The relatively selective cyclooxygenase-2 inhibitor nimesulide: What's going on?

Nimesulide is a relatively selective cyclooxygenase (COX)-2 inhibitor, non-steroidal anti-inflammatory drug; it has been discovered in 1971 and firstly commercialized in Italy in 1985. There is much evidence that the pharmacological profile of nimesulide is peculiar and not shared with the other COX-2 selective inhibitors, suggesting that other molecular mechanisms besides inhibition of COX-2 derived prostaglandins are involved. Similarly, experimental data suggest that the gastrointestinal safety of nimesulide cannot be ascribed only to a COX-1 sparing effect. On the inflammatory process, the efficacy of nimesulide is dependent upon a wide spectrum of actions, due to the combination of effects on immune and non-immune cells. Early data demonstrated a central role for cyclic AMP (cAMP) in the anti-inflammatory effect of nimesulide; more recently, we have shown the involvement of the pathway ecto-5'-nucleotidase/adenosine A_2A receptor. To date, the molecular mechanism(s) that confers uniqueness to nimesulide have not yet been defined. To go inside the mechanism of action of an existing drug, such as nimesulide, would be helpful to refine its therapeutic use but also to identify new targets for novel therapeutic anti-inflammatory approach. Here, we focus on accumulated evidence for a peculiar pharmacological profile of nimesulide.