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

2区 · 生物学

Article

作者: Nickisch, K ; Dehnhard, M ; Wedemeyer, R ; Elger, W ; Jewgenow, K ; Schneider, B ; Killeen, Z ; Santhamma, B ; Friedrich, M

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.

2014-12-01·Steroids4区 · 医学

Synthesis and biological evaluation of 11′ imidazolyl antiprogestins and mesoprogestins

4区 · 医学

Article

作者: Garfield, Robert ; Santhamma, Bindu ; Killeen, Zachary ; Amelkina, Olga ; Nickisch, Klaus ; Schneider, Birgitt ; Elger, Walter ; Meister, Reinhard

Antiprogestins with a 4' para imidazolylphenyl moiety were synthesized and their biochemical interactions with the progesterone and glucocorticoid receptor were investigated. Depending on the substitution pattern at the 17 position partial progesterone receptor (PR)-agonistic derivatives like compounds EC339 and EC336 or pure antagonists like compound EC317 were obtained. EC317 was investigated in vivo and found to be significantly more potent than RU 486 in cycling and pregnant guinea pigs. For testing the biological action progesterone receptor modulators (PRM), guinea pigs appears as a specific model when compare to pregnant human uterus. This model correlates to human conditions such as softening and widening of the cervix, the elevation of the uterine responsiveness to prostaglandins and oxytocin, and finally to induction of labor. The use of non-pregnant guinea pigs permitted the simultaneous assessment of PR-agonistic and PR-antagonistic properties and their physiological interactions with uterine and vaginal environment. These can histologically be presumed from the presence of estrogen or progesterone dominance in the genital tract tissues. The ovarian histology indicated the effects on ovulation. Corpora lutea in guinea pigs further reflects inhibitory effects of the progesterone-dependent uterine prostaglandin secretion. PRMs are initially synthesized as analogues of RU 486. They represent a heterogeneous group of compounds with different ratios of PR-agonistic and-antagonistic properties. PR-agonistic properties may be essential for uterine anti-proliferative effects. In various clinical studies these were also attributed to RU 486 or Ulipristal [1,2]. Adjusted PR-agonistic PRMs (EC312, EC313) [3] may be more effective in achieving a mitotically resting endometrium and superior uterine tumor inhibition. For the use in termination of pregnancy, progesterone-inhibitory effects are essentially needed. Even minor PR-agonistic properties compromise the therapeutic goals. Pure PR-antagonists, as EC317, clearly exceeded the gold standard RU 486 with respect to labor inducing effects. Mechanistically it is surprising that both types of compound may be potent inhibitors of ovulation.

100 项与 EC-317 相关的药物交易

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