MODULATION OF NITRIC OXIDE SYNTHASES BY BETAINES

• US 20100305206A9
• Filed: 05/10/2007
• Published: 12/02/2010
• Est. Priority Date: 11/10/2004
• Status: Active Grant

• Current Assignee: Jallal Messadek
• Original Assignee: Jallal Messadek
• Inventors: Messadek, Jallal
• Granted Patent: US 8,318,805 B2
• Time in Patent Office: Days
• US Class Current: 514/554
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• 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 31/205 Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to therapeutic compositions of betaines and L-arginine and physiologically acceptable salts thereof, and to pharmaceutical uses of betaines for up-regulating, enhancing, stimulating, controlling and/or increasing constitutive nitric oxide synthase expression a mammal, particularly in a human. Additionally, the betaines are believed to augment after administration both immunological and functional (activity) expression of Tissue Factor Pathway Inhibitor (TFPI) in a mammal, particularly a human.

Claims

1. A method for treating a patient suffering of at least one trouble related to constitutive nitric oxide deficiency, comprising the step of administering to in which the patient is administered with an efficient therapeutical amount of betaine for increasing in said patient at least one nitric oxide production pathway selected from the group consisting of constitutive nitric oxide synthase expression, constitutive Endothelial nitric oxide synthase expression, eNOS nitric oxide synthase expression, neural NOS nitric oxide synthase expression (nNOS), platelet NOS nitric oxide synthase expression, cNOS nitric oxide synthase expression, Type III nitric oxide synthase expressions, calcium dependant nitric oxide synthase expression, calcium dependant nitric oxide synthase production, endogenous nitric oxide production, and combinations thereof.

2. The method of claim 1, in which the patient is administered with an efficient therapeutical amount of glycine betaine for increasing the rate of said at least one nitric oxide production pathway in said patient.

3. The method of claim 1, in which the patient is administered with an efficient therapeutical amount of glycine betaine for increasing by a factor comprised between 1.2 and 3 the rate of said at least one nitric oxide production in said patient.

4. The method of claim 1, in which the patient is administered orally an oral composition comprising at least (a) betaine and (b) L-arginine or a physiologically acceptable salt thereof.

5. The method of claim 4, in which the oral composition comprises at least 20% by weight betaine and 20% by weight L-arginine or salt thereof.

6. The method of claim 5, in which the weight ratio L-arginine or salt thereof/betaine is comprised between 0.5 and 2.

7. The method of claim 1 for treating a patient suffering at least one trouble selected from the group consisting of vasodilation troubles, vision troubles, bone growth troubles, open angle glaucoma and combinations thereof caused by a NO deficiency in said patient, in which the patient is administered with an efficient therapeutical amount of betaine for increasing the NO level to an adapted level for treating said at least one trouble.

8. The method of claim 1 for treating a patient suffering at least of one trouble related to deficiency of neural nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for increasing neural nitric oxide synthase nNOS expressions in a mammal, particularly in a human.

9. The method of claim 1 for treating a patient suffering at least one trouble related to deficiency of platelet nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for increasing platelet nitric oxide synthase expressions in a mammal, particularly in a human.

10. The method of claim 1 for treating a patient suffering at least one trouble related to deficiency of platelet nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for increasing platelet nitric oxide production or production rate in a mammal, particularly in a human.

11. The method of claim 1 for treating a patient suffering at least one trouble related to deficiency of platelet nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for increasing platelet nitric oxide production in a mammal, particularly in a human and for controlling the venous capacitance of said mammal.

12. The method of claim 1 for treating a patient suffering at least one trouble related to deficiency of platelet nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for increasing platelet nitric oxide production in a mammal, particularly in a human and for controlling the arterial capacitance of said mammal.

13. The method of claim 1 for treating a patient suffering at least one trouble related to deficiency of nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for increasing bioavallability of endothelial nitric oxide in a mammal, particularly in a human.

14. The method of claim 1 for treating a patient suffering at least one trouble related to deficiency of nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for controlling and/or up-regulating endothelial nitric oxide bioavailability in a mammal, particularly in a human.

15. The method of claim 1 for treating a patient suffering at least one trouble related to cerebral deficiency of nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for controlling and/or up-regulating cerebral nitric oxide bioavailability in a mammal, particularly in a human.

16. The method of claim 1 for treating a patient suffering at least one trouble related to deficiency of nitric oxide, in which the patient is administered with an efficient therapeutical amount of betaine for controlling and/or up-regulating endogenous nitric oxide synthase expression in a mammal, particularly in a human

41. The method of claim 1, in which the patient is further administered a therapeutical effective amount of at least one compound selected from the group consisting of nifepidine arginine analogues, stimulators of NO release, carbachol, acetylcholine, bradykinin and combinations thereof.

42. The method of claim 1, in which the patient is further administered a therapeutical effective amount of at least one compound selected from the group consisting of statins, probucol, antioxidant vitamins, eNOS substrate, L-arginine, cofactors thereof, tetrahydrobiopterin, and combinations thereof.

43. The method of claim 1, in which the patient is further administered an effective amount of at least one active agent selected from the group consisting of natural antioxidants, vitamins C, ascorbic acid, vitamins E, tocopherol isomers, a-tocopherol, tocotrienols, vitamin E isomers, probucol, ascorbate, phytochemicals, flavonoids, isoflavones, polyphenols, anthocyans, and combinations thereof.

17. A method for treating a patient suffering at least one trouble related to Tissue Factor Pathway Inhibitor (TFPI) deficiency, in which the patient is administered with an efficient therapeutical amount of betaine for increasing Tissue Factor Pathway Inhibitor (TFPI) in said patient.

18. The method of claim 17, in which the patient is administered with an efficient therapeutical amount of glycine betaine for increasing the rate of production of Tissue Factor Pathway Inhibitor (TFPI) in said patient.

19. The method of claim 17, in which the patient is administered with an efficient therapeutical amount of glycine betaine for increasing by a factor comprised between 1.2 and 3 the rate of production of Tissue Factor Pathway Inhibitor (TFPI) in said patient.

20. The method of claim 17, in which the patient is administered orally an oral composition comprising at least (a) betaine and (b) L-arginine or a physiologically acceptable salt thereof.

21. The method of claim 20, in which the oral composition comprises at least 20% by weight betaine and 20% by weight L-arginine or salt thereof.

22. The method of claim 21, in which the weight ratio L-arginine or salt thereof/betaine is comprised between 0.5 and 2.

23. A method for treating a patient suffering at least one trouble related to excess of endothelin-1 (ET-1), in which the patient is administered with an efficient therapeutical amount of betaine for lowering endothelin-1 (ET-1) levels in said patient.

24. The method of claim 23, in which the patient is administered with an efficient therapeutical amount of glycine betaine for decreasing the rate of said endothelin-1 (ET-1) expression in said patient.

25. The method of claim 23, in which the patient is administered with an efficient therapeutical amount of glycine betaine for decreasing by a factor comprised between 1.2 and 5 the rate of said endothelin-1 (ET-1) levels expression in said patient.

26. A method for treating a patient suffering of at least one trouble selected from the group consisting of troubles related to cyclic guanosine monophosphate (cGMP) deficiency, troubles related to cyclic guanosine monophosphate (cGMP) depletion, troubles related to rapid depletion of cyclic guanosine monophosphate, troubles related to rapid metabolizing of cyclic guanosine monophosphate, troubles related to rapid degradation of cyclic guanosine monophosphate, and combinations thereof, in which the patient is administered with an efficient therapeutical amount of betaine for increasing in said patient at least one parameter selected from the group consisting of cyclic guanosine monophosphate (cGMP) expression, cyclic guanosine monophosphate (cGMP) production, cyclic guanosine monophosphate (cGMP) half-life, cyclic guanosine monophosphate (cGMP) stability, and combinations thereof.

27. The method of claim 26, in which the patient is administered orally an oral composition comprising at least (a) betaine and (b) L-arginine or a physiologically acceptable salt thereof.

28. The method of claim 26, in which the oral composition comprises at least 20% by weight betaine and 20% by weight L-arginine or salt thereof.

29. The method of claim 26, in which the weight ratio L-arginine or salt thereof/betaine is comprised between 0.5 and 2.

30. A composition suitable for treating at least one trouble related to nitric oxide deficiency, said composition comprising (a) L-arginine or a physiologically acceptable salt thereof in a therapeutically effective amount sufficient to enhance nitric oxide production and (b) at least one betaine in a therapeutically effective amount that enhances production of nitric oxide or that inhibits degradation of nitric oxide, the betaine content being advantageously greater than 20% by weight.

31. The composition of claim 30, in which the betaine content is greater than 50% by weight.

32. The composition of claim 30, which comprises an efficient amount betaine to enhance cGMP.

33. A method for treating a patient suffering at least one trouble related to Tissue Factor Pathway Inhibitor (TFPI) deficiency and at least one trouble related to a nitric oxide deficiency, in which the patient is administered with an efficient therapeutical amount of betaine for increasing in said patient at least one nitric oxide production pathway selected from the group consisting of constitutive nitric oxide synthase expression, constitutive Endothelial nitric oxide synthase expression, eNOS nitric oxide synthase expression, neural NOS nitric oxide synthase expression (nNOS), platelet NOS nitric oxide synthase expression, cNOS nitric oxide synthase expression, Type III nitric oxide synthase expressions, calcium dependant nitric oxide synthase expression, calcium dependant nitric oxide synthase production, endogenous nitric oxide production, and combinations thereof, said amount of betaine being furthermore therapeutically efficient for increasing Tissue Factor Pathway Inhibitor (TFPI) in said patient.

34. The method of claim 33, in which the patient is administered with an efficient therapeutical amount of glycine betaine for increasing the rate of production of Tissue Factor Pathway Inhibitor (TFPI) in said patient.

35. The method of claim 33, in which the patient is administered with an efficient therapeutical amount of glycine betaine for increasing by a factor comprised between 1.2 and 3 the rate of production of Tissue Factor Pathway Inhibitor (TFPI) in said patient.

36. The method of claim 33, in which the patient is administered orally an oral composition comprising at least (a) betaine and (b) L-arginine or a physiologically acceptable salt thereof.

37. The method of claim 36, in which the oral composition comprises at least 20% by weight betaine and 20%by weight L-arginine or salt thereof.

38. The method of claim 37, in which the weight ratio L-arginine or salt thereof/betaine is comprised between 0.5 and 2.

39. A method for treating a patient suffering at least one trouble related endothelial cells, in which said patient is administered an efficient therapeutical amount of betaine for improving endothelial cell function through activation of eNOS and through protection of the endothelium from oxidative stress.

40. A method for treating a patient suffering at least one trouble related to lack of activated eNOS, in which said patient is administered an efficient therapeutical amount of betaine to destabilize the complex between eNOS and caveolin for activating eNOS.

44. A method for increasing constitutive Nitric Oxide Synthase activity in a subject to treat a condition favorably affected by an increase in constitutive Nitric Oxide levels in a cell, a tissue, an organ, a bodily fluid, blood, comprising:

administering to a subject in need of such treatment an effective amount of a betaine.

45. The method of claim 44 wherein the condition is hypoxia-induced.

46. The method of claim 44 wherein the condition is pulmonary hypertension.

47. The method of claim 44 wherein the condition is an ischemic stroke.

48. The method of claim 44 wherein the condition is peripheral arterial disease.

49. The method of claim 44 wherein the condition is diabetes.

50. The method of claim 44 wherein the condition is insulin resistance.

51. The method of claim 44 wherein the condition is organs transplant rejection.

52. The method of claim 44 wherein the condition is inflammation.

53. The method of claim 44 wherein the condition is cancer.

54. The method of claim 44 wherein the condition is vascular dementia.

55. The method of claim 44 wherein the condition is sexual impotence.

56. The method of claim 44 wherein the condition is erectile dysfunction.

57. The method of claim 44 wherein the condition is heart failure.

58. The method of claim 44 wherein the condition is glaucoma.

59. The method of claim 44 wherein the condition is progressive renal disease.

60. The method of claim 44 wherein the condition is a gastric or oesophageal motility disorder.

61. The methods of claim 44 further comprising:

co-administering a substrate of Nitric Oxide.

62. A method for treating a patient suffering at least one trouble selected from the group consisting of troubles related to free radicals, troubles related to superoxide anion and troubles related to the lack of normal vaso-relaxation, in which said patient is administered an efficient amount of betaine for reducing in plasma the level of free radicals and/or for diminishing superoxide anion generation and/or for improving the endothelium-dependent vaso-relaxation.

63. A method for treating a patient at risk of brain injury resulting from a stroke or at risk of ischemic stroke, said method comprising:

administering to said patient betaine in an amount effective to increase constitutive Nitric Oxide Synthase activity in the brain tissue of the subject.

64. A method for treating a patient suffering at least one trouble selected from troubles related to TFPI activity deficiency and at least one trouble related to NO deficiency, in which the patient is administered an efficient therapeutic amount of betaine for increasing the activity of TFPI and for increasing the NO blood content or the NO activity in said patient.