Pregnancy termination in the rat “model” by a synthetic prostaglandin analogue ICI 81008

Abstract

The abortifacient efficacy of the PGF2α analogue ICI 81008 had been examined in 378 Spraque-Dawley rats. Of the 3 systemic routes of administration studied: intramuscular (i.m.), subcutaneous (s.c.) and per vaginam (p.v.), the p.v. treatment had been the most effective. Complete abortions were provoked invariably by a single p.v. dose of 20 μg ICI 81008 in the broad gestational range of 6 to 10 days of pregnancy and the “abortion rate” (AbR) remained 86% at day 12. The reduction of the p.v. dose to 10 μg only decreased efficacy slightly and its increase to 40 μg improved it. The analogue ICI 81008 was highly more effective than the natural PGs: F2α and E 2, in spite of their comparable oxytocic actions on the excised uterus. This high efficacy of ICI 81008 in p.v. formulation, without apparent side effects, is a therapeutic promise which demands early clinical investigation. At day 3 the AbR decreased to 0% and at day 14 to 30%. Plotting AbR, as a function of the gestational timing of treatment, yielded a reversed U shape curve, which reflected upon the mechanism of ICI 81008 action. The pituitary, the corpus luteum and the blastocyst are equally indispensable and accessible to drugs at days 3 and 6 of gestation. Yet the efficacy of ICI 81008 increased from 0% to 100% during this 3 days period, suggesting that the primary target of ICI 81008 is the uterine environment of the implanted conceptus. Thus the earlier premise had been substantiated that in inducing abortion PGs provoke: reduction of uterine microcirculation, sustained contracture, suppression of feto-placental endocrine function (including luteotrophic support), luteolysis, progesterone (P)-withdrawal and the evolution of uterine activity. However, progesterone treatment prevented the effect of ICI 81008, completely or partly, depending on the dose of PG administered. Furthermore, extensive studies of the ICI research team showed that ICI 81008 can provoke luteolysis without pregnancy, suggesting that under certain conditions the ovary is the primary target of this drug. If this effect on the ovary also involves a microcirculatory disturbance, then the mechanism of action of ICI 81008 is retained, in a variety of species and reproductive conditions, and only the threshold of the organ serving as primary target changes. From the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri This work was supported by the Agency for International Development Contract AID/csd 3160 and the National Institute of Health Career Award, HD 20169-11.