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The COX-2 enzyme was discovered in 1988 by Daniel Simmons, a Brigham Young University researcher. [30] The mouse COX-2 gene was cloned by UCLA scientist Harvey Herschman, a finding published in 1991. [31] The basic research leading to the discovery of COX-2 inhibitors has been the subject of at least two lawsuits.
Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). [7] It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. [7]
Common side effects include abdominal pain, dizziness, swelling, headache, and a rash. [11] Serious side effects may include heart disease, stroke, kidney problems, and stomach ulcers. [11] Use is not recommended in the third trimester of pregnancy. [11] It blocks cyclooxygenase-2 (COX-2) more than it blocks cyclooxygenase-1 (COX-1). [11]
Rofecoxib is a selective COX-2 inhibitor, or "coxib". Though the class of coxibs includes several agents, degrees of COX-2 selectivity vary among them, with celecoxib (Celebrex) being the least COX-2 selective, and rofecoxib (Vioxx), valdecoxib (Bextra), and etoricoxib (Arcoxia), being highly COX-2 selective. [10]
The selectivity of COX-2 does not seem to negate other side-effects of NSAIDs, most notably an increased risk of kidney failure, and there is evidence that indicates an increase in the risk of heart attack, thrombosis, and stroke through an increase of thromboxane unbalanced by prostacyclin (which is reduced by COX-2 inhibition). [8]
The impetus for development of selective COX-2 inhibitors was the adverse gastrointestinal side-effects of NSAIDs.Soon after the discovery of the mechanism of action of NSAIDs, strong indications emerged for alternative forms of COX, but little supporting evidence was found.
COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote thrombosis, and some of these agents substantially increase the risk of heart attack. As a result, certain COX-2 selective inhibitors—such as rofecoxib—are no longer used due to the high risk of undiagnosed vascular disease. [11]
Since PTGS2 (COX-2) is generally expressed only in cells where prostaglandins are upregulated (e.g., during inflammation), drug-candidates that selectively inhibit PTGS2 (COX-2) were suspected to show fewer side-effects [24] but proved to substantially increase risk for cardiovascular events such as heart attack and stroke. Two different ...