Effect of selective vs. non-selective cyclo-oxygenase inhibitors on fetal membrane prostaglandin synthesis.
Increased expression of the inducible isoform of cyclo-oxygenase (COX-2) and prostaglandin output from fetal membranes is a key stage in human parturition. Prostaglandin production can be inhibited by non-steroidal anti-inflammatory drugs (NSAIDs), but these may also inhibit cyclo-oxygenase enzymes in fetal tissues, and hence cause potentially serious side effects. We have compared the concentrations of NSAIDs that inhibit maximal PGE2 synthesis from intact human fetal membrane explants in vitro with those found in human plasma after standard anti-inflammatory treatment. The concentrations of all six drugs that caused a 50% inhibition of fetal membrane prostaglandin output were lower than average plasma levels achieved during treatment. This effect was greatest for nimesulide and indomethacin, indicating that these drugs require further study at low doses in vivo, as this could achieve the same tocolytic effect with diminished adverse fetal effect. These drugs were also the most potent inhibitors of fetal membrane prostaglandin output, consistent with their effects on COX-2 activity.
Sawdy
R
R
Department of Obstetrics and Gynaecology, Wolfson and Weston Research Centre for Family Health, Institute of Reproductive and Developmental Biology, Hammersmith Hospital, London, UK.
Pan
H
H
Sullivan
M
M
Bennett
P
P
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D001241:Aspirin / Q000097:blood / Q000494:pharmacology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005321:Extraembryonic Membranes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005663:Furans / Q000097:blood / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000097:blood / Q000494:pharmacology; D007213:Indomethacin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D000077239:Meloxicam; D008565:Membrane Proteins; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D013843:Thiazines / Q000097:blood / Q000494:pharmacology; D013844:Thiazoles / Q000097:blood / Q000494:pharmacology
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D008565:Membrane Proteins; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001241:Aspirin; C012655:nimesulide; D000077239:Meloxicam; D007052:Ibuprofen; D007213:Indomethacin