The ever-emerging anti-inflammatories. Have there been any real advances?

Gastrointestinal (GI) Adverse Drug Reactions (ADRs) from the NSAIDs are a m ajor cause of morbidity and mortality in arthritic patients taking these dr ugs. The recent much heralded development of COX-2 selective drugs (celecox ib, rofecoxib), the objective of which has been to spare inhibition of the production of COX-1 derived mucosal protective prostaglandins, may have rep resented an advance in reducing the risk of serious ADRs-ulcers and bleedin g-but does not appear to have reduced the incidence of symptomatic side-eff ects (nausea, vomiting, epigastric pain/heartburn, abdominal discomfort) wh ich are a major reason for withdrawal from NSAID therapy, especially in the long term. The rationale of COX-2 selectivity from these newer drugs is co ntroversial since there may be pharmacokinetic differences from established carboxylate-NSAIDs that accounts for their apparent lower ulcerogenicity. Moreover, concerns have been recently expressed that as COX-2 is important in ulcer healing, control of prostacyclin production and renal function tha t they may have adverse reactions from these effects. Indeed, recent report s of enhanced risk of congestive heart failure with rofecoxib are of import ance and may relate to impaired prostacyclin production. Moreover, there ar e other therapeutic strategies that have yielded equally low ulcerogenic NS AIDs (e.g. the prodrug, nabumetone; the established COX-2 inhibitory drug, nimesulide) and even the well-established NSAIDs ibuprofen and diclofenac h ave relatively low upper GI ulcerogenicity and have been used as benchmark standards in comparative trials of the newer "Oxib" drugs (celecoxib, rofec oxib). Much research interest has centred on the nitric oxide-donating NSAI Ds (NO-NSAIDs). The rationale for donating NSAIDs being to counteract the v asoconstriction effects of NSAIDs but this has yet to be fully evaluated. I t is not certain that this "antidote" approach will be acceptable as there may also be systemic effects of the nitrobutoxyl-or other NO-donors that ma y have toxicological consequences. Another strategy is the development of m ixed COX-5 lipoxygenase (LOX) inhibitors-the progenitors of which were beno xaprofen and BW-755C. The rationale of reducing the potential for lipoxygen ase mediated actions in the stomach (e.g. vasoconstriction, leucocyte accum ulation). Clearly, the need to develop newer NSAIDs with lower risks of ulc ers and bleeding as well as symptomatic ADRs is still representing a major challenge. (C) 2001 Elsevier Science Ltd. All rights reserved.