Original Articles
Cyclooxygenase-2 specificity and its clinical implications

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Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation by inhibiting the synthesis of prostanoids. However, these drugs inhibit both cyclooxygenase-1 (COX-1), which is essential for the regulation of homeostasis in many tissues, as well as COX-2, which is an important mediator of pain and inflammation. Disruption of COX-1 enzymatic activity by NSAIDs leads to such side effects as interference with platelet functions and gastric ulcers. The recent development of COX-2–specific inhibitors, such as celecoxib, raises the possibility of relieving pain and inflammation with reduced risk of gastrointestinal complications. In Phase II and III studies, celecoxib has demonstrated efficacy in alleviating dental pain and the signs and symptoms of osteoarthritis and rheumatoid arthritis. This COX-2–specific inhibitor was also associated with a markedly lower rate of gastroduodenal injury than is seen typically with NSAIDs. Incidence of most adverse events (including gastrointestinal) and withdrawal rates resulting from adverse events with celecoxib were similar to placebo. Celecoxib appears to be both safe and effective in the treatment of osteoarthritis and rheumatoid arthritis. Its COX-2–specific inhibitory properties thus introduce the possibility of effective relief of arthritic and other types of pain and inflammation with less risk of the mechanism-based toxicities observed with conventional NSAIDs.

Section snippets

Background: COX-2 specificity of celecoxib

Celecoxib, the structure of which is depicted in Figure 1, has a much greater potency in inhibiting COX-2 than COX-1 when studied in in vitro test systems. As Simon et al2 have discussed, celecoxib only inhibits COX-1 at concentrations greater than two orders of magnitude higher than are required for COX-1 inhibition in these in vitro test systems.

Animal models predicted that the therapeutic plasma concentration for celecoxib should be approximately 300 ng/mL, and single-dose pharmacokinetic

Alleviation of pain in a dental model

In a Phase II dental pain study, the efficacies of a range of celecoxib doses were compared with the efficacy of aspirin to determine the minimum effective therapeutic dose in this setting.

In this study, patients had one or more molars extracted. After the procedure when they indicated that they had moderate to severe pain, patients were randomly assigned to receive a single dose of placebo, aspirin 650 mg, celecoxib 100 mg, or celecoxib 400 mg.

Within 45 minutes of dosing, all three active

Methodologic considerations

Both osteoarthritis and rheumatoid arthritis Phase II trials2 were designed to assess the efficacy of celecoxib compared with placebo. These studies were considered “dose finding” in that they established the minimum effective doses of celecoxib in osteoarthritis and rheumatoid arthritis, and patients were “flared” in that they entered the treatment phase of the trial in a severe clinical state. After enrollment screening to assess exclusion criteria (Table 1), patients were instructed to

Platelet effects

Inhibition of COX-1 by nonspecific inhibitors such as NSAIDs leads to diminished formation of TXA2, a pivotal autocrine stimulator of platelet aggregation and vasoconstriction. In normal subjects, this has a mild clinical effect; however, in patients with impaired hemostasis, disruption of the formation of this prostanoid becomes a significant problem. In patients with gastrointestinal ulceration, this NSAID-induced platelet dysfunction can bring about a potentially disastrous synergy resulting

Safety profile of celecoxib

Adverse event rates for celecoxib and placebo were similar in the 4 Phase II studies described above.2 In fact, the incidence of headache in controls (19.9%) was approximately twice that of the active agent. Diarrhea was the only side effect for which these frequencies were consistently higher with the COX-2–specific inhibitor, but this did not appear to be dose related: 2.7% on placebo, 6.5% on celecoxib 40 mg twice daily, 2.8% on 100 mg twice daily, 6.4% for 200 mg twice daily, and 10.3% on

Conclusions

In Phase II clinical studies celecoxib conferred clinically significant analgesic and anti-inflammatory benefits that were similar to those typical of conventional NSAIDs without inducing the untoward complicating toxicities involving the gastrointestinal tract and platelet aggregability that are thought to be attributable to NSAIDs’ nonspecific blockade of both COX-1 and COX-2. These preliminary results have now been confirmed in longer-term Phase III clinical trials designed to establish

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