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.


METHODS
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.
Grigsby
P L
PL
Department of Physiology, Monash University, Clayton, Victoria, Australia.
Poore
K R
KR
Hirst
J J
JJ
Jenkin
G
G
D000818:Animals; D001158:Arteries; D001786:Blood Glucose / Q000032:analysis; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D003907:Dexamethasone; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000097:blood; D015232:Dinoprostone / Q000097:blood; D004359:Drug Therapy, Combination; D004576:Electromyography; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D005333:Fetus / Q000502:physiology; D005938:Glucocorticoids; D019344:Lactic Acid / Q000097:blood; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000517:prevention & control*; D010100:Oxygen / Q000097:blood; D011247:Pregnancy; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors*; D012756:Sheep; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D014599:Uterus / Q000502:physiology; D014668:Vasotocin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*
D001786:Blood Glucose; D016861:Cyclooxygenase Inhibitors; D005938:Glucocorticoids; D018045:Receptors, Oxytocin; D013449:Sulfonamides; C047046:atosiban; C008228:15-keto-13,14-dihydroprostaglandin F2alpha; D019344:Lactic Acid; D003907:Dexamethasone; D015237:Dinoprost; D015232:Dinoprostone; D010100:Oxygen; C012655:nimesulide; D014668:Vasotocin