Future trends in the development of safer nonsteroidal anti-inflammatory drugs

Gastrointestinal (GI) adverse events, ranging from mild to life-threatening, are well-recognized sequelae to nonsteroidal anti-inflammatory drug (NSAID) use. Recent improvements in our knowledge of the mechanisms responsible for NSAID-associated gastropathy have enabled several experimental approaches to decreasing the risk of these events. Whereas such strategies as preassociation of NSAIDs to zwitterionic phospholipids to prevent NSAID-mucosal interactions and concomitant administration of trefoil peptides to stimulate mucosal defense pathways represent novel approaches, their clinical feasibility remains to be determined. Other strategies that appear more immediately promising in the reduction of NSAID-associated GI toxicity are the coupling of NSAIDs to nitric oxide (NO)-releasing compounds and the introduction of NSAIDs that are preferential or specific for cyclo-oxygenase-2 (COX-2), the isoform implicated in the inflammatory response. Clinical trials of several specific COX-2 inhibitors, as well as European clinical data for a preferential COX-2 inhibitor, meloxicam, suggest that COX-2 inhibitors provide an advantage over standard NSAIDs in terms of GI tolerability. However, as recent observations have implicated COX-2 as an integral component in the maintenance of physiologic homeostasis, careful scrutiny of both the beneficial and the deleterious effects of the selective COX-2 inhibitors is requisite before their approval and widespread use. Furthermore, based on the physiologic importance of COX-2, the preferential inhibitors may ultimately prove to represent the optimal compromise for the treatment of various arthritides.