. "B12. ANtiprogestogens: Perspectives from a Global Research Program." Clinical Applications of Mifepristone (RU486) and Other Antiprogestins: Assessing the Science and Recommending a Research Agenda. Washington, DC: The National Academies Press, 1993.
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Clinical Applications of Mifepristone (RU 486) and other Antiprogestins: Assessing the Science and Recommending a Research Agenda
advantage in some situations; for example, in the use of an antiprogestogen as a late luteal, once-a-month contraceptive where a ''spillover" effect into the next cycle is to be avoided. To develop such compounds, further research into those molecular characteristics of antiprogestogens that determine their binding to carrier protein(s) may prove useful.
Pregnant Guinea Pig Model
One animal model that has been employed extensively, particularly by Elger and his colleagues at Schering AG, for the study of the abortifacient potency and mechanism of action of antiprogestogens is the guinea pig in advanced stage of pregnancy (i.e., around day 43–44 post coitum) (Table B12.1). The reasons for selecting this species and stage of pregnancy as a model of pregnancy and uterine motor function in the human have been described by Elger et al. (1987). Studies in this model and similar research in the human (Bygdeman and Swahn, 1985) led to the development of the sequential treatment regimen of mifepristone followed by prostaglandin, now used clinically in France, Great Britain, and Sweden as a nonsurgical method for early pregnancy termination (for review see, for example, Van Look and von Hertzen, 1992a). Subsequently, the same group of workers also reported a marked synergism between antiprogestogens and epostane, and between antiprogestogens and tamoxifen in inducing abortion in the pregnant guinea pig model (Elger et al., 1988). From these observations they postulated that the "estrogen background" may exert an inhibitory influence on the onset of uterine contractions in antiprogestogen-treated animals.
In order to examine if a similar effect exists in the human, a study was undertaken with the support of the Special Programme in five hospitals in Beijing, China [Wu, Clinical study of mifepristone in combination with tamoxifen and 15-methyl-prostaglandin F2a methyl ester in the termination of early pregnancy (provisional title), in preparation]. A total of 990 women with amenorrhea of up to 49 days were given a single dose of 200 mg of mifepristone followed, 72 hours later, by a vaginal suppository of 1 mg of dl-15-methylprostaglandin F2a methyl ester. In addition, half the women received tamoxifen (20 mg twice a day for two days starting at the time of mifepristone intake), and the other half received placebo tablets. The results of this trial did not confirm the synergistic effect of tamoxifen observed in the guinea pig. In fact, the complete abortion rate in the tamoxifen group (91.5 percent) tended to be lower than in the placebo controls (93.4 percent), and the interval between prostaglandin administration and expulsion of the amniotic sac was significantly (P < .02) longer in women given the antiestrogen. These results point to the need for further evaluation of the guinea pig