Combinational tocolysis: evaluating lower-dose combinations of nifedipine, indomethacin, and aminophylline for tocolytic synergism in pregnant human myometrium.

Abstract

Tocolytics, such as nifedipine, indomethacin, and aminophylline, often cause side effects that limit their clinical usefulness. It is possible that effective tocolysis could be achieved by combining tocolytics with synergistic actions so that doses of individual agents can be reduced, concurrently reducing the likelihood of off-target side effects. Since these drugs act through markedly different signaling pathways to inhibit myometrial contractions, it was hypothesized that nifedipine, indomethacin, and aminophylline in combinations would produce tocolytic synergism, which might have clinical value. To evaluate whether nifedipine, indomethacin, and aminophylline produce tocolytic synergisms when applied in dual and triple combinations on pregnant human myometrial tissue strips undergoing spontaneous rhythmic contractions ex vivo. Myometrial strips generating spontaneous contractions were treated with IC₂₅ (25% inhibitory concentration) or IC₅₀ (50% inhibitory concentration) concentrations of 3 different dual tocolytic combinations: nifedipine+indomethacin, nifedipine+aminophylline, and indomethacin+aminophylline or one triple combination: nifedipine+indomethacin+aminophylline. The area under the curve for the baseline contractility (100%) (pretreatment) and following combination treatment (post-treatment) was measured for 1 hour. For each tocolytic combination, the expected percent inhibition was calculated based on the individual tocolytic effects using the Bliss Independence Model and then compared with the experimentally observed inhibition. The combinational effect was considered synergistic if the experimentally observed inhibition (IC_25(OBS) and IC_50(OBS)) scores were significantly greater than the theoretically expected (IC_25(EXP) and IC_50(EXP)) inhibition scores. Contraction inhibition was significantly greater than expected for the dual combinations of nifedipine+indomethacin (n=6) (eg, IC_50(EXP) score [0.72] vs IC_50(OBS) score [0.86]; P=.0003) and nifedipine+aminophylline (n=6) (eg, IC_50(EXP) score [0.72] vs IC_50(OBS) score [0.92]; P=.0002), confirming synergism, whereas the dual combination of indomethacin+aminophylline produced only an additive effect (n=6) (eg, IC_50(EXP) score [0.68] vs IC_50(OBS) score [0.74]; P=.25). The triple combination of nifedipine+indomethacin+aminophylline (n=6) also yielded tocolytic synergism (IC_25(EXP) score [0.51] vs IC_25(OBS) score [0.73]; P=.0004) and achieved near-complete inhibition of ex vivo contractility when constituent drugs were applied to myometrial strips at just IC₂₅ concentrations. Of the 4 combinations examined, nifedipine+indomethacin, nifedipine+aminophylline, and nifedipine+indomethacin+aminophylline demonstrated synergism. The combination of indomethacin+aminophylline exhibited only an additive effect. Given the narrow therapeutic indications for tocolysis-primarily limited to short-term (≤48 hours) use to facilitate antenatal corticosteroid administration and maternal transfer-the synergistic lower-dose combinations identified here may enable more effective and safer tocolysis. These findings support further clinical investigation of combinational tocolysis to improve preterm birth outcomes while minimizing maternal and fetal adverse effects.