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


METHODS
In vitro animal experimental study.


METHODS
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.


METHODS
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.


METHODS
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 x 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.
Doret
Muriel
M
Department of Obstetrics and Gynaecology, Edouard Herriot Hospital, Lyon, France.
Mellier
Georges
G
Benchaib
Mehdi
M
Piacenza
Jean Michel
JM
Gharib
Claude
C
Pasquier
Jean Charles
JC
D000704:Analysis of Variance; D000818:Animals; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D007213:Indomethacin / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007783:Lactones / Q000627:therapeutic use*; D008565:Membrane Proteins; D009215:Myometrium / Q000187:drug effects; D009529:Nicardipine / Q000627:therapeutic use; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D017208:Rats, Wistar; D012312:Ritodrine / Q000627:therapeutic use; D013450:Sulfones; D015149:Tocolytic Agents / Q000627:therapeutic use*; D014590:Uterine Contraction / Q000187:drug effects; D014668:Vasotocin / Q000031:analogs & derivatives* / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D013450:Sulfones; D015149:Tocolytic Agents; C047046:atosiban; C116926:rofecoxib; D009529:Nicardipine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D012312:Ritodrine; D014668:Vasotocin; D007213:Indomethacin