Pharmacodynamics and comparative efficacy of nifedipine in delaying fetal pup delivery using a pregnant rat model
Abstract
Nifedipine (a calcium modulating agent) inhibited uterine contractions in various animal models and delayed human fetus delivery in limited clinical trials. No studies establish a pharmacodynamic relationship between nifedipine plasma levels and pharmacologic response. Data regarding effects on fetal viability also are not available. The present study attempts to determine the validity of a pregnant rat model for evaluating the tocolytic response of nifedipine to ritodrine and "no surgery" and saline controls. The study also attempts to establish a pharmacodynamic relationship for nifedipine in delaying fetal pup delivery using a pregnant rat model and assess subsequent effects on fetal viability. Wistar rats were randomly assigned to treatments including: no surgery control, saline control, nifedipine 0.25, 0.5, 1.0 and 2.0mcg/kg/min. or ritodrine 5.0mcg/kg/min. The model appeared valid for evaluating the tocolytic response to nifedipine and ritodrine. All drug treatments increased delay between pup deliveries, when compared to "no surgery" or saline controls. A progressive decrease in total number of pups delivered was seen with increasing drug dosages. "No surgery" and saline controls and nifedipine 0.25mcg/kg/min. allowed total delivery of all pups during treatment. Decreasing percentages of pups were delivered with increased doses of nifedipine and the ritodrine treatment. A plasma level response curve in a positive direction was established for the nifedipine doses resulting in a correlation coefficient of 0.6225. Since some animals exhibited complete tocolysis (giving rise to the decreasing mean number of pups delivered during drug treatment) a mean tocolytic level to these occurrences was calculated with a value of 363.1 $\pm$ 187.1ng/ml. Analysis of fetal pup viability showed no statistically significant difference among all treatments. However, a progressive decrease on the average in viability was noted with increasing amount of drug. Nifedipine 2.0mcg/kg/min. produces a delay in rat pup delivery comparable to that seen with ritodrine 5.0mcg/kg/min.
Degree
Ph.D.
Advisors
Black, Purdue University.
Subject Area
Pharmacology
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