The theme of selectivity—based on detailed understanding of molecular structure and function—underlies most recent therapeutic advances. Sometimes a biochemical “revisiting” of an old discovery enables dramatic improvements in the quality of life. Among the most widely used classes of medicines are the nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. Used for years, these pain killers and arthritis treatments work by blocking the effects of arachidonic acid on an enzyme called cyclooxygenase (COX). A major drawback to inhibiting COX is that by doing so you inadvertently block its role in protecting the gastrointestinal tract. The resulting ulcerative gastropathy is responsible for a large number of hospitalizations and deaths. Recently it was discovered that cyclooxygenase is not a single enzyme but rather a family containing at least two nearly identical members: COX-1 and COX-2. While COX-1 is responsible for the good gastroprotective effects (and shouldn’t be blocked) COX-2 is the enzyme involved with pain and inflammation (the real target). The COX-2 hypothesis stated that if one could invent a specific COX-2 inhibitor, it would be an effective anti-inflammatory and analgesic medication with substantially reduced gastrointestinal (GI) toxicity compared with the classical NSAID’s aspirin and ibuprofen.

Significant mortality is associated with NSAID gastropathy. G. Singh and G. Triadafilopoulos, Epidemiology of NSAID induced gastrointestinal complications, Journal of Rheumatology, 1999, 26, 56, 18-24, by permission of Oxford University Press.