Implantation rates after in vitro fertilization, treatment of infertility and early pregnancy loss with a nitric oxide donor alone or in combination with progesterone, and a method for contraception with nitric oxide inhibitors

• US 6,040,340 A
• Filed: 05/07/1996
• Issued: 03/21/2000
• Est. Priority Date: 05/07/1996
• Status: Expired due to Fees

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Schering Ag (Merck & Co., Inc.), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Chwalisz, Krzysztof, Garfield, Robert E.
• Primary Examiner(s): MacMillan, Keith D.
• Application Number:
  US08/646,518
• Time in Patent Office: 1,414 Days
• Field of Search: 424/608, 514/509, 514/258, 514/562, 514/307, 514/263, 514/608, 514/565
• US Class Current: 514/509
• 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 31/223 of alpha-aminoacids
• 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 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• 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 33/26 Iron; Compounds thereof
• 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 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 5/30 Oestrogens
• CPC Class Codes: A61P 5/34 Gestagens

Abstract

A method is provided for the improvement of implantation rates and/or pregnancy rates in a female mammal, comprising administering to a female mammal in whom pregnancy is desired an effective amount of

(a) a nitric oxide synthase substrate, a nitric oxide donor, or both, optionally in combination with

(b) a progestin, and,

(c) optionally, in further combination with an estrogen.

A method is also provided for fertility control for a female mammal, comprising administering to a female mammal in whom pregnancy is not desired and at risk for becoming pregnant an effective amount of nitric oxide synthase inhibitor in combination with an antiprogestin. Pharmaceutical compositions are also provided.

Claims

1. A method for improvement of implantation rates in a female mammal after in vitro fertilization which comprises administering to an afflicted female 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 50-5000 μ

molar above the normally 50-1000 μ

molar circulating levels and, optionally, also a progestin or, both of an estrogen and a progestin, in amounts effective to increase the pregnancy rates.

2. The method of claim 1, wherein the mammal is a non-pregnant human female suffering from infertility, or a pregnant female suffering from habitual abortions or a pregnant female exhibiting symptoms of impending abortion.

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

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

5. The method of claim 4, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerin, SIN-1, isosorbid mononitrate or iso sorbiddinitrate.

6. The method of claim 4, wherein the nitric oxide donor is administered orally.

7. The method of claim 4, wherein the nitric oxide donor is administered transdermally.

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

9. The method of claim 1, wherein the mammal is a pregnant human female and the nitric oxide substrate or donor is administered thereto in combination with progesterone and/or estradiol.

10. The method of claim 8, wherein the progestin is progesterone or hydroxyprogesterone caproate.

11. The method of claim 9, wherein the estradiol is estradiol valerate.

12. A method of improving implantation rates and/or pregnancy rates in a female mammal, comprising administering to a female mammal in whom pregnancy is desired an effective amount of

(a) a nitric oxide synthase substrate, a nitric oxide donor, or both, optionally in combination with

(b) a progestin, and,

(c) optionally, in further combination with an estrogen.

13. A method of claim 12, wherein the mammal is a non-pregnant human female suffering from infertility, a pregnant female suffering from habitual abortions, or a pregnant female exhibiting symptoms of impending abortion.

14. A method of claim 12, wherein the nitric oxide synthase substrate is L-arginine.

15. A method of claim 12, wherein the mammal is a pregnant human female and a nitric oxide donor is administered thereto.

16. A method of claim 15, wherein the nitric oxide donor is sodium nitroprusside, nitroglycerin, SIN-1, isosorbid mononitrate or isosorbid dinitrate.

17. A method of claim 15, wherein the nitric oxide donor is administered orally.

18. A method of claim 15, wherein the nitric oxide donor is administered transdermally.

19. A method of claim 12, wherein the mammal is a pregnant human female and a nitric oxide substrate or donor is administered thereto in combination with a progestin.

20. A method of claim 12, wherein the mammal is a pregnant human female and a nitric oxide substrate or donor is administered thereto in combination with a progestin and an estrogen.

21. A method of claim 19, wherein the progestin is progesterone or hydroxy-progesterone caproate.

22. A method of claim 20, wherein the estrogen is estradiol valerate.

23. A method of claim 12, wherein the mammal is a human female and the amount of the nitric oxide synthase substrate, nitric oxide donor or both administered is effective to raise the blood level of circulating L-arginine in said female to at least about 50-5000 μ

molar above the normally 50-1000 μ

mole circulating levels.

24. A method of claim 12, wherein the mammal is a human female and the amount of the nitric oxide synthase substrate, nitric oxide donor or both administered is effective to raise the nitric oxide donor level to about 1-1000 nmolar.

25. A method of claim 12, wherein the mammal is a human female and the amount of progestin administered is bioequivalent to 50-300 mg of injected progesterone, and the amount of estrogen administered, if any, is bioequivalent to 1-2 mg of estradiol.

26. A method of claim 12, wherein components (a) and (b) are administered sequentially.

27. A method of claim 12, wherein components (a) and (b) are administered simultaneously.