SUMMARY Intestinal permeability was estimated in healthy subjects after ingestion of aspirin (1.2+1*2 g), ibuprofen (400+400 mg) and indomethacin (75+50 mg) at midnight and an hour before starting a 51chromium labelled ethylenediaminetetraacetate absorption test. Intestinal permeability increased significantly from control levels following each drug and the effect was related to drug potency to inhibit cyclooxygenase. Intestinal permeability increased to a similar extent after oral and rectal administration of indomethacin showing that the effect is systemically mediated. Prostaglandin E2 decreased intestinal permeability significantly but failed to prevent the indomethacin induced increased intestinal permeability. These studies show that non-steroidal anti-inflammatory drugs disrupt the intestinal barrier function in man and suggest that the morphological correlates of the damage may reside at the level of the intercellular junctions.Several non-steroidal anti-inflammatory drugs (NSAIDs) induced characteristic intestinal damage in various animal species.' This is particularly severe in the rat where subcutaneous indomethacin leads to small bowel inflammation with ulceration, perforation, and ultimately death within 72 hours. 5 The precise mechanism underlying this sequence of events is unknown but there is substantial data to implicate both reduced synthesis of mucosal prostaglandings and the presence of intestinal bacteria in the pathogenesis of the lesions.6 7 Thus the macroscopic damage is preceded by a period of profound inhibition of mucosal cyclooxygenase activity8 and damage can be prevented by the simultaneous administration of a variety of prostaglandins.5 9 10 The role of intestinal bacteria is suggested by findings that intestinal ulceration after NSAIDs is rarely seen in germ free animals and the damage is greatly reduced after the coadministration of various antibiotics by a mechanism which appears to differ from their 'cytoprotective' properties. 112Until recently the human small intestine was thought to be relatively unaffected by NSAIDs.
This study assessed the effect of metronidazole on the gastroduodenal mucosa, intestinal permeability, blood loss, and inflammation in patients on non-steroidal anti-inflammatory drugs (NSAIDs). Thirteen patients were studied before and after 2-12 weeks' treatment with metronidazole 800 mg/day, while maintaining an unchanged NSAID intake. Intestinal inflammation, as assessed by the faecal excretion of indium-ill labelled neutrophils, and blood loss, assessed with chromium-51 labelled red cells, were significantly reduced after treatment (mean (SD) "'In excretion 4.7 (4.7)% v 1.5 (1.3)% (N<1-0%), p<0.001, 51Cr red cells loss 2.6 (1.6) ml/day v 0.9 (0.5) ml/day (N<1.0 mllday), p<001). Intestinal permeability assessed as the 5 hour urinary excretion ratio of 51CrEDTAIL-rhamnose did not change significantly (0.133 (0.046) v 0.154 (0.064), p>0O1) and there were no significant changes in the endoscopic or microscopic appearances of the gastroduodenal mucosa. These results suggest that the neutrophil is the main damaging effector cell in NSAID induced enteropathy. The main neutrophil chemoattractant in this enteropathy may be a metronidazole sensitive microbe.
SUMMARY Sulphasalazine treatment for inflammatory bowel disease in man causes oligospermia, reduced sperm motility and an increased proportion of abnormal forms. On withdrawal of sulphasalazine these effects are found to be reversible and 15 pregnancies occurred at a median of 2-5 months after stopping sulphasalazine therapy. Seminal plasma concentrations of acid phosphatase fructose and PGE2 as well as the hormone profiles of patients on sulphasalazine for three months were found to be within normal limits. Sulphasalazine fed to male Sprague Dawley rats caused a dose dependent and reversible infertility with a significant reduction in litter size. Rats fed the metabolite sulphapyridine also had a reduced litter size when mated, while those fed the metabolite 5'aminosalicylic acid and a polymer of 5'aminosalicylic acid did not. It seems likely that the sulphapyridine moiety of sulphasalazine is responsible for the infertility seen, the effect being mediated at a late stage in sperm maturation.Sulphasalazine has an established role in the treatment of ulcerative colitis and is increasingly used for indefinite maintenance treatment since its introduction over 40 years ago.' It has also been
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