Cyclooxygenase (COX) is the principal enzyme involved in the productio
n of prostaglandins. Inhibition of COX is also the primary mechanism o
f action of aspirin and other nonsteroidal antiinflammatory drugs (NSA
ID). Since prostaglandins are important regulators of cellular functio
n, inhibition of prostaglandin production may lead to adverse effects.
Two isoforms of COX have been identified, sequenced, and cloned. COX-
1 is constitutively produced and is believed to be involved in regulat
ing normal cellular processes, such as gastrointestinal (GI) cytoprote
ction, vascular homeostasis, and renal function. In contrast, COX-2 -
the inducible form - is undetectable in most tissues but is present in
inflamed tissue. Evidence therefore suggests that the GI toxicity ass
ociated with NSAID use is primarily the result of inhibition of COX-1,
and antiinflammatory effects are largely due to inhibition of COX-2.
A drug that specifically inhibits COX-2 without affecting COX-1 would,
theoretically, reduce inflammation without leading to GI side effects
. A variety of biologic assays have been developed to characterize the
relative activities of NSAID against COX-1 and COX-2. Such in vitro t
esting has demonstrated that individual NSAID possess different relati
ve inhibitory effects in various tissues. Several NSAID have been repo
rted to show more potent inhibition of COX-2 than of COX-1 in vitro; h
owever, the clinical relevance of differential inhibition of COX isozy
mes is as yet unknown. Some clinical studies indicating reduced toxici
ty for these NSAID may, in fact, be attributable to use of these agent
s at subtherapeutic doses. As pet, no clinically available NSAID has b
een shown to have significant in vivo effects on COX-2 while sparing C
OX-1 activity in humans. However, compounds that may be 100 to 300-fol
d more effective inhibitors of COX-2 and that therefore may have lower
risks for toxicity as well as more potent antiinflammatory effects ha
ve been developed, but are not yet available for clinical use.