Microdose therapy

• US 6,165,975 A
• Filed: 12/22/1999
• Issued: 12/26/2000
• Est. Priority Date: 06/23/1997
• Status: Expired due to Term

• Current Assignee: Queen's University At Kingston
• Original Assignee: Queen's University At Kingston
• Inventors: Adams, Michael A., Heaton, Jeremy P. W., Banting, James D.
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US09/469,649
• Time in Patent Office: 370 Days
• Field of Search: 514/2, 514/192, 514/231.2, 514/470, 514/565, 514/668
• US Class Current: 424/718
• CPC Class Codes: A61K 31/04 Nitro compounds
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• 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 38/063 Glutathione
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A method of treatment, in an organism, of a vascular condition, comprising administration of at least one agent at a level which enhances NO and which does not appreciably alter normal systemic vascular tone in said organism. At least one agent is an NO donor selected from the group consisting of glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosydnonimine molsidomine, S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, and N-hydroxy-L-arginine.

Claims

1. A method of treatment, in an organism, of a vascular condition, comprising administration of at least one agent at a level which enhances NO and which does not appreciably alter normal systemic vascular tone in said organism.

2. The method of claim 1 wherein said vascular condition is associated with a reduction in NO production.

3. The method of claim 1 wherein said vascular condition is associated with an attenuation of NO effect.

4. The method of claim 1 wherein said administration is acute.

5. The method of claim 1 wherein said administration is chronic.

6. The method of claim 1 wherein said at least one agent is selected from the group consisting of NO, CO, NO donors, CO donors, activators of guanyl cyclase, PDE inhibitors, and substances which produce an effect equivalent to that of NO.

7. The method of claim 6, wherein said at least one agent is an NO donor selected from the group consisting of glyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythrityl tetranitrate, sodium nitroprusside, 3-morpholinosydnonimine molsidomine, S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione, and N-hydroxy-L-arginine.

8. The method of claim 1 wherein said administration is by at least one route selected from the group consisting of oral, sublingual, buccal, intravenous, vaginal, rectal, transdermal, inhalation, enteral, and parenteral.

9. The method of claim 1 wherein said level of administration of said at least one agent is a concentration that is about 1/2 to about 1/20 of a concentration required to induce vasodilation in an anatomical site of said organism lacking said vascular condition.

10. The method of claim 1 wherein said level of administration of said at least one agent is a concentration that is about 1/4 to about 1/20 of a concentration required to induce vasodilation in an anatomical site of said organism lacking said vascular condition.

11. The method of claim 1 wherein said level of administration of said at least one agent is a concentration that is about 1/8 to about 1/16 of a concentration required to induce vasodilation in an anatomical site of said organism lacking said vascular condition.

12. The method of claim 1 wherein said vascular condition is associated with an anatomical site selected from the group consisting of kidney, skin, penis, vagina, brain, skeletal muscle, and gastrointestinal tract.

13. The method of claim 1 wherein said vascular condition is associated with ED.

14. The method of claim 1 wherein said vascular condition is associated with female SD.

15. The method of claim 1 wherein said at least one agent which enhances NO is GTN, and said level of administration is a plasma concentration below about 250 pg/ml of GTN.

16. The method of claim 15 wherein said GTN is delivered via at least one route selected from the group consisting of oral, sublingual, buccal, intravenous, vaginal, rectal, transdermal, inhalation, enteral, and parenteral, and said level of administration is a plasma concentration below about 250 pg/ml of GTN.

17. The method of claim 1 wherein said at least one agent is administered transdermally via a low-dose patch with short term release of an effective amount of said at least one agent over less than 6 hours.

18. The method of claim 1 wherein said at least one agent is administered transdermally via a low-dose patch with long term release of an effective amount of said at least one agent over about 6 to about 18 hours.

19. The method of claim 1 wherein said at least one agent is administered transdermally via a low-dose patch with long term release of an effective amount of said at least one agent over a period greater than 18 hours.

20. The method of claim 12 wherein said vascular condition associated with the skin is a condition selected from the group consisting of Raynaud'"'"'s phenomenon, scleroderma, and diffuse cutaneous systemic sclerosis.

21. The method of claim 14 wherein said female SD condition is selected from the group consisting of vaginal lubrication, vaginal engorgement, pain during intercourse, dyspareunia, urogenital infections;

and urogenitalia effects selected from the group consisting of post-menopause, diabetes, vascular disease, estrogen depletion conditions, sexual dysfunction, and idiosyncratic vaginal dryness.

22. The method of claim 13 wherein said male ED condition is due to a radical prostatectomy procedure where normal circulatory does not return postoperatively.

23. The method of claim 1 wherein said vascular condition is associated with physiological insult.

24. The method of claim 1 wherein said vascular condition is transient.

25. The method of claim 1 wherein said vascular condition is associated with a reduction in NO production or an attenuation of NO effect and is ED.

26. The method of claim 1 wherein said vascular condition is associated with a reduction in NO production or an attenuation of NO effect and is a female SD.

27. The method of claim 26 wherein said female SD is insufficient vaginal lubrication or insufficient vaginal engorgement.

28. The method of claim 26 wherein said female SD is dyspareunia.

29. The method of claim 25 wherein said at least one agent which enhances NO comprises GTN, and said level of administration is a plasma concentration below about 250 pg/ml of GTN.

30. The method of claim 26 wherein said at least one agent which enhances NO comprises GTN, and said level of administration is a plasma concentration below about 250 pg/ml of GTN.

31. The method of claim 10 wherein said vascular condition is associated with a reduction in NO production or an attenuation of NO effect.

32. The method of claim 31 wherein said at least one agent comprises GTN.

33. The method of claim 31 wherein said at least one agent comprises isosorbide dinitrate.

34. The method of claim 31 wherein said at least one agent comprises sodium nitroprusside.

35. The method of claim 32 wherein said vascular condition is ED and said anatomical site is the penis.

36. The method of claim 32 wherein said vascular condition is a female SD and said anatomical site is the vagina.

37. The method of claim 36 wherein said female SD is insufficient vaginal lubrication or insufficient vaginal engorgement.

38. The method of claim 36 wherein said female SD is dyspareunia.

39. The method of claim 1 wherein said vascular condition is Raynaud'"'"'s phenomenon.

40. The method of claim 1 wherein said vascular condition is associated with a reduction in NO production or an attenuation of NO effect and said vascular condition is associated with the gastro-intestinal tract.

41. The method of claim 29 wherein said GTN is administered orally, sublingually or buccally.

42. The method of claim 30 wherein said GTN is administered orally, sublingually or buccally.

43. The method of claim 29 wherein said GTN is administered transdermally.

44. The method of claim 30 wherein said GTN is administered transdermally.

45. The method of claim 1 wherein said vascular condition is associated with a reduction in NO production or an attenuation of NO effect and said at least one agent is administered transdermally via a low-dose patch.

46. The method of claim 45 wherein said at least one agent comprises GTN.

47. The method of claim 25 wherein said at least one agent is administered via inhalation.

48. The method of claim 26 wherein said at least one agent is administered via inhalation.