Non-steroidal anti-inflammatory drugs that cause relatively little gastric damage.

Abstract

Gastrointestinal damage by non-steroidal anti-inflammatory drugs (NSAID), which is common and sometimes fatal, involves inhibition of prostaglandin (PG) synthesis. The damage is less with NSAID that inhibit inflammatory cyclo-oxygenase (COX)-2 but not gastroprotective COX-1. We have compared nimesulide and acemetacin, two NSAID that cause relatively little gastric damage, with indomethacin for effects on purified COX-1 and COX-2. The results are related to findings on human gastric mucosa and leucocytes. With purified COX-1, inhibition was absent with nimesulide, weak with acemetacin (inhibitory concentration of 50% [IC50 ] 85 m̈mol/L), and potent with indomethacin (IC50 0.6 m̈mol/L). Inhibition of purified COX-2 occurred with nimesulide and indomethacin (IC50 values 90 and 4.1 m̈mol/L, respectively) but not acemetacin. All results with nimesulide are consistent with a preferential block of COX-2 that contributes to relatively little gastric damage in patients. However, our previous report on acemetacin needs re-evaluation. Acemetacin did not inhibit sheep COX-2 and only weakly inhibited COX-1. Our previous leucocyte (COX-2) experiments required 24 h incubation, and hydrolysis of acemetacin to indomethacin presumably accounted for the COX-2 inhibition. In the few minutes of enzyme incubation, virtually no hydrolysis would be expected. Acemetacin itself presumably causes relatively little gastric damage mainly because it only weakly inhibits COX-1.