective to activate the A3 receptors in the heart of said patient.

10. A method as claimed in claim 9, wherein said partial agonist is delivered using an administration means selected from the group consisting of intravenous administration, oral administration and cardiac perfusion.

11. A method as claimed in claim 9, wherein said partial agonist is selected from the group consisting of (1′

R,2′

R,3′

S,4′

R,5′

S)-4-{2-Chloro-6-[(3-iodophenylmethyl) amino]purin-9-yl}-1-(hydroxymethyl)bicyclo[3.1.0]-hexane-2,3-diol (MRS1760) and (1′

R,2′

R,3′

S,4′

R,5′

S)-1-(Hydroxymethyl)-4-{6-[(3-iodo-phenylmethyl)amino]purin-9-yl}bicyclo[3.1.0]hexane-2,3-diol(MRS1743).

12. A method as claimed in claim 9 wherein said partial agonist is administered to said patient prior to a surgical procedure having potential to cause cardiac ischemic damage.

13. A method as claimed in claim 9, wherein said partial agonist is administered to said patient during a surgical procedure having potential to cause cardiac ischemic damage.

14. A method as claimed in claim 9, wherein said agonist is administered to said patient following a surgical procedure having potential to result in cardiac ischemic damage.

15. A method as claimed in claim 9, wherein said patient is in need of said treatment due to an anginal condition selected from the group consisting of chronic stable angina, unstable angina, post myocardial infarction angina.

16. A method as claimed in claim 9, wherein said patient is in need of such treatment due to acute myocardial infarction.

17. A method for preventing or reducing apoptotic cell death mediated damage to the heart, in a patient in need thereof, comprising administering to said patient an agonist having affinity for both the A1 and A3 adenosine receptors in an amount effective to activate A3 and A1 receptors in the heart of said patient thereby reducing apoptosis.

18. A method as claimed in claim 17, wherein said agonist is delivered using an administration means selected from the group consisting of intravenous administration, oral administration and cardiac perfusion.

19. A method as claimed in claim 17, wherein said agonist is selected from the group of compounds listed in Table II.

20. A method as claimed in claim 17, wherein said agonist is N⁶-((2-trifluoromethyl)carbamoyl) adenosine-5′

uronamide.

21. A method as claimed in claim 17, wherein said agonist is N⁶-((3-iodophenyl)carbamoyl) adenosine-5′

uronamide.

22. A method as claimed in claim 17 wherein said agonist is a binary conjugate which has affinity for, and activates the A1 and A3 adenosine receptors simultaneously.

23. A method as claimed in claim 17 wherein said agonist is administered to said patient prior to a surgical procedure having potential to cause cardiac apoptotic cell death.

24. A method as claimed in claim 17, wherein said agonist is administered to said patient during a surgical procedure having potential to cause cardiac apoptotic cell death.

25. A method as claimed in claim 17, wherein said agonist is administered to said patient following a surgical procedure having potential to result in cardiac apoptotic cell death.

26. A method as claimed in claim 17, wherein said patient is in need of said treatment due to an anginal condition selected from the group consisting of chronic stable angina, unstable angina, post myocardial infarction angina.

27. A method as claimed in claim 17, wherein said patient is in need of such treatment due to acute myocardial infarction.

28. A method as claimed in claim 17, wherein said apoptotic cell death is caused by a condition selected from the group consisting of idiopathic cardiomyopathy, cardiomyopathy induced by drugs, cardiomyopathy induced by chronic alcoholism, familial cardiomyopathy, viral myocarditis and cardiomyopathy induced by immunological rejection after heart transplantation.

29. A method for preventing or reducing apoptotic cell death mediated damage to the heart, in a patient in need thereof, comprising administering to said patient a mixed agonist having affinity for the A3 and A1 adenosine receptors and an antagonist having affinity for the A2a adenosine receptor in amounts effective to activate said A3 and A1 receptors and inhibit activation of said A2a receptor in the heart of said patient.

30. A method as claimed in claim 29, wherein said agonist and said antagonist are delivered using an administration means selected from the group consisting of intravenous administration, oral administration and cardiac perfusion.

31. A method as claimed in claim 29, wherein said agonist is selected from the group of compounds listed in Table II.

32. A method as claimed in claim 29 wherein said antagonist is selected from the group of compounds listed in Table III.

33. A method as claimed in claim 29, wherein said agonist is N⁶-((2-trifluoromethyl)carbamoyl) adenosine-5′

uronamide.

34. A method as claimed in claim 29, wherein said agonist is N⁶-((3-iodophenyl) carbamoyl) adenosine-5′

uronamide.

35. A method as claimed in claim 29, wherein said agonist is selected from the group consisting of MRS 584, MRS 479, MRS 537 or MRS 1340.

36. A method as claimed in claim 29, wherein said antagonist is selected from the group consisting of CSC, DMPX, ZM241385 or SCH58261.

37. A method as claimed in claim 29, wherein said agonist and said antagonist are administered to said patient prior to a surgical procedure having potential to cause cardiac apoptotic cell death.

38. A method as claimed in claim 29, wherein said agonist and said antagonist are administered to said patient during a surgical procedure having potential to cause cardiac apoptotic cell death.

39. A method as claimed in claim 29, wherein said agonist and said antagonist are administered to said patient following a surgical procedure having potential to result in cardiac apoptotic cell death.

40. A method as claimed in claim 29, wherein said patient is in need of said treatment due to an anginal condition selected from the group consisting of chronic stable angina, unstable angina, and post myocardial infarction angina.

41. A method as claimed in claim 29, wherein said patient is in need of said treatment due to acute myocardial infarction.

42. A method as claimed in claim 29, wherein said apoptotic cell death is caused by a condition selected from the group consisting of idiopathic cardiomyopathy, cardiomyopathy induced by drugs, cardiomyopathy induced by chronic alcoholism, familial cardiomyopathy, viral myocarditis and cardiomyopathy induced by immunological rejection after heart transplantation.

43. A method for preventing or reducing apoptotic cell death mediated damage to the heart, in a patient in need thereof, comprising administering to said patient a binary conjugate, which acts as an adenosine A3 receptor agonist while simultaneously inhibiting the activation of A2a receptors in an amount effective to enhance myocardial response to said preconditioning stimuli.

44. A method as claimed in claim 43, wherein said patient is in need of such treatment due to a cardiac condition selected from the group consisting of chronic stable angina, unstable angina, post-myocardial infarction angina or acute myocardial infarction.

45. A method as claimed in claim 43 wherein said agonist is administered to said patient prior to a surgical procedure which may cause cardiac apoptotic cell death.

46. A method as claimed in claim 43, wherein said agonist is administered to said patient during a surgical procedure having potential to cause cardiac apoptotic cell death.

47. A method as claimed in claim 43, wherein said agonist is administered to said patient following a surgical procedure which may result in cardiac apoptotic cell death.

48. A method as claimed in claim 43, wherein said apoptotic cell death is caused by a condition selected from the group consisting of idiopathic cardiomyopathy, cardiomyopathy induced by drugs, cardiomyopathy induced by chronic alcoholism, familial cardiomyopathy, viral myocarditis and cardiomyopathy induced by immunological rejection after heart transplantation.

49. A method for preventing or reducing apoptotic cell death mediated damage to the heart, in a patient in need thereof, comprising administering to said patient both an adenosine A3 receptor agonist and at least one adenosine A1 receptor agonist in an amount effective to activate the A1 and A3 adenosine receptors in the heart of said patient.

50. A method as claimed in claim 49, wherein said agonists are delivered using an administration means selected from the group consisting of intravenous administration, oral administration and cardiac perfusion.

51. A method as claimed in claim 49, wherein said agonist and said agonists are administered to said patient prior to a surgical procedure having potential to cause cardiac apoptotic cell death.

52. A method as claimed in claim 49, wherein said agonist and said antagonist are administered to said patient during a surgical procedure having potential to cause cardiac apoptotic cell death.

53. A method as claimed in claim 49, wherein said agonist and said antagonist are administered to said patient following a surgical procedure having potential to result in cardiac apoptotic cell death.

54. A method as claimed in claim 49, wherein said patient is in need of said treatment due to an anginal condition selected from the group consisting of chronic stable angina, unstable angina, and post myocardial infarction angina.

55. A method as claimed in claim 49, wherein said patient is in need of said treatment due to acute myocardial infarction.

56. A method as claimed in claim 49, wherein said A3 agonist is selected from the group of compounds consisting of IB-MECA, Cl-IB-MECA, MRS 584, MRS 479, MRS 537, MRS 1340 and DBXMR and said A1 agonist is selected from the group of compounds listed in Table I.

57. A method as claimed in claim 49, wherein said apoptotic cell death is caused by a condition selected from the group consisting of idiopathic cardiomyopathy, cardiomyopathy induced by drugs, cardiomyopathy induced by chronic alcoholism, familial cardiomyopathy, viral myocarditis and cardiomyopathy induced by immunological rejection after heart transplantation.

58. A method for preventing or reducing apoptotic cell death mediated damage to the heart, in a patient in need thereof, comprising administering to said patient a binary conjugate acting as an agonist at the A3 adenosine receptor and an antagonist at the A2a adenosine receptor.

59. A method as claimed in claim 58, wherein said conjugate is delivered using an administration means selected from the group consisting of intravenous administration, oral administration and cardiac perfusion.

60. A method as claimed in claim 58, wherein said conjugate is administered to said patient prior to a surgical procedure having potential to cause cardiac apoptotic cell death.

61. A method as claimed in claim 58, wherein said conjugate is administered to said patient during a surgical procedure having potential to cause cardiac apoptotic cell death.

62. A method as claimed in claim 58, wherein said conjugate is administered to said patient following a surgical procedure having potential to result in cardiac apoptotic cell death.

63. A method as claimed in claim 58, wherein said patient is in need of said treatment due to an anginal condition selected from the group consisting of chronic stable angina, unstable angina, and post myocardial infarction angina.

64. A method as claimed in claim 58, wherein said patient is in need of said treatment due to acute myocardial infarction.

65. A method as claimed in claim 58, wherein said apoptotic cell death is caused by a condition selected from the group consisting of idiopathic cardiomyopathy, cardiomyopathy induced by drugs, cardiomyopathy induced by chronic alcoholism, familial cardiomyopathy, viral myocarditis and cardiomyopathy induced by immunological rejection after heart transplantation.

66. A method for preventing or reducing apoptotic cell death mediated damage to the heart, in a patient in need thereof, comprising administering to said patient a binary conjugate acting as an agonist at the A3 adenosine receptor and an agonist at the A1 adenosine receptor.

67. A method as claimed in claim 66, wherein said conjugate is delivered using an administration means selected from the group consisting of intravenous administration, oral administration and cardiac perfusion.

68. A method as claimed in claim 66, wherein said conjugate is administered to said patient prior to a surgical procedure having potential to cause cardiac apoptotic cell death.

69. A method as claimed in claim 66, wherein said conjugate is administered to said patient during a surgical procedure having potential to cause cardiac apoptotic cell death.

70. A method as claimed in claim 66, wherein said conjugate is administered to said patient following a surgical procedure having potential to result in cardiac apoptotic cell death.

71. A method as claimed in claim 66, wherein said patient is in need of said treatment due to an anginal condition selected from the group consisting of chronic stable angina, unstable angina, and post myocardial infarction angina.

72. A method as claimed in claim 66, wherein said patient is in need of said treatment due to acute myocardial infarction.

73. A method as claimed in claim 66, wherein said apoptotic cell death is caused by a condition selected from the group consisting of idiopathic cardiomyopathy, cardiomyopathy induced by drugs, cardiomyopathy induced by chronic alcoholism, familial cardiomyopathy, viral myocarditis and cardiomyopathy induced by immunological rejection after heart transplantation.