Prostaglandin synthase (cyclooxygenase) is now known to exist in two separate isoforms, termed prostaglandin synthase 1 and 2 (or COX1 and COX2). This has prompted a dramatic increase in research regarding the contribution of these isoforms to inflammatory disease and their relationship to the efficacy and safety of nonsteroidal anti-inflammatory drugs (NSAIDs). The emerging picture is that COX1 is responsible for maintaining prostaglandin synthesis in the gastric mucosa, platelets, and kidney, whereas COX2 is responsible for prostaglandin production in inflamed tissues, including rheumatoid arthritis (RA) synovium. This review examines the validity of the hypothesis that NSAIDs exhibiting selectivity for COX2 demonstrate an improved safety and efficacy profile when compared with NSAIDs exhibiting selectivity for COX1.
Literature on the efficacy and safety (gastric, renal, and hemostatic) of various NSAIDs are compared with published data on their relative COX1 and COX2 in vitro specificity.
No differences in clinical efficacy are evident between NSAIDs exhibiting preferential activity for either COX1 or COX2. NSAIDs representing the extremes in terms of selectivity for COX1 or COX2 do exhibit some differences with respect to gastric, renal, and hemostatic safety; those exhibiting a preferential action on COX2 are generally less toxic than those exhibiting a preferential activity on COX1. Exceptions do exist.
There is some support for the hypothesis that NSAIDs exhibiting a preferential action on COX2 are safer than those exhibiting a preferential activity on COX1, but there exists no support for improved efficacy. A strict correlation does not exist between the COX1 and COX2 specificity and the gastric, renal, and hemostatic toxicity of NSAIDs. This lack of correlation is believed to stem from the fact that both the safety and efficacy of NSAIDs may result from mechanisms distinct from prostaglandin inhibition. Preferential COX2 activity can reduce the level of toxicity for a given NSAID but may not be sufficient to overcome toxicities resulting from other mechanisms.