Clinical Q&A

By Nathan, Joseph P; Hembree, Joseph W; Cicero, Lorraine A; Rosenberg, Jack M | Drug Topics, October 19, 1998 | Go to article overview

Clinical Q&A


Nathan, Joseph P; Hembree, Joseph W; Cicero, Lorraine A; Rosenberg, Jack M, Drug Topics


Q# What is the therapeutic potential of COX-2 inhibitors?

A: About 40 million people suffer from arthritis in the United States, a figure that is expected to reach 60 million by the year 2020. Almost 1% of the gross national product, or $65 billion, is the estimated annual cost of arthritis to the economy in medical care and lost wages.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have formed the foundation of pharmacologic therapy for arthritis since it was discovered that inflammation was the principal cause of pain. Despite their efficacy, however, NSAIDs continue to be problematic because of the adverse effects associated with their use. Serious adverse gastrointestinal effects have reportedly resulted in more than 70,000 hospitalizations and 7,000 deaths each year in the United States.

Researchers have recently focused on developing alternatives to conventional NSAIDs that would share their benefits but have a reduced adverse effect profile. Two groups of compounds investigated as alternatives to conventional NSAIDs are the cyclooxygenase-2 (COX-2) inhibitors and the nitroNSAIDs. The compounds furthest along in development are the COX2 inhibitors.

Cyclooxygenase is an enzyme involved in the biosynthesis of prostaglandins. In the 1990s, two isoforms of COX have been identified. Cyclooxygenase-1 is present in the stomach and the kidney, where it is responsible for the biosynthesis of prostaglandins, which provide cytoprotection. Cyclooxygenase-1 also plays a role in the production of substances responsible for platelet aggregation. The larger cytokineinduced COX-2 enzyme is found in the joints, where it is associated with producing pain and inflammation in people with arthritis.

Conventional NSAIDs inhibit the synthesis of both COX-1 and COX2, thus producing both beneficial and deleterious effects, including analgesia, reduction of inflammation, and inhibition of platelet aggregation, as well as gastrointestinal ulceration, perforation, bleeding, and nephrotoxicity. Researchers have been successful in developing agents that selectively inhibit COX-2, thereby circumventing the undesired renal and gastrointestinal effects resulting from COX-1 inhibition. Because these agents do not inhibit platelet aggregation, they may be beneficial when bleeding is of concern or can be viewed as an incidental therapeutic loss when cardioprotection is warranted. The selectivity of these drugs toward the COX-2 enzyme appears to be maintained when therapeutic doses are used.

Some granted accelerated status

Cyclooxygenase-2 inhibitors closest to Food & Drug Administration approval are celecoxib (Celebra, G. …

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