Treatment of urinary incontinence with nitric oxide synthase substrates and/or nitric oxide donors alone or in combination with estrogen or progesterone and/or other agents

• US 5,789,442 A
• Filed: 01/18/1996
• Issued: 08/04/1998
• Est. Priority Date: 01/18/1996
• Status: Expired due to Fees

• Current Assignee: Schering Ag (Merck & Co., Inc.), Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Chwalisz, Kristof, Garfield, Robert E.
• Primary Examiner(s): Witz, Jean C.
• Application Number:
  US08/588,586
• Time in Patent Office: 929 Days
• Field of Search: 514/182, 514/177, 514/178, 514/179, 514/180, 514/181, 514/561, 514/21, 514/412, 514/12, 514/645
• US Class Current: 514/561
• 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 31/198 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 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/566 having an oxo group in position 17, e.g. estrone
• CPC Class Codes: A61K 31/569 substituted in position 17 alpha, e.g. ethisterone
• 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 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system

Abstract

The invention provides a method for the treatment and prevention of urinary incontinence in mammals, e.g., human males and females, especially nonpregnant female mammals, by administering a nitric oxide synthase substrate and/or nitric oxide donor, alone or in combination with an estrogenic agent and/or a progestational substance, with or without supplementation with an alpha-adrenergic agonist, beta-adrenergic receptor blocking agent, cholinergic-receptor blocking compound or a cholinergic-receptor-stimulating drug, as well as pharmaceutical compositions useful in practicing the methods of this invention.

Claims

1. A method of treating urinary incontinence symptoms in a female mammal, comprising administering to said female an effective amount of

(a) a nitric oxide synthase substrate, a nitric oxide donor, or both, and, optionally, further administering an effective amount of

(b) one or more of a progestin, an estrogen or a partial estrogen agonist.

2. The method of claim 1, wherein the mammal is a non-pregnant human female suffering from urinary incontinence.

3. The method of claim 1, wherein the mammal is a non-pregnant human female who has exhibited or is a candidate for hormone replacement therapy.

4. The method of claim 1, wherein the mammal is a non-pregnant female human and a nitric oxide synthase substrate is administered thereto.

5. The method of claim 1, wherein the mammal is a pregnant or postpartum human female.

6. The method of claim 1, wherein the nitric oxide substrate is L-arginine.

7. The method of claim 1, wherein the mammal is a non-pregnant human female and a nitric oxide donor is administered hereto.

8. The method of claim 1, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerin, glyceryl trinitrate, SIN-1, isosorbid mononitrate or isosorbid dinitrate.

9. The method of claim 8, wherein the nitric oxide donor is administered transdermally.

10. The method of claim 8, wherein the nitric oxide donor is administered orally.

11. The method of claim 1, wherein the mammal is a non-pregnant human female and the nitric oxide substrate or donor is administered thereto in combination with an estrogen.

12. The method of claim 11, wherein the estrogen is estradiol valerate, conjugated equine estrogens, 17β

-estradiol, estrone or estriol.

13. The method of claim 1, wherein the mammal is a non-pregnant human female and the nitric oxide substrate or donor is administered thereto in combination with a partial estrogen agonist.

14. The method of claim 13, wherein the partial estrogen agonist is raloxifen, centchroman or tamoxifen.

15. The method of claim 1, wherein the mammal is a non-pregnant human female and the nitric oxide substrate or donor is administered thereto in combination with a progestin.

16. The method of claim 15, wherein the progestin is progesterone, dydrogesterone, medroxyprogesterone, norethisterone, levonorgestrel, norgestrel, gestodene or drospirenone.

17. The method of claim 1, wherein the mammal is a non-pregnant human female and concurrently a hormone replacement amount of an estrogen or a progestin is administered thereto continuously.

18. The method of claim 1, wherein the mammal is a non-pregnant human female and concurrently hormone replacement amounts of an estrogen and a progestin are administered sequentially.

19. The method of claim 1, wherein the mammal is a human female and the nitric oxide substrate or donor is administered thereto in further combination with one or more of an alpha-adrenergic agonist, a beta-receptor blocking agent, a cholinergic-blocking compound or a cholinergic stimulating drug.

20. The method of claim 19, where in the mammal is administered estrogen and/or progestin with an alpha-adrenergic agonist, a beta-receptor blocking agent, a cholinergic-blocking compound or a cholinergic stimulating drug.

21. The method of claim 1, wherein the amount of a nitric oxide synthase substrate, a nitric oxide donor, or both is effective to raise the blood level of circulating L-arginine to at least about 50-5000 μ

molar above the normally 50-1000 μ

molar circulating levels or raise nitric oxide donor levels to about 10 nM to 100 μ

M.