Assessment of salicylate derivatives for potential use in ulcerative colitis: proposal for a new action of 5-aminosalicylic acid?

The therapeutic efficacy of salicylate drugs for ulcerative colitis in vivo is related to the capacity of each drug to suppress fatty acid oxidation in colonocytes in vitro. The suppression index of fatty acid oxidation (SIFO) was assessed with 17 salicylate drugs of either known or unknown therapeutic efficacy. The high SIFO value of 5-aminosalicylic acid (5-ASA) was reduced to zero when the amino group was replaced with a methyl, nitro, hydroxyl or bromine group. The SIFO of 3-ASA was dose-related and 2- to 3-fold greater than the SIFO of 5-ASA. The antioxidants methyl- or propyl-4-hydroxybenzoate have a high SIFO, but show a 'toxic' action towards colonocytes not observed with 3-ASA, 4-ASA or 5-ASA. A new cellular action proposed for 5-ASA is that acetylation of the amino group of 5-ASA in colonocytes releases free CoA countering sequestration of CoA observed in epithelial cells during active colitis.

Specific metabolic effect of sodium nitrite on fat metabolism by mucosal cells of the colon.

The effect on the mucosa of sodium nitrite that enters the colon from the ileum or transmucosally from the circulation is unknown. Isolated colonic mucosal cells and Roux-en-Y colostomies were used to test whether high doses of sodium nitrite (5-40 mM) had any harmful histological or inhibitory metabolic actions on the mucosa. Luminal instillation of 40 mM NaNO2 (3 ml/24 hr) for 7-14 days produced no microscopic changes in the mucosa either of damage (ulceration, mucus cell depletion) or of new growth (dysplasia, neoplasia). Beta oxidation of bacterial fatty acids (n-butyrate) by colonic epithelial cells in rat and man was enhanced by 50% (P less than 0.001) with 10 mM NaNO2, while oxidation of glucose and amino acid (proline) was not affected. Sodium nitrite significantly depressed ketogenesis (P less than 0.001) by the colonic mucosa of rat and man. In conclusion, sodium nitrite in the presence of bacteria has no damaging effect on the colonic mucosa but causes selective stimulation of fatty acid oxidation in the colonic mucosa of rat and man.

The pathology of experimental chronic fibrosing pancreatitis--light microscopic and ultrastructural observations.

The light microscopic and ultrastructural changes seen in a canine model of chronic fibrosing pancreatitis are described. The distribution of the experimental lesion is similar to that of human chronic obstructive pancreatitis. The canine lesion is also compared to that of human chronic calcifying pancreatitis. It is suggested that the common denominator in all these conditions is an increased pressure in the terminal intercalated ducts which produces pressure atrophy of the acinar cells in the periphery of the obstructed lobules.