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

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

Animals, Cyclooxygenase Inhibitors, Dexamethasone, Drug Therapy, Combination, Electromyography, Female, Fetal Blood, Fetus, Glucocorticoids, Obstetric Labor, Premature, Pregnancy, Receptors, Oxytocin, Sheep, Uterus, Journal Article
0002-9378
649-57
Grigsby, P L
cee5dbfe-0fcd-47f0-a9c7-1a4765b6f20c
Poore, K R
b9529ba3-6432-4935-b8fd-6e382f11f0ad
Hirst, J J
2bf58dec-089c-46c7-81f2-aed8d8a28029
Jenkin, G
37ed29d7-648f-46d5-af31-7881b388ddc5
Grigsby, P L
cee5dbfe-0fcd-47f0-a9c7-1a4765b6f20c
Poore, K R
b9529ba3-6432-4935-b8fd-6e382f11f0ad
Hirst, J J
2bf58dec-089c-46c7-81f2-aed8d8a28029
Jenkin, G
37ed29d7-648f-46d5-af31-7881b388ddc5

Grigsby, P L, Poore, K R, Hirst, J J and Jenkin, G (2000) Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist. American Journal of Obstetrics and Gynecology, 183 (3), 649-57. (doi:10.1067/mob.2000.106584).

Record type: Article

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(2)(alpha) 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(2alpha) 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(2alpha) 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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More information

Published date: September 2000
Keywords: Animals, Cyclooxygenase Inhibitors, Dexamethasone, Drug Therapy, Combination, Electromyography, Female, Fetal Blood, Fetus, Glucocorticoids, Obstetric Labor, Premature, Pregnancy, Receptors, Oxytocin, Sheep, Uterus, Journal Article
Organisations: Human Development & Health

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Local EPrints ID: 409043
URI: http://eprints.soton.ac.uk/id/eprint/409043
ISSN: 0002-9378
PURE UUID: 6cb5a904-cb18-4eea-9ed0-e9351e246cb8
ORCID for K R Poore: ORCID iD orcid.org/0000-0002-1455-0615

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Date deposited: 28 May 2017 04:05
Last modified: 03 Dec 2019 01:51

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Author: P L Grigsby
Author: K R Poore ORCID iD
Author: J J Hirst
Author: G Jenkin

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