Nitric oxide-modulating agents for gastrointestinal disorders

Almost 20 years after the identification of the biological role of nitric oxide (NO), the full therapeutic potential of novel agents that mimic the activity of NO or interfere with its synthesis has yet to be realised for utilities involving the gastrointestinal tract. New utilities for classical NO donors, which were used as vasodilators for decades, in the treatment of motility disorders have been explored and a product for treating anal fissure was recently launched. New classes of compounds incorporating a NO-donating moiety into standard non-steroidal anti-inflammatory drugs, the NO-non-steroidal anti-inflammatory drugs (NO-NSAIDs) or COX-inhibiting nitric oxide donors (CINODs) have also been developed. These have been shown to exhibit reduced gastrointestinal injury in experimental models, and reports on their efficacy and safety in Phase I and II studies are now available. Modulation of the inducible NO synthase isoform that generates excessive NO that can lead to subsequent cytotoxic moieties, such as peroxynitrite, may have therapeutic possibilities in a range of inflammatory diseases of the gut. Likewise, agents that promote the decomposition of peroxynitrite or removal of its other component, superoxide, may also prove to be of use. Further targets for pharmaceutical exploitation are likely to come from both genomic and molecular insights into the processes that regulate the NO system.