General Obstetrics and Gynecology: Obstetrics
Delay of preterm birth in sheep by THG113.31, a prostaglandin F receptor antagonist

https://doi.org/10.1016/j.ajog.2004.11.009Get rights and content

Objective

A novel prostaglandin F receptor antagonist, THG113.31, was tested for the suppression of uterine contractility and delay of preterm labor in sheep.

Study design

We determined the tocolytic effectiveness of THG113.31 on contractions that were stimulated in vitro by prostaglandin F and E2 in longitudinal and circular myometrial strips. We also tested the ability of THG113.31 in vivo to lower uterine electromyographic activity that was induced by the progesterone receptor blocker, RU486, and to delay preterm birth.

Results

THG113.31 suppressed the amplitude of prostaglandin F, but not prostaglandin E2–induced contractions of both circular and longitudinal myometrium (P < .01). The times to delivery after RU486 were 34.8 ± 1.1 hours (saline solution) and 41.9 ± 0.5 hours (THG113.31; P < .001) or an average delay of 7.1 hours. There were no changes in fetal blood gases (Pao2, Paco2, pH, or Sao2) because of THG113.31. Fetal cortisol levels rose in each group, and fetal and maternal prostaglandin E2 and F metabolite concentrations rose similarly in both groups.

Conclusion

THG113.31 specifically suppresses prostaglandin F–induced myometrial contractility and delays delivery.

Section snippets

Material and methods

All experiments and procedures were approved by the Monash University Animal Ethics Committee.

In vitro inhibitory activity of THG113.31

Incubation of strips of longitudinal or circular myometrium with THG113.31 had no effect on spontaneous contractile activity. PGF evoked concentration-dependent increases in tension in strips of both longitudinal and circular myometrium. Although co-incubation with THG113.31 had no effect on the sensitivity to PGF per se (pD2 in Table I), analysis of variance (ANOVA) revealed a significant (P = .002 and <.0001, for longitudinal and circular myometrium, respectively) inhibitory effect of

Comment

Here we show that the novel FP inhibitor THG113.31 specifically decreases PGF-induced contractions in sheep myometrial strips in vitro and that it suppresses myometrial electromyographic activity and prolongs pregnancy in RU486-induced preterm labor in vivo. These actions suggest that THG113.31 presents 3 distinct advances in tocolytic therapy. First, they identify a new target for tocolysis, the FP receptor. Second, they demonstrate the usefulness of a new platform technology, antagonizing G

Acknowledgments

We thank Mrs Eileen Marco for assistance with the manuscript and Theratechnologies (Montreal, Canada) for the gift of THG113.31.

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