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 μmol/L), and potent with indomethacin (IC50 0.6 μmol/L). Inhibition of purified COX‐2 occurred with nimesulide and indomethacin (IC50 values 90 and 4.1 μmol/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.