Treatment of climacteric disorders with nitric oxide synthase substrates and/or donors

• US 5,595,970 A
• Filed: 11/16/1993
• Issued: 01/21/1997
• Est. Priority Date: 07/16/1993
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Chwalisz, Krzysztof, Garfield, Robert E., Bukowski, Radoslaw, Yallampalli, Chandra
• Primary Examiner(s): Lilling, Herbert J.
• Application Number:
  US08/153,345
• Time in Patent Office: 1,162 Days
• Field of Search: 514/12, 514/21, 514/412, 514/561, 514/171
• US Class Current: 424/718
• 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 31/04 Nitro compounds
• 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 31/26 Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
• 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 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/557 Eicosanoids, e.g. leukotrienes or prostaglandins
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system

Abstract

The symptoms of the climacterium are ameliorated by the administration to an afflicted individual one or both of a nitric oxide substrate and/or nitric acid donor, alone or optionally in combination with a progestin or, in the case of a non-pregnant female, either a progestin or an estrogen or both.

Claims

1. A method of treating climacterium (climacteric symptoms) in a non-pregnant female mammal suffering from menopausal symptoms of climacterium, exhibiting climacteric symptoms, or who is a candidate for hormone replacement therapy, comprising

administering to said female mammal

an amount of nitric oxide synthase substrate, a nitric oxide donor, or both, effective to raise the blood level of circulating L-arginine to at least about 10-50 nmolar above the normally 50-100 nmolar circulating levels and,

optionally, also a progestin or both of an estrogen and a progestin, in amounts effective to ameliorate the symptoms thereof.

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

3. The method of claim 1, wherein the mammal is a non-pregnant human female exhibiting climacteric symptoms or who 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 4, wherein the nitric oxide substrate is L-arginine.

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

7. The method of claim 6, wherein the nitric oxide donor is sodiumnitroprusside, nitroglycerin, glyceryltrinitrate, SIN-1, isosorbidmononitrate or isosorbiddinitrate.

8. The method of claim 6, wherein the nitric oxide donor is administered orally.

9. 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.

10. The method of claim 9, wherein the estrogen is estradiol valerate, conjugated equine estrogens, 17β

-estradiol, estrone or estriol.

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 a progestin.

12. The method of claim 11, wherein the progestin is progesterone, dydrogesterone, medroxyprogesterone, norethisterone, levonorgestrel or norgestrel.

13. 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.

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