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Objective: Our purpose was to evaluate the pharmacokinetics of atosiban, an oxytocin antagonist, during and after intravenous infusion in pregnant patients having at least six contractions per hour. The relationship between atosiban infusion and uterine activity was also assessed., Study Design: Plasma samples from eight pregnant patients treated with intravenous atosiban (300 micrograms/min for 6 to 12 hours) were analyzed for atosiban concentration by a specific radioimmunoassay procedure. Contraction rate data were obtained by external tocodynamometry for 1 hour before the infusion and during the subsequent infusion., Results: The average steady-state plasma concentrations of patients receiving intravenous atosiban were 442 +/- 73 ng/ml (mean +/- SD), with steady state achieved by 1 hour after the start of the infusion. After the completion of the infusion, plasma concentrations declined rapidly in a biexponential manner with initial and terminal half-life estimates of 13 +/- 3 and 102 +/- 18 minutes, respectively. The effective half-life was 18 +/- 3 minutes. The plasma clearance of atosiban was relatively high (42 L/hr) and the volume of distribution (approximately 18 L) was consistent with distribution into extracellular fluid. Of the seven patients evaluated for uterine activity, the mean contraction rate decreased by 75% during the third hour of treatment and remained low until treatment termination., Conclusion: On the basis of earlier published reports, the pharmacokinetics of atosiban in pregnant patients are similar to those in nonpregnant women. Although the patient population was small, a consistent reduction in uterine activity was observed during atosiban infusion.

Objectives: Atosiban is a synthetic oxytocin antagonist that is currently undergoing dose-ranging clinical trials. To date, no data are available on the cardiovascular effects of combined oxytocin and vasopressin blockade during late pregnancy. Our aims were (1) to determine the effects of atosiban infusion on the maternal and fetal cardiovascular system and on uterine blood flow and (2) to determine the maternal pharmacokinetics and the rate of placental transfer of atosiban., Study Design: Five chronically catheterized pregnant sheep were treated with a 2-hour infusion of atosiban (300 micrograms.min-1) at 116 to 126 days' gestation. Maternal and fetal blood pressure and heart rate and uterine blood flow were measured before and during the infusion. Maternal and fetal arterial blood samples were obtained throughout the experiment for measurement of plasma atosiban levels and blood gas values., Results: No significant change in maternal cardiovascular parameters or uterine blood flow were observed. Similarly, no changes in fetal blood pressure and arterial blood gases were present during the infusion of the atosiban. Maternal plasma levels of atosiban reached a maximum of 585.2 +/- 82.2 (ng/ml mean +/- SD) at the end of the infusion and decreased biexponentially with a mean t1/2 alpha of 17 minutes and a mean t1/2 beta of 2.2 hours. Fetal plasma levels of atosiban were at or below the detection limit., Conclusion: Atosiban does not significantly affect maternal or fetal cardiovascular parameters when it is administered for 2 hours in late-pregnant sheep. Although significant levels were measured in maternal blood, negligible transfer to the fetus occurred.

Two subchronic studies were conducted to assess the potential toxicity of N-D-ornithyl amphotericin B methyl ester (OAME). In both studies the comparative control substance was amphotericin B (AMB). Dogs (5/sex/group) were given OAME (82% pure, based on high-pressure liquid chromatographic (HPLC) analysis) at 0.6, 2.5, and 10 mg/kg or AMB at 0.6 mg/kg intravenously once daily for 3 months. Two dogs per sex per group were retained for a 7-week postdose observation period. Rats (15/sex/group) were given daily doses of OAME at 4, 12, 24, and 36 mg/kg or AMB at 5 and 12 mg/kg intraperitoneally for 3 months. The principal organs of toxicity in both species were the liver, kidneys, and circulating erythrocytes. Hepatic changes in dogs consisted of periportal and centrilobular inflammation in animals of all dosed groups and were equivalent in dogs given 0.6 mg/kg OAME or AMB. In rats, acute hepatic necrosis with periportal, centrilobular, or panlobular distribution in animals of all OAME (except 4 mg/kg) and AMB-dosed groups was observed. These changes were equivalent in the 36-mg/kg OAME- and 12-mg/kg AMB-dosed animals. Renal changes, evidenced by increases in serum urea nitrogen water consumption, urine volume, decreased urine osmolality, and renal tubular changes (ranging from degeneration and regeneration to necrosis), were observed in both species. In dogs, these changes in the OAME-dosed animals were less severe at all doses than those observed in the AMB-dosed dogs. Renal changes in rats, which were mild in comparison to the dogs, were equivalent at doses of 5 and 12 mg/kg AMB and 36 mg/kg OAME. Decreased erythrocyte counts, hematocrit, and hemoglobin values were observed in both species. Unique to the dog study, however, were irreversible behavioral (somnolence, ataxia, tremors, and compulsive searching) and/or morphologic brain changes (gliosis with astrocytic hypertrophy and hyperplasia) at doses of 2.5 and 10 mg/kg OAME. Similar changes were observed in two dogs given 10 mg/kg OAME (100% pure, based on HPLC analysis) in a 6-week pilot study, indicating that the neurological changes were induced by OAME rather than by an impurity. These changes appear related to prolonged exposure to high plasma concentrations of OAME.