New molecules may overtake the COX 2 inhibitors debate

For many years, non-steroidal anti-inflammatory drugs were regarded as a treatment for which there was no gain in arthritis without the pain of gastroduodenal toxicity. This reflected the understanding that non-steroidal anti-inflammatory drugs (NSAIDs) were cyclo-oxygenase inhibitors that reduced prostaglandin synthesis both in inflamed joints with benefit and in the stomach with detriment (figure). Recognition that a highly inducible enzyme, cyclo-oxygenase-2, largely subserved the former and a constitutive enzyme, cyclo-oxygenase-1, the latter provided an obvious selective target. The consequent success of cyclo-oxygenase-2 (COX 2) inhibitors arises, in part, from the conceptual simplicity of this idea. The journey from concept to reality has, however, inevitably been more complex, and one controversial issue is dealt with in an accompanying editorial.1 The failure of the celecoxib long term arthritis safety study (the CLASS study) may have more to do with the design of the trial than with inadequacies of cyclo-oxygenase-2 inhibitors. Other limitations of these agents may eventually deserve more attention. In particular, it was never likely that they would go beyond the indication of pain and arthritis that characterises NSAIDs, given that the goal was to mimic their action more selectively.