Effects of long term administration of KUR‐1246, a selective β2‐adrenoceptor agonist, on pregnant sheep and their fetuses

Abstract

To evaluate the safety of KUR-1246 as a tocolytic agent, we examined the effects of its long term infusion on respiratory and cardiovascular systems and general metabolism in pregnant sheep and their fetuses. Animal experiment with chronically instrumented ewes and their fetuses. Center for animal experiments, Hokkaido University School of Medicine, Japan. Eight Suffolk ewes at 117 to 120 days of gestation. At 120-124 days of gestation, ewes (n= 4) were infused intravenously for 24 hours with KUR-1246 at 0.03 microg/kg/minute, a dose that completely inhibits oxytocin-induced uterine contractions in pregnant sheep. The controls received saline instead (n= 4). Statistical comparisons were carried out by repeated-measures ANOVA followed by Dunnett's test. Maternal and fetal values of heart rate, blood pressure, plasma electrolytes, glucose, insulin and non-esterified fatty acid levels, and blood gases and lactate level. The maternal plasma levels of KUR-1246 increased and reached a plateau at 15 hours or later from the start of the infusion, whereas the fetal levels of it were below the lower limit of quantification (0.1 ng/mL) throughout the experiment. Significant differences over time between the ewes that had received with KUR-1246 and the controls were found for the following parameters: maternal heart rate, blood lactate, plasma glucose, and plasma insulin levels, and fetal plasma glucose and plasma insulin levels (P < 0.05). In the KUR-1246 treated ewes, significant changes from the pre-infusion value were detected in maternal blood lactate and fetal plasma glucose levels within 6 hours from the start of the infusion (P < 0.05). No significant differences were observed in other parameters in either ewes or fetuses. The physiologic changes induced by a 24-hour infusion of KUR-1246 were transient and considered to be within the compensatory capacity in both pregnant ewes and their fetuses, suggesting that KUR-1246 is a potentially safe tocolytic agent for use by long term infusion.