Where is the evidence that cyclooxygenase inhibition is the primary cause of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal injury? Topical injury revisited

In this commentary, we take a critical look at the concept that the gastroi ntestinal (GI) side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs ) are due to the ability of these drugs to inhibit cyclooxygenase-1 (COX-1) that is constitutively expressed in the GI mucosa. Indeed, development of the new "super aspirins," such as Celebrex and Vioxx, that Selectively inhi bit the inducible COX-2, expressed in areas of inflammation, is a direct ou tgrowth of this concept. We discuss evidence from both the laboratory and t he clinic that appears to be inconsistent with the above concept, and cite a number of examples where the depletion of mucosal prostaglandin levels an d the development of GI injury can be dissociated. Instead, we revisit the possibility that NSAID-induced GI side-effects are mostly due to the abilit y of these drugs to topically injure the GI mucosa. We devote the remainder of the commentary to presenting evidence from our and other laboratories t hat NSAIDs can directly attenuate the surface hydrophobic barrier of the GI mucosa due to their ability to bind to zwitterionic phospholipids, and tha t even systemically administered NSAIDs that are secreted into the bile may induce GI ulceration and/or bleeding due to phospholipid interactions and the development of topical mucosal injury. (C) 2001 Elsevier Science Inc. A ll rights reserved.