Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Patent
1995-06-23
1998-06-02
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
A61K 3160
Patent
active
057600244
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/02657 filed Dec. 24, 1993.
The present invention is concerned with human conception and embryo development, in particular embryo implantation into the uterine endometrium.
In humans, the inability to conceive often causes considerable distress and frequently adults with fertility problems undergo protracted and expensive courses of treatment in an effort to achieve a successful pregnancy. Unfortunately, the failure rate of such treatment remains high.
Research into the causes of infertility has shown several contributing factors, each or any of which could be responsible for the problem experienced by a particular patient. Thus, poor gamete quality, congenital anatomical abnormalities and/or surgical complications can all result in infertility.
Some causes of infertility have been treated with ovarian stimulants to regulate follicle growth, oocyte maturation and ovulation. For example, the gonadotrophins HMG (human menopausal gonadotrophin) and HCG (human chorionic gonadotrophin) have been used to induce superovulatory responses in amenorrhoeic women and stimulated menstrual cycles have been induced using clomiphene or HMG.
Following the development of methodologies suitable for in vitro fertilisation and in vitro growth of the fertilised oocyte up to the blastocyst stage, in vitro fertilisation (IVF) has become a popular, and reasonably successful, means of achieving pregnancy. In IVF gametes are collected from each of the parents, optionally after hormonal treatments to induce gamete production. The collected oocytes are then matured and fertilised in vitro. The resulting pronucleate eggs are transferred to a richer culture medium and grown for up to 4 or 5 days to form a blastocyst. Up to three embryos usually developed to the early cleavage stages may be selected for replacement into the uterus which has either been prepared for implantation naturally or by hormonal treatments.
Cryopreservation of pronucleate eggs, early cleavage stage embryos and blastocysts is now possible allowing more flexibility both in the treatment regime and also in research.
However, the improvements in embryological techniques since the 1980s-has failed to significantly increase the proportion of pregnancies achieved by patients treated. Successful implantation requires not only the correct development of the embryo and the preparation of a receptive endometrium within the uterus, but also the successful attachment of the embryo to the uterine epithelial surface with decidualisation of the endometrium and maintenance of the corpus luteum. Despite the transfer of multiple embryos fertilised in vitro, 90% of these embryos do not thrive and the overall chance of an embryo implanting remains at a mere 15%. Generally up to 3 embryos are replaced (ie. introduced into the uterus) to improve the prospects of implantation but pregnancy still only occurs in 20-30% of all patients.
Implantation involves a complex series of events involving both the embryo and uterus, and is deemed to have taken place when the embryo is physically established at a fixed position within the uterus and, in humans, when trophoblastic invasion of the endometrial lining has occurred. The hormonal events required for implantation are involved and remain poorly understood (see Bonney et al in Baillieres Clinical Endocrinology and Metabolism 4:207-231 (1990) and Smith in Baillieres Clinical Obstetrics and Gynaecology 5:73-93 (1991)) and it is now generally accepted that an improvement in implantation rates would significantly enhance the success of in vitro fertilisation and embryo transfer.
One explanation given for the failure of implantation by embryos and thus infertility is poor uterine perfusion (see Goswamy et al. Human Reproduction 3, No.8 pages 955-959 (1988)). Several different stimuli have been shown to cause an increase in endometrial vascular permeability and decidualisation and in each case the mechanism involved appears to be associated with the synthesis and/or release of prostaglandins (see Bonney et al. sup
REFERENCES:
Kautiainen M., et al., "Effects of Drugs on Perfusion and Intrauterine Pressure in Isolated Human Uterus", Database Embase, Elsevier Science Publishers, Amsterdam, NL. (1979).
Takashima, M., et al., "A Trial of Low-Dose Aspirin Therapy in High-Risk Pregnancy", Database Medline, U.S. National Library of Medicine (NLM), Bethesda, MD. (abstract), 1980.
Zeev Weiner, et al., "Umbilical and Uterine Artery Flow Velocity Waveforms in Pregnant Women With Systemic Lupus Erthematosus Treated With Aspirin and Glucocorticosteroids", Am. J. Repr. Immunol., vol. 28, No. 3-4, 1992, pp. 168-171.
C.M.G. Thomas, et al., "Effect of Prostaglandin F2 Alpha, Indomethacin and Estradiol on Ovum Transport and Pregnancy in the Golden Hamster", Biology of Reproduction, vol. 23, 1980, pp. 687-698.
R.K. Goswamy, et al., "Decreased Uterine Prefusion--A Cause of Infertility", Human Reproduction, vol. 3, No. 8, 1988, pp. 955-959.
K. Wollenhaupt, et al., "Untersuchungen zur Beeinflussung des Implantationsgeschehens bei Ratten und Sauen durch perorale Verabreichung von Prostaglandinsynthetasehemmern", Arch. Exper. Vet. Med., vol. 35, No. 3, 1981, pp. 465-470.
Applied Research Systems ARS Holding N.V.
Cintins Marianne M.
Moezie M.
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