In the 1970s, Vane suggested that the biological effects of nonsteroidal anti-inflammatory drugs (NSAIDS) were mediated by COX.21 After the discovery of the different isoforms of COX, studies revealed that the analgesic and antiinflammatory effects of these drugs were mediated by their ability to block COX-2.22 However, nonselective NSAIDS might be harmful because they also block COX-1, leading to altered gastrointestinal function, mucosal ulceration, pain, and bleeding.23 The development of selective COX-2 inhibitors promised to relieve pain and inflammation without the adverse events associated with COX-1 inhibition.24 In the United States, celecoxib and rofecoxib were the first COX-2 inhibitors approved for use by the FDA.24 Celecoxib was labeled for treatment of RA and rofecoxib for treatment of acute pain and menstrual pain. COX-2 inhibitors were studied rigorously to determine whether they provided antiinflammatory and analgesic effects without gastrointestinal complications. In a study of patients with RA, Celecoxib (100 to 400 mg BID) was effective, with lower incidence of endoscopic ulcers compared with naproxen.25 Another study in patients with RA and osteoarthritis examined whether celecoxib was associated with a lower incidence of significant gastrointestinal complications and other adverse effects compared with conventional NSAIDS.26 Celecoxib at high doses (400 mg BID) was associated with a lower incidence of gastrointestinal side effects and other complications compared with the NSAIDS ibuprofen and diclofenac.26 Similarly, rofecoxib was shown to have a favorable gastrointestinal profile when compared with naproxen.27,28 The successes of the COX-2 inhibitors led to the popularity of these drugs and billions of dollars in sales per year.29 Was there an ominous adverse event signal that had been ignored?
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