Model for Hormonal Emergency Contraception (HEC) in cycling and mated guinea pigs - Studies with the Progesterone Receptor Modulators (PRM) Ulipristal Acetate (UPA/CDB2914) and EC317.

A guinea pig model for new HEC methods is proposed. Two targets for HEC (Hormonal Emergency Contraception), ovulation and conception (post-mating study), were investigated using adjusted PRM treatments: (a) Ovulation inhibition study: Injections on cycle days 10-17, study of ovarian histology on day 18; (b) post-mating study: Injections on cycle days 1 and 2; rate of pregnant females was recorded at autopsy on day 18. P plasma levels permitted assessment of effects on ovulation in non-conceiving animals. RESULTS: (a) All controls had recently ovulated. Statistically significant anti-ovulatory effects (p < 0.05, Fisher's Exact Test) were seen at 10 mg UPA (ulipristal acetate, CDB2914) and ≥0.3 mg EC317; 100% inhibition was found for EC317 at 10, 3, and 1 mg/day. No dosage of UPA was 100% effective. (b) In post-mating studies, 16 of 30 controls were pregnant. Both PRMs (progesterone receptor modulator) exerted inhibitory effects on conception, none on imminent ovulation; 1 of 10 animals had living conceptuses after 10 mg UPA, none following 10 and 1 mg EC317/day, respectively. At pairwise comparison with controls, 10 mg was the lowest effective dosage for UPA (p < 0.05), and 1 mg for EC317 (p < 0.01). P plasma levels: Significantly lower P (p < 0.05) in subsequently pregnant vs non-pregnant controls was found on cycle day 3 or 4; this difference disappeared on day 8 or 9. This stage thus appears vulnerable to hormonal constellations and possibly PRM effects. HEC model: Effects on ovulation and conception were seen at the same dose levels of both PRM. Superior and more consistent effects of EC317 vs UPA (factor ≥10) suggest higher efficacy using EC317 for HEC.

Estradiol prodrugs (EP) for efficient oral estrogen treatment and abolished effects on estrogen modulated liver functions.

Oral compared to parenteral estrogen administration is characterized by reduced systemic but prominent hepatic estrogenic effects on lipids, hemostatic factors, GH-/IGF I axis, angiotensinogen. In order to avoid such adverse metabolic effects of oral treatment, estradiol (E2) prodrugs (EP) were designed which bypass the liver tissue as inactive molecules. Carbone17-OH sulfonamide [-O2-NH2] substituted esters of E2 (EC508, others) were synthesized and tested for carbonic anhydrase II (CA-II) binding. CA II in erythrocytes is thought to oppose extraction of EP from portal vein blood during liver passage. Ovariectomized (OVX, day minus 14) rats were orally treated once daily from day 1-3. Sacrifice day 4. Uteri were dissected and weighed. Cholesterol fractions and angiotensinogen were determined in plasma. Oral E2 and ethinyl estradiol (EE) generated dose related uterine growth and important hepatic estrogenic effects. EP induced uterine growth at about hundred-fold lower doses. This was possible with almost absent effects on plasma cholesterol or angiotensinogen. Preliminary pharmacokinetic studies with EC508 used intravenous and oral administration in male rats. Resulting blood levels revealed complete oral bioavailability. Further high blood- but low plasma concentrations indicated erythrocyte binding of EC508 in vivo as potential mechanism of low extraction at liver passage. Very high systemic estrogenicity combined with markedly lower or absent adverse hepatic estrogenic effects is evidence for a systemic release of E2 from sulfonamide EP. In conclusion, tested oral EP bypass the liver in erythrocytes furnishing systemic estradiol at hydrolysis. This mechanism avoids the hepatic estrogenic impact of conventional oral estrogen therapy.