Therapeutic effect of cyclo-oxygenase inhibitors with different isoform selectivity in lipopolysaccharide-induced preterm birth in mice.
OBJECTIVE
Cyclo-oxygenase inhibitors have different selectivity for inhibitory action on the isoforms of the enzyme. Our purpose was to compare the tocolytic and maternal toxic effects of various cyclo-oxygenase inhibitors in the lipopolysaccharide-induced preterm birth in pregnant mice.


METHODS
We randomly assigned 50 ICR pregnant mice into five groups of 10 mice each and treated them intraperitoneally with either phosphate-buffered saline solution or lipopolysaccharide (50 microg) on day 15 of pregnancy. Of the four groups that received lipopolysaccharide, three groups also were treated either with nonselective cyclo-oxygenase inhibitors (indomethacin [1 mg/kg/d] or diclofenac [2 mg/kg/d]) or with the cyclo-oxygenase-2 preferential inhibitor, meloxicam (2 mg/kg/d), with a gavage tube on days 15 through 18 of pregnancy or until maternal death. The mice were killed immediately after preterm birth or on day 21 of pregnancy. Preterm birth rates and maternal side effect profiles were evaluated.


RESULTS
Preterm birth occurred in 90% of mice after intraperitoneal lipopolysaccharide injection and in 20% of mice after phosphate-buffered saline solution injection. Indomethacin and meloxicam, but not diclofenac, significantly decreased the incidence of preterm birth that was induced by lipopolysaccharide (33.3% and 33.3%, respectively; P =.028). Although the overall incidence of maternal gastric and/or renal toxicities was not significantly increased in the indomethacin or meloxicam groups, a significant increase was noticed in the diclofenac group compared with the lipopolysaccharide-treated control group (P =.006).


CONCLUSIONS
Indomethacin and meloxicam, but not diclofenac, inhibit the lipopolysaccharide-induced preterm birth in an animal model. Meloxicam appears to have no advantage over indomethacin with regard to tocolysis and maternal side effects.
Lee
Pil Ryang
PR
Departments of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea. prlee@amc.seoul.kr
Kim
So-Ra
SR
Jung
Bok-Kyung
BK
Kim
Kyu-Rae
KR
Chung
Ji-Youn
JY
Won
Hye-Sung
HS
Kim
Ahm
A
D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004008:Diclofenac / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D007213:Indomethacin / Q000009:adverse effects / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007674:Kidney Diseases / Q000139:chemically induced; D008070:Lipopolysaccharides; D000077239:Meloxicam; D051379:Mice; D008813:Mice, Inbred ICR; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000517:prevention & control*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011451:Prostaglandin-Endoperoxide Synthases; D013272:Stomach Diseases / Q000139:chemically induced; D013843:Thiazines / Q000009:adverse effects / Q000627:therapeutic use; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D013843:Thiazines; D013844:Thiazoles; D004008:Diclofenac; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000077239:Meloxicam; D007213:Indomethacin