The choreography of cyclooxygenases in the kidney

Consideration of the cardiovascular effects of cyclooxygenase (COX) inhibition has generated much heat and some light since the emergence of selective inhibitors of COX2 onto the US market in January 1999.COX2 inhibitors have gained an increasingly dominant share of the prescription market for nonsteroidal anti-inflammatory drugs (NSAIDs), currently dividing yearly sales of over $6 billion among three products: celecoxib, rofecoxib, and valdecoxib.Approval of these first three coxibs was based on their superiority over conventional NSAIDs (which inhibit both COX1 and COX2) in surrogate studies of endoscopically visualized gastric ulceration.Gastric epithelial COX1 is thought to generate the prostaglandins (PGs) -PGE 2 and prostacyclin (PGI 2 ) -that afford cytoprotection, while COX2 is thought to be the dominant source of PGs -interestingly, also PGE 2 and PGI 2 -that mediate pain and inflammation (1).The results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study (2) verified the COX2 hypothesis.More than 8,000 patients, mostly with rheumatoid arthritis, were randomized to receive therapeutically equivalent doses of rofecoxib or naproxen, a traditional NSAID.The incidence of prespecified primary and secondary clinical endpoints reflecting ulceration and its complications was significantly reduced, from around 4% on naproxen to around 2% on the COX2 inhibitor.Perhaps surprisingly, the incidence of cardiovascular events diverged between the groups, with an almost fivefold difference in the incidence of myocardial infarction.