NO-NSAIDs: from inflammatory mediators to clinical readouts.

Non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase (COX)-2 selective inhibitors (COXIBs) are widely used drugs. However, their use is hampered by gastrointestinal, cardiovascular and renal side effects. Nitric oxide (NO)-releasing NSAIDs, NO-NSAID, are a new class of anti-inflammatory and analgesic drugs generated by adding a nitroxybutyl or a nitrosothiol moiety to the parent NSAID via a short-chain ester linkage. While efficacy of nitrosothiol-NSAIDs still awaits investigation, nitroxybutyl-NO-NSAIDs have been extensively studied in humans. The combination of balanced inhibition of the two main COX isoforms with release of NO confers to NO-NSAIDs reduced gastrointestinal and cardiorenal toxicity. It is suggested that the NO, which is released as the compounds are broken down, may counteract the consequences of the NSAID-induced decrease in gastric mucosal prostaglandins. Recent clinical trials with NO-NSAIDs have provided data consistent with pre-clinical observations.