Treatment of osteoporosis and metabolic bone disorders with nitric oxide substrate and/or donors

• US 6,133,320 A
• Filed: 10/22/1998
• Issued: 10/17/2000
• Est. Priority Date: 03/19/1996
• Status: Expired due to Fees

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Wimalawansa, Sunil J., Yallampalli, Chandrasekhar
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US09/177,978
• Time in Patent Office: 726 Days
• Field of Search: 514/632, 514/634, 514/742
• US Class Current: 514/632
• 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 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/295 Iron group metal compounds
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

Primary and secondary osteoporosis in a female or a male mammal is treated by administering thereto a nitric oxide synthase substrate, a nitric oxide donor or both, optionally; in further combination with one or more of an estrogen, a progestin, an anabolic steroid. Nitric oxide substrate or donor also can be combined with one or more of other medications acting on bone, such as bisphosphonate, calcitonin, fluoride, androgen and other novel therapeutic agents. Either nitric oxide donor or substrate by itself or combination with other medications as described above can be used in both women and men, (preferably human) for prevention and treatment of osteoporosis and other metabolic bone disorders.

Claims

1. A method for prevention or treatment of primary and secondary osteoporosis of a female or male mammal comprising administering to the susceptible or afflicted mammal at least one of L-arginine effective to raise the blood level of circulating L-arginine to at least about 1 mM above the normally circulating levels or a nitric oxide donor in an amount producing a level of nitric oxide about equivalent to that produced by the elevated L-arginine levels.

2. The method of claim 1, where the mammal is female, further comprising administration of at least one of an estrogen and progestin.

3. The method of claim 1, where the mammal is male, further comprising administration of an androgen.

4. The method of claim 1 further comprising administration of an agent affecting bone metabolism.

5. The method of claim 4 where the agent is at least one of calcitonin, anabolic steroid and fluoride.

6. The method of claim 1, wherein the mammal is a female human suffering from primary or secondary osteoporosis.

7. The method of claim 1, wherein the mammal is a female human subject to hormone replacement therapy, a candidate for hormone replacement therapy or for osteoporosis therapy.

8. The method of claim 1 wherein the mammal is a male human having osteoporosis or being a candidate for osteoporosis therapy.

9. The method of claim 1, wherein the mammal is a human and L-arginine is administered thereto.

10. The method of claim 1, wherein the mammal is a human and a nitric oxide donor is administered thereto.

11. The method of claim 10, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerine, SIN-1, isosorbidmononitrite or isosorbiddinitrite.

12. The method of claim 10, wherein the nitric oxide donor is administered orally or parenterally.

13. The method of claim 10 where the administration is transdermal, by inhalation, percutaneous, intravenous, intramuscular, subcutaneous, depot preparation, sublingual or rectal.

14. The method of claim 1, wherein the mammal is a human female and the L-arginine or nitric oxide donor is administered in combination with an estrogen.

15. The method of claim 14, wherein the estrogen is estradiol valerate, conjugated equine estrogens, 17b-estradiol, estrone or estriol.

16. The method of claim 14 where the estrogen is an estrogen analog and an antiestrogen.

17. The method of claim 1, wherein the mammal is a female human and the L-arginine or nitric oxide donor is administered in combination with a progestin.

18. The method of claim 17, wherein the progestin is progesterone, dyprogesterone, medroxyprogesterone, norethisterone, levonorgestrel, or norgestrel.

19. The method of claim 17 where the progestin is a progestational compound or progestin analog.

20. The method of claim 2, wherein the mammal is a female human and the estrogen or progestin are administered continuously.

21. The method of claim 2, wherein the mammal is a female human and the estrogen or progestin is administered cyclically.

22. The method of claim 1, wherein the mammal is a human and the L-arginine or nitric acid donor is administered in combination with calcitonin.

23. The method of claim 22, wherein the calcitonin is salmon calcitonin, eel calcitonin, human calcitonin, α

calcitonin, β

calcitonin or calcitonin analog.

24. The method of claim 1, wherein the mammal is a human and the L-arginine or nitric oxide donor is administered in combination with a fluoride salt.

25. The method of claim 24, wherein the fluoride salt is a rapid or slow release sodium fluoride formulation.

26. The method of claim 1, wherein the mammal is a human and the L-arginine or nitric oxide donor is administered in combination with an anabolic steroid.

27. The method of claim 26, wherein the anabolic steroid is nondrolone decanoate.

28. The method of claim 5 wherein the mammal is a human and calcitonin, fluoride, or anabolic steroid is administered continuously.

29. The method of claim 5 wherein the mammal is a human and calcitonin or fluoride is administered cyclically.

30. The method of claim 1 wherein the male mammal is a human and L-arginine or nitric acid donor is administered in combination with an androgen.

31. The method of claim 30, wherein the androgen is testosterone.

32. The method of claim 3 wherein the mammal is a male human and the androgen is administered continuously.

33. The method of claim 3, wherein the mammal is a male human and the androgen is administered cyclically.

34. A pharmaceutical composition comprising (a) at least one of L-arginine and a nitric oxide donor, and (b) at least one of, an estrogen, a progestin, a calcitonin, a fluoride, an anabolic steroid, or an androgen.

35. The composition of claim 34 wherein L-arginine is in an amount effective to raise blood level of circulating L-arginine to at least about 10-50 nM above normally circulating levels upon administration to a patient.

36. The composition of claim 34 wherein the nitric oxide donor is in an amount effective, upon administration to raise nitric oxide levels to about 1-1000 nmolar.

37. The composition of claim 34 wherein estrogen is in an amount equivalent to 1-2 mg of estradiol.

38. The composition of claim 34 wherein the progestin is in an amount bioequivalent to 50-300 mg of injected progesterone.

39. The composition of claim 34 wherein calcitonin is in an amount equivalent to 10-200 I.U. of human calcitonin.

40. The composition of claim 34 wherein fluoride is in an amount equivalent to 10-50 mg of sodium fluoride.

41. The composition of claim 34 wherein anabolic steroid is in an amount equivalent to 50 mg of nondrolone decanoate, and androgens are in an amount equivalent to 100 mg of testosterone.

42. The composition according to claim 34, wherein L-arginine is present.

43. The composition according to claim 34, wherein a nitric oxide donor is present.

44. The composition according to claim 43, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerine, glyceryltrinitrate, SIN-1, isosorbidmononitrate or isosorbiddinitrate.

45. The composition according to claim 34, wherein the estrogen is natural or synthetic estrogen or antiestrogen.

46. The composition according to claim 34, wherein the progestin is norgestrel.

47. The composition according to claim 34, wherein the calcitonin is human, salmon or eel calcitonin.

48. The composition according to claim 34, wherein the fluoride is sodium fluoride or a slow release fluoride preparation.

49. The composition according to claim 34, wherein the anabolic steroid is nondrolone decanoate.

50. The composition according to claim 34, wherein the androgen is testosterone.

51. A method for prevention or treatment of primary and secondary osteoporosis comprising administering a nitric oxide donor in an amount effective to provide a level of nitric oxide donor of about 1-1000 nM to a female or male mammal susceptible to or suffering from primary or secondary osteoporosis.

52. The method of claim 51, where the mammal is female, further comprising administration of at least one of an estrogen and progestin.

53. The method of claim 51, where the mammal is male, further comprising administration of an androgen.

54. The method of claim 51, further comprising administration of an agent affecting bone metabolism.

55. The method of claim 54, wherein the agent is at least one of a calcitonin, anabolic steroid and fluoride.

56. The method of claim 51, wherein the mammal is a female human suffering from primary or secondary osteoporosis.

57. The method of claim 51, wherein the mammal is a female human subject to hormone replacement therapy, a candidate for hormone replacement therapy or for osteoporosis therapy.

58. The method of claim 51, wherein the mammal is a male human having osteoporosis or being a candidate for osteoporosis therapy.

59. The method of claim 51, wherein the nitric oxide donor may be selected from the group consisting of sodium nitroprusside, nitroglycerine, SIN-1, isosorbidmononitrite and isosorbiddinitrite.

60. The method of claim 51, wherein the nitric oxide donor is administered orally or parenterally.

61. The method of claim 51, wherein the nitric oxide donor is administered transdermally, by inhalation, percutaneously, intravenously, intramuscularly, subcutaneously, by depot preparation, sublingually or rectally.

62. The method of claim 52, wherein the nitric oxide donor is administered in combination with an estrogen.

63. The method of claim 62, wherein the estrogen may be selected from the group consisting of estradiol valerate, conjugated equine estrogens, 17b-estradiol, estrone and estriol.

64. The method of claim 62, wherein the estrogen is an estrogen analog and an antiestrogen.

65. The method of claim 52, wherein the nitric oxide donor is administered in combination with a progestin.

66. The method of claim 65, wherein the progestin be selected from the group consisting of progesterone, dyprogesterone, medroxyprogesterone, norethisterone, levonorgestrel and norgestrel.

67. The method of claim 65, wherein the progestin is a pregestational compound or progestin analog.

68. The method of claim 52, wherein the estrogen or progestin are administered continuously.

69. The method of claim 52, wherein the estrogen or progestin is administered cyclically.

70. The method of claim 55, wherein the nitric oxide donor is administered in combination with a calcitonin.

71. The method of claim 70, wherein the calcitonin be selected from the group consisting of salmon calcitonin, eel calcitonin, human calcitonin, α

calcitonin, β

calcitonin and calcitonin analog.

72. The method of claim 55, wherein the nitric oxide donor is administered in combination with a fluoride salt.

73. The method of claim 72, wherein the fluoride salt is a rapid or slow release sodium fluoride formulation.

74. The method of claim 55, wherein the nitric oxide donor is administered in combination with an anabolic steroid.

75. The method of claim 74, wherein the anabolic steroid is nondrolone decanoate.

76. The method of claim 55, wherein the calcitonin, fluoride or anabolic steroid is administered continuously.

77. The method of claim 55, wherein the calcitonin, fluoride or anabolic steroid is administered cyclically.

78. The method of claim 53, wherein the androgen is testosterone.

79. The method of claim 53, wherein the androgen is administered continuously.

80. The method of claim 53, wherein the androgen is administered cyclically.

81. A pharmaceutical composition comprising a nitric oxide donor and at least one compound selected from the group consisting of an estrogen, a progestin, a calcitonin, a fluoride, an anabolic steroid, and an androgen.

82. The composition of claim 81, wherein the nitric oxide donor is in an amount effective to raise nitric oxide levels to about 1-1000 molar upon administration.

83. The composition of claim 81, further comprising an estrogen.

84. The composition of claim 83, wherein the estrogen is natural or synthetic estrogen or antiestrogen.

85. The method of claim 83, wherein the estrogen is in an amount equivalent to 1-2 mg of estradiol.

86. The composition of claim 81, further comprising a progestin.

87. The composition of claim 86, wherein the progestin is norgestrel.

88. The composition of claim 86, wherein the progestin is in an amount bioequivalent to 50-300 mg of injected progesterone.

89. The composition of claim 81, further comprising calcitonin.

90. The composition of claim 89, wherein the calcitonin be human, salmon or eel calcitonin.

91. The composition of claim 89, wherein the calcitonin is in an amount equivalent to 10-200 I.U. of human calcitonin.

92. The composition of claim 81, further comprising fluoride.

93. The composition of claim 92, wherein the fluoride be sodium fluoride or a slow release fluoride preparation.

94. The composition of claim 92, wherein the fluoride is in an amount equivalent to 10-50 mg of sodium fluoride.

95. The composition of claim 81, further comprising an anabolic steroid and androgen.

96. The composition of claim 95, wherein the anabolic steroid is nondrolone decanoate and the androgen is testosterone.

97. The composition of claim 95, wherein the anabolic steroid is in an amount equivalent to 50 mg of nondrolone decanoate and androgen is in an amount equivalent to 100 mg of testosterone.

98. The composition of claim 81, wherein the nitric oxide donor be selected from the group consisting of sodium nitroprusside, nitroglycerine, glyceryltrinitrate, SIN-1, isosorbidmononitrate and isosorbiddinitrate.