Nitric oxide-releasing non-steroidal anti-inflammatory drugs: a novel approach for reducing gastrointestinal toxicity.
The use of non-steroidal anti-inflammatory drugs (NSAID) for treatment of inflammatory conditions is significantly limited by the untoward effects of these compounds on the gastrointestinal tract. While the pathogenesis of 'NSAID-gastropathy' is not completely understood, there is good evidence that the process is directly linked to suppression of prostaglandin synthesis and possibly to neutrophil adherence to the vascular endothelium. Pretreatment of rats with a nitric oxide (NO) donor (sodium nitroprusside) was found to significantly reduce the extent of gastric injury induced by flurbiprofen. We therefore tested the effects of a novel derivative of flurbiprofen. This compound contains a moiety similar to the NO-releasing moieties found in many organic nitrates. This compound suppressed gastric prostaglandin synthesis as effectively as flurbiprofen, but caused significantly less haemorrhagic damage. The compound was also found not to induce small intestinal injury. Since the compound was found to exert anti-inflammatory effects comparable with flurbiprofen, NO-releasing NSAID may represent a novel class of drugs with markedly reduced gastrointestinal toxicity.
Wallace
J L
JL
Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Alberta, Canada.
Reuter
B K
BK
Cirino
G
G
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000633:toxicity*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009599:Nitroprusside; D009569:Nitric Oxide; D005480:Flurbiprofen; C002385:linsidomine; D008981:Molsidomine