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Sigthorsson G, Jacob M, Wrigglesworth J, Somasundaram S, Tavares I, Foster R, Roseth A, Rafi S, Mahmud T, Simpson R, Bjarnason I. Scand. J Gastroenterol. Comparison of indomethacin and nimesulide, a selective cyclooxygenase-2 inhibitor, on key pathophysiologic steps in the pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in the rat. Scand. J. Gastroenterol. 1998; 33(7):728-735. (CA) The predicted gastrointestinal tolerability of specific cyclooxygenase-2 inhibitors could be due to either a lack of "topical" irritation and/or lack of effect on cyclooxygenase-1. Key pathophysiol. steps (in vitro and in vivo uncoupling, intestinal prostanoid levels (prostaglandin E, thromboxane B2, and 6-keto-prostaglandin F1a), intestinal permeability (51Cr-EDTA), inflammation (fecal excretion of a granulocyte marker protein), and ulcer counts) in enteropathy induced by nonsteroidal anti-inflammatory drugs were assessed after administration of indomethacin, 10 mg/kg, and 15 (roughly equipotent), 30, and 60 mg/kg of the preferential cyclooxygenase-2 inhibitor nimesulide. Indomethacin uncoupled oxidative phosphorylation at lower concns. than nimesulide in vitro. Indomethacin was assocd. with electron microscopy changes suggestive of uncoupling in 60%-70% of enterocytes examd., whereas nimesulide affected 10%-30% of enterocytes, depending on the dose. Indomethacin increased intestinal permeability and caused inflammation and ulcers with 71%-96% redns. in prostanoid levels. Nimesulide at 15 mg/kg caused no damage, whereas 30 and 60 mg/kg nimesulide were assocd. with significant decreases in mucosal prostanoids (46%-75%), but only the 60-mg/kg dose caused a transient increase in intestinal permeability. However, at none of the doses did nimesulide cause intestinal inflammation or ulcers. These results endorse the idea that selective cyclooxygenase-2 inhibitors may be assocd. with some gastrointestinal tolerance due to their selectivity for cyclooxygenase-2, inhibiting cyclooxygenase-1 at only very high doses, and reduced topical irritation.

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