COX is a common target for anti-inflammatory drugs. The most significant difference between the isoenzymes, which allows for selective inhibition, is the substitution of
isoleucine at position 523 in COX-1 with
valine in COX-2. The smaller Val523 residue in COX-2 allows access to a
hydrophobic side-pocket in the enzyme (which Ile523 sterically hinders). Drug molecules, such as DuP-697 and the coxibs derived from it, bind to this alternative site and are considered to be selective inhibitors of COX-2.
Rofecoxib (brand name Vioxx) was withdrawn in 2004 because of such concerns. Some other COX-2 selective NSAIDs, such as
celecoxib and etoricoxib, are still on the market.
Natural COX inhibition Culinary mushrooms, like
maitake, may be able to partially inhibit COX-1 and COX-2. A variety of
flavonoids have been found to inhibit COX-2.
Fish oils provide alternative fatty acids to arachidonic acid. These acids can be turned into some anti-inflammatory
prostacyclins by COX instead of pro-inflammatory
prostaglandins.
Hyperforin has been shown to inhibit COX-1 around 3-18 times as much as aspirin.
Calcitriol (
vitamin D) significantly inhibits the expression of the COX-2 gene. Caution should be exercised in combining low dose aspirin with COX-2 inhibitors due to potential increased damage to the gastric mucosa. COX-2 is upregulated when COX-1 is suppressed with aspirin, which is thought to be important in enhancing mucosal defense mechanisms and lessening the erosion by aspirin.
Cardiovascular side-effects of COX inhibitors COX-2 inhibitors have been found to increase the risk of
atherothrombosis even with short-term use. A 2006 analysis of 138 randomised trials and almost 150,000 participants showed that selective COX-2 inhibitors are associated with a moderately increased risk of vascular events, mainly due to a twofold increased risk of
myocardial infarction, and also that high-dose regimens of some traditional NSAIDs (such as
diclofenac and
ibuprofen, but not
naproxen) are associated with a similar increase in risk of vascular events. This evidence, however, has been contradicted by the 2016 PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen) trial of 24,081 participants, which shows a lower incidence of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke for Celecoxib as compared to both Naproxen and Ibuprofen. Fish oils (e.g.,
cod liver oil) have been proposed as a reasonable alternative for the treatment of
rheumatoid arthritis and other conditions as a consequence of the fact that they provide less cardiovascular risk than other treatments including NSAIDs. == See also ==