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Notes: Objective To compare the tocolytic potency of ritodrine, nicardipine and atosiban, used alone and in dual combinations, to see whether combinations of these drugs, which act via different pathways, could improve inhibition of uterine contractility.Design Study on myometrial contractility in vitro.Setting Laboratory of physiology, Lyon, France.Sample Longitudinal myometrial strips from non-labouring timed pregnant Wistar rats (18 gestational days).Methods Strips were simultaneously exposed to EC25, EC50 or EC75 of dual combinations of either ritodrine and nicardipine, ritodrine and atosiban or nicardipine and atosiban (n= 10/group). Basal contractile activity and contractile activity after addition of each combination was measured using the 10 min integral of activity. Changes were expressed as percentage from the basal 10 min integral activity. The observed percentage inhibition of activity was compared with the expected percentage inhibition in an additive pharmacological model. When no significant difference occurred, the combination was deemed simply to have an additive tocolytic effect. When inhibition of activity was significantly greater compared with the expected percentage inhibition, the combination was deemed to have a synergistic effect.Main outcome measure Changes in integral contractile activity in response to tocolytic combinations.Results Ritodrine and atosiban inhibited integral activity to a greater extent than expected [e.g. using EC50: observed inhibition 88.9% (13.8%) vs expected inhibition 75%; P 〈 0.015]. Actual inhibition by nicardipine/ritodrine [78.55% (20.4%) vs 75%; P= n.s.] and nicardipine/atosiban [78.94% (17.8%) vs 75%; P= n.s.] was not significantly different from expected.Conclusions A combination of ritodrine plus atosiban exhibits a synergistic inhibition for myometrial activity, thus allowing the use of lower concentrations of each drug to achieve the same effect compared with each drug used alone. Combination of nicardipine plus ritodrine and nicardipine plus atosiban achieves only an additive effect. The potential for decreasing side effects (beta-mimetics) and costs (atosiban) when using a combination in clinical practice needs to be evaluated.

Notes: 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. EC50 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.