Method and formulation of stimulating nitric oxide synthesis

• US 5,767,160 A
• Filed: 08/05/1996
• Issued: 06/16/1998
• Est. Priority Date: 10/05/1994
• Status: Expired due to Term

• Current Assignee: Palmetto Pharmaceuticals LLC
• Original Assignee: Notol, Inc.
• Inventors: Kaesemeyer, W. H.
• Primary Examiner(s): Killos, Paul J.
• Application Number:
  US08/693,882
• Time in Patent Office: 680 Days
• Field of Search: 514/565
• US Class Current: 514/565
• 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 31/21 Esters, e.g. nitroglycerine, selenocyanates
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

A therapeutic in vitro or in vivo mixture comprising L-arginine and an agonist of nitric oxide synthase, namely nitroglycerin is disclosed for the treatment of diseases related to vasoconstriction, wherein the vasoconstriction is relieved by stimulating the constitutive form of nitric oxide synthase (cNOS) to produce native nitric oxide (NO). The native NO having superior beneficial effect when compared to exogenous NO produced by a L-arginine independent pathway in terms of the ability to reduce clinical endpoints and mortality.

Claims

1. A formulation comprising a biological equivalent of arginine and an agonist of nitric oxide synthase, said agonist being different than said biological equivalent of arginine.

2. The formulation of claim 1, wherein said agonist is nitroglycerin.

3. The formulation of claim 1, wherein the biological equivalent of arginine is citrulline.

4. The formulation of claim 1, wherein the biological equivalent of arginine is an arginase inhibitor.

5. The formulation of claim 1, wherein the biological equivalent of arginine is an antioxidant.

6. The formulation of claim 1, wherein said biological equivalent of arginine is hydralazine.

7. The formulation of claim 1, wherein said biological equivalent of arginine is lysine.

8. The formulation of claim 4, wherein said arginase inhibitor is comprised of ornithine.

9. A method of treating a disease condition in a subject by vasodilation or vasorelaxation comprising:

selecting a subject;

mixing a biological equivalent of arginine and an agonist of nitric oxide synthase, said biological equivalent of arginine being different from said nitric oxide synthase;

administering to said subject a formulation comprising said mixture;

obtaining periodic indicators of vasorelaxation for the subject; and

;

continuing administration of the formulation until a desirable state of vasorelaxtion is obtained.

10. The method of claim 9, wherein said biological equivalent of arginine is citrulline.

11. The method of claim 9, wherein said biological equivalent of arginine is selected from the group consisting of hydralazine, Vitamin E, minoxidil, procardia, papaverine, nycetapine, and calcium antagonist.

12. The method of claim 9, wherein said agonist of nitric oxide synthase is a nitrate.

13. The method of claim 12, wherein said nitrate is nitroglycerin.

14. The method of claim 9, wherein said biological equivalent of arginine is comprised of an arginase inhibitor.

15. The method of claim 9, wherein said biological equivalent of arginine is lysine.

16. The method of claim 9, wherein said biological equivalent of arginine is ornithine.

17. A method of treating nitrate tolerance in a mammal, comprising:

administering a biological equivalent of arginine to said mammal when nitrate tolerance is indicated in said mammal;

continuing administration of said biological equivalent of arginine until tolerance is ameliorated.

18. The method of claim 17, wherein said nitrate is nitroglycerin.

19. The method of claim 18, wherein said biological equivalent of arginine is administered in excess of said nitrate.

20. The method of claim 17, wherein the biological equivalent of arginine is an arginase inhibitor.