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 1.6Â10 À7 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.

The in vitro effect of dual combinations of ritodrine, nicardipine and atosiban on contractility of pregnant rat myometrium

“…Indeed, ritodrine/atosiban is the only combination where a drug stimulating the cAMP relaxant pathway and a drug preventing the calcium release from intracellular storage sites and calcium influx across plasma membranes through inhibition of IP 3 production are used simultaneously 13,14 . In a recently published study, we found that rofecoxib, a specific inhibitor of the inducible isoform of cyclooxygenase (COX‐2), a drug that also prevents IP 3 production induced by the production of prostaglandins, exhibited a synergistic effect on the inhibition of uterine contractile activity when used in combination with ritodrine 17 . Therefore, targeting these two pathways appears to produce an improved tocolytic effect.…”

“…Changes in the 10 min integral 10 min after application of each concentration of each single drug or combinations were expressed as percentage of changes from the basal 10 min integral. The concentration–response curves of each single drug were previously determined and used to calculate the effective concentrations that inhibited 25% (EC 25 ), 50% (EC 50 ) and 75% (EC 75 ) of basal activity (Table 1) 17 .…”

Uterine contractions in rodent models and humans

“…The COX2 inhibitor indomethacin has been shown to inhibit uterine contractions in explanted tissue strips from mice, rats, guinea pigs, and humans. 164,172‐174 . Indomethacin is used clinically as a tocolytic, although results from clinical trials have been mixed 158 .…”

Understanding Spontaneous Preterm Birth: From Underlying Mechanisms to Predictive and Preventive Interventions

“…Cyclooxygenase enzymes are fundamental to the production of PGs and inhibitors that reduce uterine contractions. 159 Cyclooxygenase inhibitors are easily administered (orally or rectally) and have fewer maternal side effects than betamimetics. 160 Cyclooxygenase inhibitors, however, freely cross the placenta and can interfere with PGs homeostasis in the fetus.…”