CYP2C9. Although not a substrate, celecoxib also is an inhibitor of CYP2D6. Clinical vigilance is necessary during coadministration of drugs that are known to inhibit CYP2C9 and drugs that are metabolized by CYP2D6.
PHARMACOLOGICAL PROPERTIES, ADVERSE EFFECTS, AND THERAPEUTIC USES
Effects attributed to inhibition of prostaglandin production in the kidney—hypertension and edema—occur with nonselective COX inhibitors and also with celecoxib. Studies in mice and some epidemiological evidence suggest that the likelihood of hypertension on NSAIDs reflects the degree of inhibition of COX-2 and the selectivity with which it is attained. Thus, the risk of thrombosis, hypertension, and accelerated atherogenesis are mechanistically integrated. The coxibs should be avoided in patients prone to cardiovascular or cerebrovascular disease. None of the coxibs has established clinical efficacy over tNSAIDs, while celecoxib has failed to establish superiority over tNSAIDs in reducing GI adverse events. While selective COX-2 inhibitors do not interact to prevent the antiplatelet effect of aspirin, it now is thought that they lose their GI advantage over a tNSAID alone when used in conjunction with aspirin. Experience with selective COX-2 inhibitors in patients who exhibit aspirin hypersensitivity is limited, and caution should be observed.
Celecoxib is approved in the U.S. for the treatment of osteoarthritis and rheumatoid arthritis. The recommended dose for treating osteoarthritis is 200 mg/day as a single dose or as two 100-mg doses. In the treatment of rheumatoid arthritis, the recommended dose is 100-200 mg twice per day. In the light of recent information on a potential cardiovascular hazard, physicians are advised to use the lowest possible dose for the shortest possible time. Current evidence does not support use of a coxib as a first choice among the NSAIDs.
OTHER NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Apazone (Azapropazone)
Apazone is a tNSAID that has anti-inflammatory, analgesic, and antipyretic activity and is a potent uricosuric agent. It is available in Europe but not the U.S. Some of its function may arise from its ability to inhibit neutrophil migration, degranulation, and superoxide production.
Apazone has been used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and gout but usually is restricted to cases where other tNSAIDs have failed. Typical doses are 600 mg three times per day for acute gout. Once symptoms have abated, or for nongout indications, typical dosage is 300 mg three-four times per day. Clinical experience to date suggests that apazone is well tolerated. Mild GI side effects (nausea, epigastric pain, dyspepsia) and rashes occur in ~3% of patients, while CNS effects (headache, vertigo) are reported less frequently. Precautions appropriate to other nonselective COX inhibitors also apply to apazone.
Nimesulide is a sulfonanilide compound available in Europe that demonstrates COX-2 selectivity similar to celecoxib in whole blood assays. Additional effects include inhibition of neutrophil activation, decrease in cytokine production, decrease in degradative enzyme production, and possibly activation of glucocorticoid receptors. Its structure is:
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