Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs.

The injurious effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the small intestine was not appreciated until the widespread use of capsule endoscopy. Animal studies found that NSAID-induced small intestinal injury depends on the ability of these drugs to be secreted into the bile. Because the individual toxicity of amphiphilic bile acids and NSAIDs directly correlates with their interactions with phospholipid membranes, we propose that the presence of both NSAIDs and bile acids alters their individual physicochemical properties and enhances the disruptive effect on cell membranes and overall cytotoxicity. We utilized in vitro gastric AGS and intestinal IEC-6 cells and found that combinations of bile acid, deoxycholic acid (DC), taurodeoxycholic acid, glycodeoxycholic acid, and the NSAID indomethacin (Indo) significantly increased cell plasma membrane permeability and became more cytotoxic than these agents alone. We confirmed this finding by measuring liposome permeability and intramembrane packing in synthetic model membranes exposed to DC, Indo, or combinations of both agents. By measuring physicochemical parameters, such as fluorescence resonance energy transfer and membrane surface charge, we found that Indo associated with phosphatidylcholine and promoted the molecular aggregation of DC and potential formation of larger and isolated bile acid complexes within either biomembranes or bile acid-lipid mixed micelles, which leads to membrane disruption. In this study, we demonstrated increased cytotoxicity of combinations of bile acid and NSAID and provided a molecular mechanism for the observed toxicity. This mechanism potentially contributes to the NSAID-induced injury in the small bowel.

A study to determine the association between medical decision-making and the performance of an institutional ethics committee

This study developed proxy measures to test the independent effects of medical specialty, institutional ethics committee (IEC) and the interaction between the two, upon a proxy for the dependent variable of the medical decision to withhold/withdraw care for the dying--the resuscitation index (R-index). Five clinical vignettes were constructed and validated to convey the realism and contextual factors implicit in the decision to withhold/withdraw care. A scale was developed to determine the range of contact by an IEC in terms of physician knowledge and use of IEC policy.^ This study was composed of a sample of 215 physicians in a teaching hospital in the Southwest where proxy measures were tested for two competing influences, medical specialty and IEC, which alternately oppose and support the decision to withhold/withdraw care for the dying. A sub-sample of surgeons supported the hypothesis that an IEC is influential in opposing the medical training imperative to prolong life.^ Those surgeons with a low IEC score were 326 percent more likely to continue care than were surgeons with a high IEC score when compared to all other specialties. IEC alone was also found to significantly predict the decision to withhold/withdraw care. Interaction of IEC with the specialty of surgery was found to be the best predictor for a decision to withhold/withdraw care for the dying. ^