Exacerbation of experimental colitis by nonsteroidal anti-inflammatory drugs is not related to elevated leukotriene B4 synthesis
| Autor: | Catherine M. Keenan, John L. Wallace, T. Scott Shoupe, Donna Donigi Gale |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
Male
Naproxen medicine.drug_class Leukotriene B4 Colon medicine.medical_treatment Indomethacin Pharmacology Granulocyte Anti-inflammatory Dinoprostone chemistry.chemical_compound In vivo medicine Animals Colitis Peroxidase Hepatology business.industry Anti-Inflammatory Agents Non-Steroidal Gastroenterology Rats Inbred Strains medicine.disease Rats Drug Combinations medicine.anatomical_structure chemistry Toxicity Immunology Quinolines business Misoprostol medicine.drug Prostaglandin E |
| Zdroj: | Gastroenterology. 102(1) |
| ISSN: | 0016-5085 |
| Popis: | The ability of nonsteroidal anti-inflammatory drugs to exacerbate experimental colitis, and the possible contributions of the "shunting" of arachidonate via the 5-lipoxygenase pathway, were investigated using a rat model in which colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid in a vehicle of 50% ethanol. Twice daily treatment with indomethacin (0.1–1 mg/kg SC) during the first week after trinitrobenzene sulfonic acid/ethanol administration resulted in dose-dependent increases in the severity of colitis and in the incidence of mortality. Mortality was not observed in vehicle-treated colitic rats or in normal rats treated with indomethacin. Similar exacerbation of colitis was observed in rats treated with naproxen (5 mg/kg). Whereas treatment with a 5-lipoxygenase inhibitor, PF-5901 (100 mg/kg PO), resulted in a significant reduction of the severity of colitis, concomitant administration of PF-5901 and indomethacin (0.5 mg/kg SC) did not inhibit the exacerbative effects of the indomethacin in this model. In separate studies, administration of indomethacin was found to significantly increase colonic myeloperoxidase activity (a measure of tissue granulocyte numbers) and suppress colonic prostaglandin E 2 synthesis, while not significantly affecting colonic leukotriene B 4 synthesis. The effect on myeloperoxidase activity was seen during the period 21–24 hours after trinitrobenzene sulfonic acid ethanol administration, but not during the period 45–48 hours after induction of colitis. In in vitro studies using samples of inflamed colon and in vivo studies in which colonic eicosanoid production was measured by colonic dialysis, inhibition of prostaglandin E 2 synthesis was not accompanied by significant changes in leukotriene B 4 synthesis. These results suggest that inhibitors of colonic prostaglandin synthesis can markedly exacerbate colitis, and that this effect is unrelated to alterations in colonic leukotriene B 4 synthesis. Endogenous prostaglandins may exert anti-inflammatory effects during the acute stages of colitis. |
| Databáze: | OpenAIRE |
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