No abstract

Background-The "topical" eVect of nonsteroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage. Aim-To examine the possible mechanism of the "topical" phase of damage in the small intestine. Methods-Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode. Results-The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the "topical" phase of NSAID induced damage. Conclusion-Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the "topical" phase of damage induction.

Intestinal permeability changes were significantly more pronounced and frequent with the hypo-and hyperosmolar as opposed to the isoosmolar test. Sequential studies showed that four and nine patients (of 13) developed inflammation after three and six months treatment with NSAIDs, respectively. There was no significant diVerence (p>0.1) in the prevalence (54-72%) or severity of intestinal inflammation in the 286 patients taking the various NSAIDs apart from those on aspirin and nabumetone, these having no evidence of intestinal inflammation. There was no significant correlation between the inflammatory changes and age, sex, dose of NSAID, length of disease, or NSAID ingestion. Conclusions-Intestinal permeability test dose composition is an important factor when assessing the eVects of NSAIDs on intestinal integrity. All the conventional NSAIDs studied were equally associated with small intestinal inflammation apart from aspirin and nabumetone which seem to spare the small bowel. (Gut 1998;43:506-511)