Two forms of cyclooxygenase, cyclooxygenase-1 (COX-1) and cyclooxygenase 2 (COX-2), act as rate-limiting enzymes in prostaglandin and thromboxane synthesis. Discovery of these compounds led to the development of drugs that selectively or specifically inhibit the COX-2 isoform. Although the COX-1 isoform is expressed at fairly constant levels in cells, including the gastrointestinal mucosa and platelets, expression of COX-2 varies greatly. In many cells, low expression of COX-2 can be upregulated by various stimuli, including inflammatory cytokines, bacterial toxins, and growth factors; this suggests that COX-2 plays a role in inflammation, infection, and cellular proliferation.
It was thought that newly developed drugs designed to block COX-2 but not COX-1 would have anti-inflammatory properties and would avoid inhibiting the synthesis of gastrointestinal prostaglandins (thereby avoiding ulcers) and platelet thromboxane (thereby avoiding bleeding). Gastrointestinal ulcers and bleeding are side effects of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) that block COX-1 and COX-2. Meloxicam and nimesulide, selective COX-2 inhibitors available outside the United States, are as effective as traditional NSAIDs but have similar gastrointestinal side effects. Celecoxib (Celebrex, G.D. Searle and Co., Chicago, Illinois) and rofecoxib (Vioxx, Merck and Co., Inc., West Point, Pennsylvania), selective COX-2 inhibitors approved in the United States in the past year, are also as effective as traditional NSAIDs. However, celecoxib and rofecoxib have no antiplatelet activity and lead to fewer endoscopically detected gastric and duodenal ulcers than traditional NSAIDs, such as ibuprofen or naproxen.
Preliminary analyses of data pooled from several trials suggest that celecoxib and rofecoxib are associated with fewer clinically symptomatic ulcers and ulcer complications than traditional NSAIDs are. Postmarketing surveillance should help clarify the actual risk for serious ulcer complications with these new COX-2 inhibitors and reveal other potential nongastrointestinal toxic reactions that can result from their use.