Method and agents for inducement of endogenous nitric oxide synthase for control and management of labor during pregnancy

• US 5,830,848 A
• Filed: 05/25/1995
• Issued: 11/03/1998
• Est. Priority Date: 10/09/1992
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Harrison, Michael R., Heymann, Michael A., Natuzzi, Eileen Stack, Riemer, Robert Kirk
• Primary Examiner(s): Walsh, Stephen
• Assistant Examiner(s): Basham, Daryl A.
• Application Number:
  US08/450,126
• Time in Patent Office: 1,258 Days
• Field of Search: 514/2, 424/85.1, 424/85.2, 424/85.5, 530/399
• US Class Current: 424/85.2
• 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 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/191 Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/2006 IL-1
• CPC Class Codes: A61K 38/204 IL-6
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

A method and agents for endogenous control, treatment, management and prevention of preterm labor by inducement of endogenous nitric oxide synthase. The method for endogenous production of nitric oxide in myometrium involves administering to a pregnant mammal a cytokine, hormone or growth factor agent able to induce production of nitric oxide or nitric oxide synthase. A non-invasive diagnostic procedure for detecting the presence and/or impending onset of premature labor.

Claims

1. A method for control, treatment, and management of preterm labor by endogenously inducing an inhibition of preterm labor, said method comprising a step of:

administering to a pregnant mammal experiencing preterm labor a composition consisting essentially of one or more compounds augmenting an inducible nitric oxide synthase (iNOS) production in an amount effective to endogenously inhibit preterm labor.

2. The method of claim 1 wherein said compound is a cytokine alone or in combination with a progestin.

3. The method of claim 2 wherein said cytokine or a combination thereof with the progestin has an uterine-selective effect on inducing or up-regulating the expression of inducible nitric oxide synthase in the myometrium.

4. The method of claim 3 wherein the cytokine is selected from the group consisting of interferon gamma, interleukin-1 β

, interleukin-6, interleukin-8, tumor necrosis factor alpha, colony stimulating factor and transforming growth factor β

.

5. The method of claim 4 wherein the cytokine is administered orally, intravenously, intravaginally, intraperitoneally, transdermally, subcutaneously, intramuscularly, intranasally, rectally or intravaginally.

6. The method of claim 3 wherein the cytokine is administered intravenously by infusion.

7. The method of claim 6 wherein the cytokine is colony stimulating factor-1.

8. The method of claim 6 wherein the cytokine is transforming growth factor-β

.

9. The method of claim 6 wherein the cytokine is interleukin-1β

.

10. The method of claim 6 wherein the cytokine is interferon gamma.

11. The method of claim 6 wherein the cytokine is interleukin-6.

12. The method of claim 6 wherein the cytokine is tumor necrosis factor alpha.

13. The method of claim 3 wherein the cytokine is the growth factor selected from the group consisting of epidermal growth factor and fibroblast growth factor.

14. The method of claim 3 wherein said progestin is progesterone present in the composition in an amount of about 0.5-30 wt %.

19. The method of claim 1 wherein the transcriptional regulating protein is nuclear factor kappa B Jun/fos.

20. The method of claim 1 wherein the agent is tumor necrosis factor .English Pound. (TNF-d).

15. A method for control, treatment and management of preterm labor by endogenous inducement of preterm labor inhibition, said method comprising administering to a pregnant mammal experiencing preterm labor a composition comprising an agent which activates the expression of transcriptional regulatory protein controlling the expression of gene encoding an inducible nitric oxide synthase (iNOS), thereby augmenting uterine nitric oxide production, wherein said nitric oxide is produced in an amount effective to endogenously inhibit preterm labor.

16. The method of claim 15 wherein the uterine nitric oxide production is augmented by activation of transcription of inducible nitric oxide synthase (iNOS).

17. The method of claim 16 wherein the agent induces transcription of iNOS by activating the expression of transcriptional regulating protein controlling the expression of a gene encoding iNOS transcription.

18. The method of claim 17 wherein the transcriptional regulating protein activating transcription of iNOS is activator protein-1, octamer protein-1, octamer binding protein-2 or gamma-activation factor.