Differential inhibition of cyclooxygenase isoforms: an explanation of the action of NSAIDs.
Salicylate-containing plants have long been used to alleviate fever and pain. The synthesis (in 1897) and marketing( in 1899) of acetylsalicylic acid (aspirin) were milestones in the treatment of inflammation. In the 1960s, other nonsteroidal anti-inflammatory drugs (NSAIDs) were introduced, having similar therapeutic actions and side effects. The elucidation of the mode of action of aspirin and other NSAIDs, through inhibition of prostaglandin biosynthesis, was another milestone that was reached in the 1971. It was the discover of the a second, inducible prostaglandin biosynthetic enzyme, cyclooxygenase-2 (COX-2), in 1991 that provided an explanation for the variations in toxicity of theses drugs; inhibition of COX-2 provides a therapeutic effect, whereas inhibition of COX-1 have higher toxicity than compound that are preferential or highly selective for the pro-inflammatory COX-2 isoform. Therefore, inhibition of COX-2 provides a target for the limitation of NSAID toxicity. The development and subsequent testing of preferential or highly selective COX-2 inhibitors further support the hypothesis and suggest that an effective NSAID without gastric toxicity is a realizable goal. In addition, these COX-2 selective compounds may be used as tools to define more clearly the functions of the tow isoforms.
Vane
S J
SJ
William Harvey Research Institute, London, England.