In vitro study of tocolytic effect of rofecoxib, a specific cyclo-oxygenase 2 inhibitor. Comparison and combination with other tocolytic agents

Abstract

Objective The aim of this work was to study and compare the tocolytic effects of rofecoxib with indomethacin, ritodrine, nicardipine and atosiban. We also studied the combination of rofecoxib with each agent. Design In vitro animal experimental study. Setting Non-selective cyclo-oxygenase (COX) inhibitors have potent tocolytic effect. However, they also have major fetal side effects that seem to be due to COX-1 inhibition. A specific COX-2 inhibitor could be a potent tocolytic agent with less fetal toxicity. Sample Myometrial strips from pregnant Wistar rats at 18 days of gestation. Methods Isometric tension was recorded from 112 pregnant rat myometrial strips in vitro. Strips were exposed to increase molar concentration of one drug or combination. Main outcome measures Contractile activity was assessed by calculating the area under the curve, to obtain a dose–response curve of each drug. EC 50 and mean maximal inhibiting concentration were compared using ANOVA. Chemical interaction was defined for each combination. Results The in vitro tocolytic effect of rofecoxib was demonstrated. Contractile activity stopped at a concentration of 1.6 × 10 −7 M. Effective concentrations were 1000 times less than for indomethacin and significantly lower than ritodrine and atosiban. Rofecoxib combined with ritodrine had a synergic effect. Other combinations only had an additive effect. Conclusions Rofecoxib has a potent tocolytic effect in vitro. The high specificity and low effective concentrations of COX-2 may result in low fetal toxicity. Animal fetal side effects need to be explored.