Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist

OBJECTIVE: The aim of this study was to compare the effects of the selectiv e prostaglandin synthase type 2 inhibitor nimesulide, alone or in combinati on with the oxytocin receptor antagonist atosiban, on the progression of gl ucocorticoid-induced premature labor in sheep. Effects on circulating mater nal and fetal prostaglandin concentrations and on fetal well-being were als o examined. STUDY DESIGN: Premature labor was induced in ewes with long-term catheteriz ed fetuses by infusion of dexamethasone (1 mg/d) starting at 138 +/- 1 days ' gestation. Ewes also received an infusion of either nimesulide and atosib an (20.0 and 4.12 mg/kg per day, respectively; n = 5), nimesulide alone (20 .0 mg/kg per day; n = 5), or vehicle only (n = 9). Plasma 13,14-dihydro-15- keto-prostaglandin F-2 alpha and prostaglandin E-2 concentrations were meas ured before and during infusions in plasma samples obtained from the matern al and fetal carotid arteries and the utero-ovarian vein. RESULTS: No fetuses from ewes treated with nimesulide and atosiban were del ivered during treatment. These animals were killed electively 98.0 +/- 6.8 hours after the commencement of dexamethasone induction. This was significa ntly longer than the delivery times for those ewes treated with nimesulide alone (71.2 +/- 3.9 hours; n = 5) and for vehicle-treated ewes (51.4 +/- 1. 7 hours; n = 9). Both maternal and fetal plasma 13,14-dihydro-15-keto-prost aglandin F-2 alpha and prostaglandin E-2 concentrations in nimesulide and a tosiban-treated ewes and in nimesulide-treated ewes decreased during treatm ent. In contrast, vehicle-treated ewes showed a significant increase in mat ernal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F-2 alpha and pr ostaglandin E-2 concentrations during dexamethasone induction. Uterine elec tromyographic activity observed in nimesulide and atosiban-treated ewes was significantly suppressed with respect to activities in both vehicle- and n imesulide-treated ewes during the treatment period. All fetuses were alive at delivery or scheduled death. CONCLUSIONS: These results indicate that the combination of an inhibitor of prostaglandin endoperoxidase H synthase type 2 with an oxytocin receptor a ntagonist is more effective in inhibition of preterm labor than is treatmen t with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. Th e clinical use of atosiban to prevent the oxytocin-stimulated increase in u terine activity associated with labor in combination with nimesulide may pe rmit reduction of the dose of nimesulide used to a level that has minimal i mpact on fetal well-being.