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

Peta Grigsby, Kirsten R. Poore, Jonathan J. Hirst, Graham Jenkin

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

OBJECTIVE: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. STUDY DESIGN: Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 ± 1 days' gestation. Ewes also received an infusion of either nimesulide and atosiban (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(2α) and prostaglandin E 2 concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. RESULTS: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 ± 6.8 hours after the commencement of dexamethasone induction. This was significantly 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-prostaglandin F(2α) and prostaglandin E 2 concentrations in nimesulide and atosiban-treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F(2α) and prostaglandin E 2 concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban-treated ewes was significantly suppressed with respect to activities in both vehicle-and nimesulide-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 antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being.

Original languageEnglish (US)
Pages (from-to)649-657
Number of pages9
JournalAmerican Journal of Obstetrics and Gynecology
Volume183
Issue number3
DOIs
StatePublished - 2000
Externally publishedYes

Fingerprint

nimesulide
Oxytocin Receptors
Cyclooxygenase Inhibitors
Premature Obstetric Labor
Sheep
Prostaglandins F
Prostaglandins E
Mothers
Dexamethasone
Fetus
Cyclooxygenase 2
atosiban
Induced Labor

Keywords

  • Labor
  • Nimesulide
  • Oxytocin receptor antagonists
  • Prostaglandin endoperoxidase H synthase inhibitors
  • Sheep

ASJC Scopus subject areas

  • Medicine(all)
  • Obstetrics and Gynecology

Cite this

Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist. / Grigsby, Peta; Poore, Kirsten R.; Hirst, Jonathan J.; Jenkin, Graham.

In: American Journal of Obstetrics and Gynecology, Vol. 183, No. 3, 2000, p. 649-657.

Research output: Contribution to journalArticle

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abstract = "OBJECTIVE: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. STUDY DESIGN: Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 ± 1 days' gestation. Ewes also received an infusion of either nimesulide and atosiban (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(2α) and prostaglandin E 2 concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. RESULTS: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 ± 6.8 hours after the commencement of dexamethasone induction. This was significantly 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-prostaglandin F(2α) and prostaglandin E 2 concentrations in nimesulide and atosiban-treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F(2α) and prostaglandin E 2 concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban-treated ewes was significantly suppressed with respect to activities in both vehicle-and nimesulide-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 antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being.",
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T1 - Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist

AU - Grigsby, Peta

AU - Poore, Kirsten R.

AU - Hirst, Jonathan J.

AU - Jenkin, Graham

PY - 2000

Y1 - 2000

N2 - OBJECTIVE: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. STUDY DESIGN: Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 ± 1 days' gestation. Ewes also received an infusion of either nimesulide and atosiban (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(2α) and prostaglandin E 2 concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. RESULTS: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 ± 6.8 hours after the commencement of dexamethasone induction. This was significantly 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-prostaglandin F(2α) and prostaglandin E 2 concentrations in nimesulide and atosiban-treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F(2α) and prostaglandin E 2 concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban-treated ewes was significantly suppressed with respect to activities in both vehicle-and nimesulide-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 antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being.

AB - OBJECTIVE: The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. STUDY DESIGN: Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 ± 1 days' gestation. Ewes also received an infusion of either nimesulide and atosiban (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(2α) and prostaglandin E 2 concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. RESULTS: No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 ± 6.8 hours after the commencement of dexamethasone induction. This was significantly 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-prostaglandin F(2α) and prostaglandin E 2 concentrations in nimesulide and atosiban-treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F(2α) and prostaglandin E 2 concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban-treated ewes was significantly suppressed with respect to activities in both vehicle-and nimesulide-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 antagonist is more effective in inhibition of preterm labor than is treatment with a prostaglandin endoperoxidase H synthase type 2 inhibitor alone. The clinical use of atosiban to prevent the oxytocin-stimulated increase in uterine activity associated with labor in combination with nimesulide may permit reduction of the dose of nimesulide used to a level that has minimal impact on fetal well-being.

KW - Labor

KW - Nimesulide

KW - Oxytocin receptor antagonists

KW - Prostaglandin endoperoxidase H synthase inhibitors

KW - Sheep

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