Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic

The beneficial actions of nonsteroidal anti-inflammatory drugs (NSAIDs) have been linked to their ability to inhibit inducible COX-2 at sites of inflammation, and their side effects (e.g., gastric damage) to inhibition of constitutive COX-1. Selective inhibitors of COX-2, such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, and valdecoxib have been developed and the greatest recent growth in our knowledge in this area has been come from the clinical use of these compounds. Although clinical data indicate that COX-2 selectivity is associated with a reduction in severe gastrointestinal events, they also reveal there are roles for constitutive COX-2 within tissues such as the brain, kidney, pancreas, intestine, and blood vessels. We now better understand the roles of COX-1 and COX-2 in functions as disparate as the perception of pain and the progression of cancers. Clinical use of COX-2-selective compounds has ignited strong debates regarding potential side effects, most notably those within the cardiovascular system such as myocardial infarctions, strokes, and elevation in blood pressure. This review will discuss how the latest studies help us understand the roles of COX-1 and COX-2 and what clinically proven benefits the newer generation of COX-2-selective inhibitors offer