The effectiveness of mifepristone, onapristone, and ORG 31806 alone or in combination with anordiol to terminate pregnancy in the rat was evaluated. ORG 31806 at a dose of 2 mg/kg/day, mifepristone at 4 mg/kg/day, and onapristone at 8 mg/kg/day, terminated pregnancy in all treated animals. Anordiol, an antiestrogen, at a dose of 5 mg/kg/day, terminated pregnancy in all treated animals. Anordiol acted synergistically with all three antiprogestins terminating pregnancy in the rat. The antiprogestins at doses that were either partially effective or non-effective became 100% effective when administered with a non-effective dose of anordiol. Thus, combination of ORG 31806 (1 mg/kg/day) plus anordiol (0.31 mg/kg/ day), mifepristone (1 mg/kg/day) plus anordiol (0.62 mg/ kg/day), and onapristone (2 mg/kg/day) plus anordiol (2.5 mg/kg/day) terminated pregnancy in all treated animals. These combinations of the antiprogestins and anordiol decreased significantly the serum progesterone levels but not serum 17 beta-estradiol levels. The present results indicate that the most potent combination was ORG 31806 plus anordiol.
PIP: The pregnancy termination potency of varying doses of mifepristone, onapristone, and ORG 3806--alone and in combination with the estrogenic/antiestrogenic compound anordiol--was evaluated in adult rats. The antiprogestins and anordiol alone were administered to pregnant female rats on days 7, 8, and 9 of pregnancy and the presence or absence of embryos in utero was determined on day 16. ORG 31806 at a dose of 2 mg/kg/day, mifepristone at 4 mg/kg/day, and onapristone at 8 mg/kg/day terminated pregnancy in 100% of animals; 5 mg/kg/day of anordiol was required. Anordiol acted synergistically with all three antiprogestins. Antiprogestin doses that were either partially effective or ineffective became 100% effective when administered with a noneffective dose of anordiol. The combination of ORG 31806 (1 mg/kg/day) and anordiol (0.31 mg/kg/day) had the most potent pregnancy termination activity. The administration of antiprogestins in combination with anordiol at doses that effectively terminate pregnancy was associated with a significant, persistent reduction in serum progesterone, but no change in serum estradiol levels. The effectiveness of ORG 31806 and anordiol in terminating pregnancy should be evaluated in a non-human primate model to determine its potential clinical use.