allopurinol and Intestinal-Diseases

Topics: Animals; Blood Platelets; Capillary Permeability; Cell Adhesion; Endopeptidases; Endothelium, Vascular; Intestinal Diseases; Intestinal Mucosa; Lipid Peroxides; Mast Cells; Microcirculation; Neutrophils; Oxidation-Reduction; Reactive Oxygen Species; Reperfusion Injury; Xanthine Oxidase

Gastrointestinal damage and bleeding are the major side effects of non-steroidal anti-inflammatory drugs (NSAID), however the mechanisms of this ulcerogenic action are not fully understood. It has recently been proposed that neutrophil-and oxygen radical-dependent microvascular injuries may be important prime events that lead to mucosal injury. In addition, other factors like bile flow, intact bacterial flora or feeding conditions may contribute to the formation of lesions. Ketoprofen is a NSAID that exists as a pair of R(-) and S (+) enantiomers; like other 2-arylpropionic acids, its anti-inflammatory effects resides almost exclusively in the S (+) isomer. The present study was undertaken to explore the role of oxidative stress in the pathogenesis of intestinal injury induced by oral administration of racemic ketoprofen and its enantiomers given as their water soluble tromethamine salts.. Evaluation of intestinal damage and activities of oxidative stress related enzymes such as myeloperoxidase (MPO), xanthine-oxidase (XO) and superoxide dismutase (SOD) were studied in an experimental animal model using refed rats.. After the oral treatment followed by a refeeding period of 24 h, ketoprofen (100, 50, 25 mg/Kg b.w.) dose-dependently caused longitudinal ulcers on the mesenteric side of the middle and lower intestine lumen. The intestinal toxicity caused by S(+)-ketoprofen was significantly lower than the effect observed after racemate and R(-) enantiomer treatments (P <0.001), though the bioinversion of R(-)-ketoprofen to S(+)-enantiomer that occurs in the rat has to be considered. XO activity was unaffected by the studied drugs. Enhanced enteropathy by the racemate and its R (-)-enantiomer was correlated with a significant increase of MPO activity as an index of neutrophil infiltration, and a decrease in SOD activity (p<0.05 Vs control). S(+)-ketoprofen did not significantly change these parameters.. These results suggest that reactive oxygen metabolites can contribute significantly to the development of intestinal lesions, and that R(-)-ketoprofen present in racemic preparations can enhance the toxic intestinal effects of S (+)-enantiomer via modification of neutrophil migration and oxidative stress.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Intestinal Diseases; Intestinal Mucosa; Ketoprofen; Male; Neutrophil Infiltration; Oxidative Stress; Peroxidase; Rats; Rats, Wistar; Stereoisomerism; Superoxide Dismutase; Tromethamine; Ulcer; Xanthine Oxidase

Aspirated gastric contents can evoke multiorgan failure. We hypothesized that secondary intestinal epithelial dysfunction after lung damage would be mediated by xanthine oxidase (XO) and antagonized by endogenous gut nitric oxide (NO). Isosmotic saline or HCl solutions were instilled intratracheally in anesthetized rats, and intestinal injury was assessed 190 min later by measuring the blood-to-lumen clearance of 51Cr-labeled EDTA (51Cr-EDTA clearance) and gut wall neutrophil population density. Intratracheal HCl increased 51Cr-EDTA clearance, and this transepithelial leak was attenuated by either systemic L-arginine or intraluminal NO and by chronic dietary pretreatment with allopurinol or sodium tungstate. Conversely, lung damage-induced gut leak was exaggerated by NO synthase inhibition or intravenous XO administration. Intratracheal HCl also increased intestinal wall neutrophil density and myeloperoxide activity. We conclude that two enzymatic systems involved in remote gut barrier dysfunction after endobronchial acidification are XO as mediator and NO synthase as antagonist.

Topics: Animals; Arginine; Capillary Permeability; Edetic Acid; Enzyme Inhibitors; Hydrochloric Acid; Intestinal Diseases; Lung; Lung Diseases; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Trachea; Xanthine Oxidase

Topics: Animals; Cats; Colic; Horse Diseases; Horses; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Laparotomy; Necrosis; Peroxidase; Rats; Reperfusion Injury; Swine; Xanthine Dehydrogenase; Xanthine Oxidase

Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used and may cause small intestinal inflammation and damage. Reactive oxygen metabolites are involved in various gastrointestinal inflammatory processes, but there is little information about their role in small intestinal mucosal damage induced by NSAIDs. We studied the effect of the oxygen radical scavengers superoxide dismutase (SOD), catalase (CAT), and allopurinol (ALLO) on indomethacin (INDO)-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg of INDO 30 min after refeeding 24 h-fasted rats. Total ulcer area was measured 24 h after INDO administration. Study groups each consisted of eight animals which received either i.p. CAT, SOD, or both together, at a dosage of 5,000 U/kg each. All drugs were divided into five doses, given once an hour over a 4-h period, starting at the time of INDO injection. Another group received 100 mg/kg ALLO in two doses. Total ulcer area was reduced by SOD from 228 +/- 12 (sq mm, mean +/- SEM) to 153 +/- 12 (p < 0.001), by CAT to 179 +/- 13 (p < 0.01), and by both together to 95 +/- 5 (p < 0.0001). ALLO administration reduced the total ulcer area to 176 +/- 7 (p < 0.003). The protective effect of oxyradical scavengers supports the hypothesis that oxygen radicals are involved in the pathogenesis of INDO-induced small intestinal ulceration in the rat.

Topics: Allopurinol; Animals; Anti-Inflammatory Agents, Non-Steroidal; Catalase; Free Radical Scavengers; Indomethacin; Intestinal Diseases; Male; Rats; Rats, Wistar; Superoxide Dismutase; Ulcer

A vibration technique was used to dislocate the epithelium from the rat small intestine, in order to study the possible regulatory role of the epithelium on intestinal motility. Complete removal of the epithelium led to a slightly potentiated contraction of the longitudinal smooth muscle by the muscarinic agonist methacholine (pD2. 6.5 +/- 0.1 vs. 6.2 +/- 0.2). The maximal beta-adrenergic response expressed relative to the relaxation by 0.5 mM dibutyryl cyclic AMP increased from 55.9 +/- 9.0% to 72.6 +/- 9.1% by this treatment. Efforts were made to relate these observations to the endothelium-dependent relaxation in blood vessels, but no indication was found for a similar mechanism in the small intestine. Not only mechanical dislocation can be employed to affect the mucosal layer, but also intestinal ischemia has been reported to lead to mucosal damage. In this study we mimicked ischemia by applying in vitro anoxia and subsequent reoxygenation to isolated intestinal segments. When intestinal segments are isolated and kept in physiological buffer, xanthine dehydrogenase is converted slowly to xanthine oxidase, irrespective of whether the buffer is oxygenated or not. No evidence was found for oxygen radical damage after anoxia and reoxygenation. However, the intestinal mucosa was damaged both after normoxia, and after anoxia and reoxygenation. Anoxia and subsequent reoxygenation did not affect muscarinic contraction, but slightly increased the beta-adrenergic relaxation, which partly correlates with the effects of mechanical dislocation of the epithelium. The increased sensitivity of the smooth muscle after epithelial damage might be involved in motility changes during intestinal inflammatory diseases.

Topics: Animals; Epithelium; Gastrointestinal Motility; Hydrogen Peroxide; Hypoxia; Intestinal Diseases; Intestinal Mucosa; Intestine, Small; Lipid Peroxidation; Male; Oxidation-Reduction; Rats; Rats, Wistar; Stress, Physiological; Vibration; Xanthine Oxidase

Topics: Allopurinol; Animals; Intestinal Diseases; Male; Mesenteric Arteries; Peristalsis; Rabbits; Reperfusion Injury; Xanthine Oxidase

Topics: Allopurinol; Animals; Dimethyl Sulfoxide; Diterpenes; Female; Free Radicals; Ginkgolides; Intestinal Diseases; Intestinal Mucosa; Ischemia; Lactones; Platelet Activating Factor; Rats; Rats, Inbred Strains; Reperfusion Injury; Superoxide Dismutase

Studies demonstrating protective effects of allopurinol in intestinal ischemia have been carried out using i.v. allopurinol (presently unavailable for human use) or enteral allopurinol at supra-normal doses and, therefore, have questionable clinical relevance. We evaluated the protective effects of clinically used doses of enteral allopurinol in rats with intestinal ischemia. One hundred nine male Sprague-Dawley rats (250-300 gm) received enteral allopurinol (5-30 mg/kg) or water daily for 1 week and were subjected to superior mesenteric artery occlusion for 20, 30, or 45 min. Mortality in water-fed controls after 20 min of mesenteric ischemia was 50%, but there was no mortality in rats pretreated with allopurinol (5, 10, and 20 mg/kg/day) in this group (P = 0.016). There was no reduction in mortality after allopurinol pretreatment at any dose in rats with 30 or 45 min of ischemia. We concluded that 1) prolonged intestinal ischemia causes lethal damage during the hypoperfusion phase that cannot be prevented by allopurinol pretreatment even at supra-normal doses, and 2) allopurinol at recommended enteral doses (5-10 mg/kg/day) can reduce morality from reperfusion injury when the phase of hypoperfusion is not, in itself, lethal. Allopurinol is effective in reducing reperfusion injury in the currently available enteral form in dose ranges that should not cause prohibitive side effects.

Topics: Allopurinol; Animals; Dose-Response Relationship, Drug; Intestinal Diseases; Intestines; Ischemia; Male; Rats; Rats, Inbred Strains

Topics: Acute Disease; Allopurinol; Animals; Deferoxamine; Drug Combinations; Free Radicals; Intestinal Diseases; Rats; Rats, Inbred Strains; Reperfusion Injury; Trifluoperazine

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cholestasis; Chromatography, Gel; Female; Hemochromatosis; Hepatic Encephalopathy; Hepatitis; Hepatitis A; Humans; Intestinal Diseases; Liver Cirrhosis; Liver Diseases; Male; Myocardial Infarction; Rats; Spectrophotometry; Xanthine Oxidase