Abstract: | ABSTRACTIt has been more than 30 years since Sir John Vane first reported that the pharmacological actions of aspirin-like drugs could be explained by their ability to inhibit cyclooxygenase (COX). Since then, a second isoform of COX, named COX‐2, has been discovered and highly selective inhibitors of this isoform have been marketed. Most recently, a splice variant of COX‐1 mRNA, retaining intron 1, and given the names COX‐3, COX‐1b or COX‐1v, has been described.Non‐selective NSAIDs such as ibuprofen and naproxen, which inhibit both COX‐1 and COX‐2, have proven highly effective and safe in the short-term management of acute pain. Highly selective COX‐2 inhibitors including celecoxib, rofecoxib, valdecoxib, lumiracoxib, and etoricoxib were developed with the hope of significantly reducing the serious gastrointestinal toxicities associated with chronic high‐dose NSAID use. While long-term studies demonstrated that rofecoxib and lumiracoxib reduced the incidence of GI perforations, ulcerations and bleeds by approximately 60% compared to non-selective NSAIDs, recent reports also demonstrated that the chronic use of rofecoxib and celecoxib in arthritis and colorectal polyp patients, and the short-term use of parecoxib and valdecoxib in patients who had undergone coronary artery bypass surgery, resulted in a significant increase in serious cardiovascular events, including myocardial infarction and stroke compared to naproxen or placebo.COX‐3 mRNA has been isolated in many tissues including canine and human cerebral cortex, human aorta, and rodent cerebral endothelium, heart, kidney and neuronal tissues. In transfected insect cells, canine COX‐3 protein is expressed and was selectively inhibited by acetaminophen. However, in humans and rodents an acetaminophen sensitive COX‐3 protein is not expressed because the retention of intron‐1 adds 94 and 98 nucleotides to the COX‐3 mRNA structure respectively. Since the genetic code is a triplicate code (3 nucleotides to form one amino acid), the retention of the intron in both species results in a frame shift in the RNA message and the production of a truncated protein with a completely different amino acid sequence than COX‐1 or COX‐2 lacking acetaminophen sensitivity.Advances made through a combination of basic molecular biological and pharmacological techniques, and well designed randomized controlled clinical trials have demonstrated that the apparent gastrointestinal advantage of selective COX‐2 inhibitors appears to be outweighed by their potential for cardiovascular toxicity and that acetaminophen's analgesic and antipyretic effects do not involve the inhibition of the COX-1 splice variant protein, putative COX‐3. |