Grigsby P L, Poore K R, Hirst J J, Jenkin G
Department of Physiology, Monash University, Clayton, Victoria, Australia.
Am J Obstet Gynecol. 2000 Sep;183(3):649-57. doi: 10.1067/mob.2000.106584.
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.
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.
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.
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.
本研究旨在比较选择性前列腺素合成酶2型抑制剂尼美舒利单独使用或与催产素受体拮抗剂阿托西班联合使用对绵羊糖皮质激素诱导的早产进程的影响。还研究了其对母体和胎儿循环中前列腺素浓度以及胎儿健康状况的影响。
在妊娠138±1天开始，通过静脉输注地塞米松（1mg/d）诱导长期插管胎儿的母羊发生早产。母羊还分别接受尼美舒利和阿托西班输注（分别为每天20.0和4.12mg/kg；n = 5）、单独使用尼美舒利（每天20.0mg/kg；n = 5）或仅输注赋形剂（n = 9）。在从母体和胎儿颈动脉以及子宫卵巢静脉采集的血浆样本中，于输注前和输注期间测量血浆13,14 - 二氢 - 15 - 酮 - 前列腺素F2α和前列腺素E2浓度。
接受尼美舒利和阿托西班治疗的母羊所怀胎儿在治疗期间均未分娩。这些动物在开始地塞米松诱导后98.0±6.8小时被选择性处死。这明显长于单独接受尼美舒利治疗的母羊（71.2±3.9小时；n = 5）和接受赋形剂治疗的母羊（51.4±1.7小时；n = 9）的分娩时间。接受尼美舒利和阿托西班治疗的母羊以及接受尼美舒利治疗的母羊在治疗期间母体和胎儿血浆13,14 - 二氢 - 15 - 酮 - 前列腺素F2α和前列腺素E2浓度均下降。相比之下，接受赋形剂治疗的母羊在接受地塞米松诱导期间母体和胎儿血浆13,14 - 二氢 - 15 - 酮 - 前列腺素F(2α)和前列腺素E2浓度显著升高。在治疗期间，接受尼美舒利和阿托西班治疗的母羊观察到的子宫肌电图活动相对于接受赋形剂和尼美舒利治疗的母羊的活动均受到显著抑制。所有胎儿在分娩或预定死亡时均存活。
这些结果表明，前列腺素内过氧化物合酶2型抑制剂与催产素受体拮抗剂联合使用在抑制早产方面比单独使用前列腺素内过氧化物合酶2型抑制剂更有效。阿托西班与尼美舒利联合用于预防与分娩相关的催产素刺激的子宫活动增加，可能允许将尼美舒利的使用剂量降低到对胎儿健康影响最小的水平。
