Nonsteroidal antiinflammatory drugs (
NSAID) are effective for the relief of
pain and
inflammation, yet their use is tempered by the development of side effects, primarily in the gastrointestinal (GI) tract. It is now known that inhibition of the
enzyme cyclooxygenase (COX) is the principal mechanism for both the efficacy and the toxicity of
NSAID. Recent research has shown that COX exists as at least two
isoenzymes, COX-1 and COX-2. Compelling evidence suggests that COX-1 synthesizes
prostaglandins that are involved in the regulation of normal cell activity (including G1 cytoprotection), whereas COX-2 appears to produce
prostaglandins mainly at sites of
inflammation. These findings led to the search for compounds that would inhibit COX-2 without affecting COX-1. Several agents are under investigation in this new therapeutic category, including
celecoxib (SC-58635).
Celecoxib was developed as an antiinflammatory and
analgesic agent, and has been studied in preclinical studies and in clinical trials. This paper focuses on the results of 5 key clinical trials of
celecoxib: an efficacy trial in dental
pain, a 2 week
osteoarthritis (OA) efficacy trial, a 4 week
rheumatoid arthritis (RA) efficacy trial, a one week endoscopic study of GI mucosal effects, and
a 10 day study of effects on platelet function. The
arthritis trials identified
celecoxib doses that were effective in treating OA and RA and that were distinguished from placebo on standard
arthritis scales. In the upper GI endoscopy study, no
ulcers occurred in subjects receiving
celecoxib or placebo, whereas 19% of subjects receiving
naproxen developed
gastric ulcers. In the platelet effects trial, no statistically significant difference from placebo was seen in the effect of
celecoxib on platelet aggregation or bleeding time. In contrast,
naproxen caused statistically significant reductions in platelet aggregation and a statistically significant increase in bleeding time. These preliminary trials show that
celecoxib achieves
analgesic and antiinflammatory efficacy in
arthritis through specific COX-2 inhibition without showing evidence of two of the toxic effects of COX-1 inhibition associated with
NSAID.