Effect of a selective nonsteroidal anti-inflammatory inhibitor of cyclooxygenase-2 on the small bowel of rats

Abstract

The pathogenesis of nonsteroidal anti-inflammatory drug (NSAID) enteropathy is a complex process involving the uncoupling of mitochondrial oxidative phosphorylation and inhibition of cyclooxygenase (COX). Rofecoxib, a selective inhibitor of COX-2, has shown less gastric damage, but the same beneficial effect is not clear in the case of the small bowel. Fifty-seven male Wistar rats (250-350 g) were divided into three groups (N = 19 each) to evaluate the effect of this NSAID on the rat intestine. The groups received 2.5 mg/kg rofecoxib, 7.5 mg/kg indomethacin or water with 5% DMSO (control) given as a single dose by gavage 24 h before the beginning of the experiment. A macroscopic score was used to quantify intestinal lesions and intestinal permeability was measured using [ 51 Cr]-ethylenediaminetetraacetic acid ([ 51 Cr]-EDTA). The extent of intestinal lesion, indicated by a macroscopic score, was significantly lower when rofecoxib was administered compared to indomethacin (rofecoxib = 0.0 vs indomethacin = 63.6 ± 25.9; P < 0.05) and did not differ from control. The intestinal permeability to [ 51 Cr]-EDTA was significantly increased after indomethacin (control = 1.82 ± 0.4 vs indomethacin = 9.12 ± 0.8%; P < 0.0001), but not after rofecoxib, whose effect did not differ significantly from control (control = 1.82 ± 0.4 vs rofecoxib = 2.17 ± 0.4%; ns), but was significantly different from indomethacin (indomethacin = 9.12 ± 0.8 vs rofecoxib = 2.17 ± 0.4%; P < 0.001). In conclusion, the present data show that rofecoxib is safer than indomethacin in rats because it does not induce macroscopic intestinal damage or increased intestinal permeability.

Assessment of intestinal permeability in preruminant calves by lactulose/mannitol test

“…Nevertheless, this cyclooxygenase inhibition does not fully explain pathogenesis of the drug-induced enteropathy. The second mechanism involves specific biochemical damage to mitochondria, with uncoupling of oxidative phosphorylation reaction and calcium release into cytosol, which in turn cause secondary biochemical damage of enterocytes resulting to increased IP (Leite et al, 2004).…”

“…The doses commonly used in laboratory animals, e.g., 7.5 mg . kg -1 (Leite et al, 2004), 10 mg . kg -1 (Anthony et al, 1997) or 15 mg .…”

The Histological Study to Correlate the Effect of NSAIDIbuprofen on the Proportion of Epithelial Height in the Wall of Lower Respiratory Airways

“…Many studies have also given doses to non-fasting animals similar to our method. [17][18][19][20] Some researchers used fasted animals for dosing of NSAID. [21][22][23] We believe that the method of sacrificing by cervical dislocation without any premedication used by us is the most suitable method of sacrifice.…”

Live probiotic cultures and the gastrointestinal tract: symbiotic preservation of tolerance whilst attenuating pathogenicity

“…Hence it was reasoned that NSAID's thereby uncoupled mitochondrial oxidative phosphorylation by inducing an injurious insult on the organelle (Somasundaram et al, 1997 ). Animal studies have demonstrated mitochondrial morphological changes with the administration of pharmaceutical products such as NSAIDs (Leite et al, 2004 ).…”