The effects of meloxicam, indomethacin or NS-398 on eicosanoid synthesis by fresh human gastric mucosa.
BACKGROUND
In the stomach, constitutive cyclooxygenase (COX-1) synthesizes prostaglandins that maintain the integrity of the gastric mucosa, while their inhibition contributes to gastric mucosal damage. In contrast COX-2, an inducible enzyme, forms prostanoids involved in pain and inflammation.


OBJECTIVE
To compare prostaglandin synthesis inhibition by meloxicam, a selective COX-2 NSAID reported to have better gastric tolerability, with indomethacin and NS-398 in human gastric mucosa and in whole blood assays.


METHODS
Meloxicam, indomethacin or NS-398 were incubated with fresh human gastric mucosa pieces (100 mg in 1 mL phosphate buffered saline, pH 7.4, 37 degrees C, 30 min), clotting human blood (1 mL, 37 degrees C, 60 min) or with lipopolysaccharide-stimulated heparinized blood (1 mL, 37 degrees C, 24 h). Prostanoids were analysed by radioimmunoassay.


RESULTS
Meloxicam was a less potent inhibitor of gastric mucosal eicosanoid compared to indomethacin, showing a sixfold difference in IC50 with gastric mucosal prostaglandin E (PGE) (11.8 and 1.8 microM, respectively). In the whole blood assays, the COX-2/COX-1 ratio for meloxicam was 0.2 compared to 0.9 for indomethacin confirming meloxicam's COX-2 selectivity.


CONCLUSIONS
The results with human mucosa pieces would suggest that the better gastric tolerability of meloxicam compared to indomethacin is related to its relatively lower inhibition of gastric mucosal PGE synthesis by COX-1.
Tavares
I A
IA
Academic Department of Surgery, The Rayne Institute, Guys, King's and St. Thomas' School of Medicine and Dentistry, London, UK. ignatius.tavares@kcl.ac.uk
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology*; D046508:Culture Techniques; D051545:Cyclooxygenase 1; D015777:Eicosanoids / Q000096:biosynthesis*; D006801:Humans; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007527:Isoenzymes / Q000378:metabolism; D000077239:Meloxicam; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000009:adverse effects / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology*; D013843:Thiazines / Q000009:adverse effects / Q000494:pharmacology*; D013844:Thiazoles / Q000009:adverse effects / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; D013843:Thiazines; D013844:Thiazoles; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000077239:Meloxicam; D007213:Indomethacin