Endothelin antagonist and/or endothelin synthase inhibitor in combination with a progestin, an estrogen, a cyclooxygenase inhibitor, or a nitric acid donor or substrate

• US 5,811,416 A
• Filed: 05/08/1995
• Issued: 09/22/1998
• Est. Priority Date: 06/06/1994
• Status: Expired due to Fees

• Current Assignee: Bayer Schering Pharma AG (Bayer AG), Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Schering Ag (Merck & Co., Inc.), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Chwalisz, Kristof, Garfield, Robert E.
• Primary Examiner(s): JORDAN, KIMBERLY R
• Application Number:
  US08/437,462
• Time in Patent Office: 1,233 Days
• Field of Search: 514/177, 514/548, 514/565, 514/899
• US Class Current: 514/177
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/223 of alpha-aminoacids
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

A pharmaceutical composition for and methods of treatment of menstrual disorders, e.g., dysmenorrhea, in a non-pregnant female, preterm labor, preeclampsia and/or fetal growth retardation in a pregnant female mammal, treatment of atherosclerotic vascular disease and hypertension in males as well as females, and for hormone replacement therapy in peri- and post-menopausal females, comprising administering effective amounts of an endothelin antagonist and/or an endothelin synthase inhibitor or both, in combination with

a progestin, and/or an estrogen, and/or

a cyclooxygenase inhibitor, and/or

a nitric oxide donor and/or nitric oxide substrate,

to prevent and/or ameliorate said conditions, are disclosed. In the method aspects, the endothelin antagonist and/or endothelin synthase inhibitor can be administered alone for treatment of menstrual disorders, e.g., dysmenorrhea, in a non-pregnant female, preterm labor, preeclampsia and/or fetal growth retardation in a pregnant female mammal. Further, methods for screening compounds for such treatments are disclosed.

Claims

1. A pharmaceutical composition comprising synergistically effective amounts of

(a) an endothelin antagonist, an endothelin synthase inhibitor, or both, in combination with

(b) at least one of a progestin, an estrogen, a combination of a progestin and an estrogen, a cyclooxygenase inhibitor, or a nitric oxide (NO) donor, an NO substrate, or both,

together with a pharmaceutically acceptable excipient.

2. A method of treating a menstrual disorder in a non-pregnant female mammal, comprising administering to the female in need of such treatment an effective amount of a composition of claim 1.

3. A method of claim 2, wherein the female is a human suffering from dysmenorrhea.

4. A method of claim 2, wherein the female mammal is a human and (a) is an endothelin antagonist.

5. A method of claim 4, wherein the endothelin antagonist is BQ-123.

6. A method of claim 2, wherein the female mammal is a human and (a) is an endothelin synthase inhibitor.

7. A method of claim 6, wherein the endothelin synthase inhibitor is SQ 28 608.

8. A method of claim 2, wherein the female mammal is a human and (b) is a progestin.

9. A method of claim 8, wherein the progestin is progesterone.

10. A method of claim 2, wherein the female mammal is a human and (b) is an NO donor or NO substrate.

11. A method of claim 10, wherein the NO substrate is L-arginine.

12. A method of claim 2, wherein the endothelin antagonist is administered orally.

13. A method of claim 2, wherein the endothelin synthase inhibitor is administered orally.

14. A method of treating preterm labor, preeclampsia or fetal growth retardation in a pregnant female mammal, comprising administering to the female in need of such treatment an effective amount of a composition of claim 1.

15. A method of claim 14, wherein the female mammal is a human suffering from preterm labor.

16. A method of claim 14, wherein the female mammal is a human female suffering from preeclampsia or fetal growth retardation.

17. A method of claim 14, wherein the female mammal is a human and (a) is an endothelin antagonist.

18. A method of claim 11, wherein the endothelin antagonist is BQ-123.

19. A method of claim 14, wherein the female mammal is a human and (a) is an endothelin synthase inhibitor.

20. A method of claim 19, wherein the endothelin synthase inhibitor is SQ 28 608.

21. A method of claim 14, wherein the female mammal is a human and (b) is a progestin.

22. A method of claim 14, wherein the progestin is progesterone.

23. A method of claim 14, wherein the female mammal is a human and (b) is an NO donor or NO substrate.

24. A method of claim 23, wherein the NO substrate is L-arginine.

25. A method of claim 14, wherein the endothelin antagonist is administered orally.

26. A method of claim 14, wherein the endothelin synthase inhibitor is administered orally.

27. A composition of claim 1, wherein (a) is an endothelin antagonist.

28. A composition of claim 27, wherein the endothelin antagonist is BQ-123.

29. A composition of claim 1, wherein (a) is an endothelin synthase inhibitor.

30. A composition of claim 29, wherein the endothelin synthase inhibitor is SQ 28 608.

31. A composition of claim 1, wherein the progestin is progesterone.

32. A composition of claim 31, wherein the cyclooxygenase inhibitor is aspirin.

33. A pharmaceutical composition of claim 1, comprising

(a) an endothelin antagonist, an endothelin synthase inhibitor, or both, and

(b) a progestin, an estrogen, or a combination of an estrogen and a progestin, or

(c) a nitric oxide donor, a nitric oxide substrate, or both, or both (b) and (c),

and, optionally, a cyclooxygenase inhibitor, together with a pharmaceutically acceptable excipient.

34. A method of treating atherosclerotic vascular disease or hypertension in a male or female mammal, comprising administering to the mammal in need of such treatment an effective amount of a composition of claim 33, wherein, when the mammal is male, component (b) does not include an estrogen.

35. A method of claim 34, wherein the mammal is a human female suffering from hypertension, and (b) is an estrogen or a combination of an estrogen and a progestin.

36. A method of claim 34, wherein the mammal is a human male suffering from hypertension, and (b) is a progestin.

37. A method of claim 34, wherein the mammal is a human and (a) is an endothelin antagonist.

38. A method of claim 37, wherein the endothelin antagonist is BQ-123.

39. A method of claim 34, wherein the mammal is a human and (a) is an endothelin synthase inhibitor.

40. A method of claim 39, wherein the endothelin synthase inhibitor is SQ 28 608.

41. A method of claim 34, wherein the mammal is a human female suffering from atherosclerotic vascular disease and (b) is an estrogen or a combination of an estrogen and a progestin.

42. A method of claim 34, wherein the mammal is a human male suffering from atherosclerotic vascular disease and (b) is a progestin.

43. A method of claim 34, wherein the mammal is a human and the composition includes a nitric oxide donor and/or nitric oxide substrate.

44. A method of claim 34, wherein the progestin is progesterone.

45. A method of claim 34, wherein the nitric oxide donor and/or nitric oxide substrate are nitroglycerin and L-arginine, respectively.

46. A method of claim 34, wherein the endothelin antagonist is administered orally.

47. A method of claim 34, wherein the endothelin synthase inhibitor is administered orally.

48. A method of providing hormone replacement therapy in a female mammal, comprising administering to the female in need of such treatment an effective amount of a composition of claim 33.

49. A method of claim 48, wherein the female mammal is a human female, and (b) is a progestin or a combination of an estrogen and a progestin.

50. A method of claim 48, wherein the female mammal is a human and (a) is an endothelin antagonist.

51. A method of claim 39, wherein the endothelin antagonist is BQ-123.

52. A method of claim 48, wherein the female mammal is a human and (a) is an endothelin synthase inhibitor.

53. A method of claim 52, wherein the endothelin synthase inhibitor is SQ 28 608.

54. A method of claim 48, wherein the female mammal is a human and the composition includes a nitric oxide donor and/or nitric oxide substrate.

55. A method of claim 48, wherein the progestin is progesterone.

56. A method of claim 48, wherein the nitric oxide donor and/or nitric oxide substrate are nitroglycerin and L-arginine, respectively.

57. A method of claim 48, wherein the endothelin antagonist is administered orally.

58. A method of claim 48, wherein the endothelin synthase inhibitor is administered orally.

59. A composition of claim 53, wherein (a) is an endothelin antagonist.

60. A composition of claim 59, wherein the endothelin antagonist is BQ-123.

61. A composition of claim 59, wherein (a) is an endothelin synthase inhibitor.

62. A composition of claim 61, wherein the endothelin synthase inhibitor is SQ 28 608.

63. A composition of claim 33, wherein the progestin is progesterone.

64. A composition of claim 33, wherein the nitric oxide donor and/or nitric oxide substrate are nitroglycerin and L-arginine, respectively.