Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-12-27
1993-08-31
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514219, 514220, 514523, A01N 4300, A01N 4362, A01N 3734
Patent
active
052409228
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to methods of enhancing fertility in mammals, in particular to increasing the implantation potential of embryos within the uterus following in vivo or in vitro pre-implantation development.
BACKGROUND ART
It is now thought that a major cause of infertility and subfertility in humans arises due to failure of implantation of the fertilised embryo within the uterus. Implantation failure also contributes to the difficulties encountered in in-vitro fertilisation programmes and in animal breeding.
Although hormonal manipulation is effective in certain selected cases, at present there is no uniformly successful therapy available to address this problem.
Australian Patent Application No 77189/87, relates to the discovery that the fertility of mammals can be controlled by causing artificial changes to the level (or activity) of the ether phospholipid Platelet Activating Factor (PAF) which is produced and secreted by mammalian embryos. Specifically the above application discloses that such changes can result in a contraceptive effect or fertility enhancement. The specification states that "to increase the chance of implantation it was necessary to increase the in vivo concentration of PAF, usually by the artificial addition of exogenous PAF or PAF analogue or by reducing the rate of destruction of PAF by acetylhydrolase" during the pre and peri-implantation period.
An increase in PAF concentration can be easily achieved in vitro simply by adding synthetic PAF. In vivo this is more difficult. Adding PAF to biological fluids results in its very rapid deactivation by serum acetylhydrolase and other systems. This fluid phase catabolism seems not to be of great significance for embryo-derived PAF since the evidence to date shows that it is bound, probably to a protein carrier, in such a manner as to make it not readily susceptible to the action of serum acetylhydrolase. The predominant route of embryo-derived PAF catabolism therefore is via cellular catabolism.
This route is thought to involve the binding of PAF to its plasma membrane receptor, and on cellular activation the PAF is internalised and cytosolic acetylhydrolase converts it to lyso-PAF followed soon after by the action of acyltransferase which leads to the production of a long chain acyl alkyl glycerophosphocholine which is not active biologically.
It is possible to overcome the lability of exogenously added PAF by the use of PAF analogues that have biological activity, but which are not susceptible to hydrolysis. A number of these have been reported but the one most fully studied to date is a carbamyl derivative. This compound is quite resistant to the actions of acetylhydrolase. Another alternative is to use embryo-derived PAF that has been generated in vitro and which is in a bound form and thus non-hydrolysable. This is a real possibility but the cost of production is likely to be prohibitive. Both of these approaches have the disadvantage that administration of exogenous PAF can be dangerous. It is a potent mediator of anaphylaxis and allergic responses. Therefore the systemic administration of PAF must be performed extremely carefully. Local administration of PAF into the uterus does not appear to expose the mother to these dangers (at least in the mouse and the sheep). Local administration of PAF however is of only limited therapeutic practicality, systemic administration is by far the most desirable.
The present invention comes from the entirely unexpected observation that a variety of pharmacological inhibitors of PAF activity have a bi-phasic effect on the establishment of pregnancy. At low dose (the dose where they are first effective at inhibiting the action of PAF) they inhibit implantation in both the mouse and rat. This effect reaches a maximum and further increases, (by as little as 4-10 fold concentration) result in a loss of this contragestational action and enhancement of implantation. This is entirely unexpected because for all other PAF mediated patho-physiological events investigated to d
REFERENCES:
CA 112(13), Milligan et al, "Failure of platelet activating factor to induce decidualization . . . ".
CA 109(21), Spinks et al, "Antagonists of embryo derived PAF prevent implantation . . . ".
CA 110(9), O'Neill, "Composition and methods for fertility control using PAF . . . ".
CA 108(25), Acker et al "Role of PAF in the oviplantation in the rat . . . ".
Biology of Reproduction, "Effects of Indomethacin and ICI 46,474 Administered During Ovum Transport on Fertility in Rabbits", vol. 14, No. 4, May 1976, pp. 451-457.
Acta Endocrinologica, "Prostaglandin E2: Analysis of Effects on Pregnancy and Corpus Luteum in Hamsters and Rats", vol. 71, supplement 170, 1972, pp. 3-32.
Cintins Marianne M.
Cook Rebecca
Northern Sydney Area Health Service
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