Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-09-30
1999-06-01
Davenport, Avis M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530324, A61K 3800, C07K 500, C07K 700
Patent
active
059088290
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a treatment for ripening of the cervix, particularly in the induction of labour to assist mammals to give birth.
2. Description of the Related Art
Parturition (expulsion of the fetus from the uterus), requires both contractions of the myometrium, the smooth muscle of the uterus, and a softening of the highly connective tissue of the cervix, so that it will stretch and dilate sufficiently to allow the fetus to be expelled. This softening is known as "ripening".
The current preferred method of cervical ripening is by the use of prostaglandin E2. This is used as a vaginal gel or tablet or as a gel placed in the cervix. One worry about the use of PGE.sub.2 is that there is a possibility of hyper-stimulation of the uterus, leading to myometrial contractions before the cervix is ripened and therefore before a comfortable or safe birth is possible. The ideal preparation would soften and efface the cervix without causing myometrial contractions. This would allow the subsequent contractions (inducible if necessary with a small dose of prostaglandin) to deliver the baby with a minimum of resistance.
There is good evidence from animal experiments that the antiprogestins such as RU486 would meet these requirements, but the problem with this drug is that it has associated antiglucocorticoid activity leading to elevated 375-380 (1994)! and might also be detrimental to the fetus.
The use of interleukin-8 has also been proposed previously as an agent to ripen the cervix (WO 93/09796). It is known that IL-8 production is (1992); R W Kelly et al. Human reproduction 9, 253-258 (1994)!.
SUMMARY OF THE INVENTION
It has now surprisingly been found that monocyte chemotactic peptide-1 (MCP-1) production by choriodecidual tissue is inhibited by progesterone. Choriodecidual tissue is that found on the outside of the fetal sac and therefore in contact with the uterus in the cervical region. It follows that MCP-1 and its functional derivatives can be used for cervical ripening.
The invention accordingly provides the use of a monocyte chemotactic peptide-1 (MCP-1) or a functional derivative thereof in the manufacture of a medicament for inducing ripening of the cervix of a female mammal. The female mammal can be a human being or an animal. Typically it is a female human. MCP-1 or a functional derivative thereof can thus be used in assisting mammalian birth or fetal removal.
MCP-1 or a functional derivative thereof can initiate a localised action and not induce the excessive myometrial contractility sometimes associated with the use of prostaglandin. They would not therefore prejudice the fetus. During birth the cervix normally ripens without help from outside. However, the compounds of the invention can help during the normal ripening and during all birth situations in which ripening is not sufficient. Further they will support normal ripening to make the birth process easier for the women. There can therefore be a reduction or avoidance of pain during birth, abortion and surgical and diagnostic treatment.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
MCP-1, also known as monocyte chemotactic and activating factor (MCAF) can Letters, 244, 487-493; T Yoshimura et al J Immunol 144, 2377-2383 (1990); M W Rolfe et al, Am J Physiol 263 L536-L545 (1992)!. MCP-1 can be obtained by recombinant DNA synthesis or by peptide synthesis using a modification 3128-3135 (1991)!. MCP-1 can also be obtained from biological sources such as polyI/polyC stimulated fibroblasts in culture. Natural variants of MCP exist due to different carbohydrate substitution. The peptide has a terminal sialic acid residue and a degree of O-glycosylation which gives and Sorg, C "Interleukin-8 (NAP-1) and related cytokines" Karger, Basel, 131-152 (1992)!.
A "functional derivative" of MCP-1 is also capable of inducing cervical ripening. That may be determined by testing. The term "functional derivative" is intended to include "fragments", "variants", "analogues", "chemical derivatives" or "poly
REFERENCES:
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Ibelgaufts, H. Dictionary of Cytokines VCH Inc. Weinheim, Germany pp. 147-148, and p. 503.
Hartung, et al.; "Ripening of the Uterine Cervix of the Guinea-Pig after Treatment withthe Progesterone Antagonist Onapristone (ZK 98.299): an Electron Microscopic Study"; Human Reproduction; vol. 4, pp. 369-377; 1989.
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Yoshimura, et al.; "Interleukin-8 (NAP-1) and Related Cytokines"; Basel, Karger, 1992; vol. 4; pp. 131-152.
Rolfe, et al.; "Expression and Regulation of Human Pulmonary Fibroblast-derived Monocyte Chemotactic Peptide-1"; Am J Physiol; 263; pp. L-536-L-545.
Yoshimura, et al.; "Secretion by Human Fibroblasts of Monocyte Chemoattractant Protein-1, the Product of Gene JE"; J Immunol; 144; pp. 2377-2383.
Yoshimura, et al.; "Human Monocyte Chemoattractant Protein-1 (MCP-1)"; FEBS Letters; 244; pp. 487-493.
Kelly, et al.; Progesterone Control of Interleukin-8 Production in Endometrium and Chorio-decidual Cells Underlines the Role of the Neutrophil in Menstruation and Parturition; Human Reproduction; 9, pp. 253-258.
Kelly, et al.; Choriodecidual Production of Interleukin-8 and Mechanism of Parturition; Lancet; vol. 339; Mar. 1992; pp. 776-777.
Abstract; JP-05271092-A.
Davenport Avis M.
Medical Research Council
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