Indomethacin-induced intestinal lesions in the rat

Brodie, David A.; Cook, Patricia G.; Bauer, Barbara J.; Dagle, G.E.

doi:10.1016/0041-008x(70)90036-0

Cited by 196 publications

(68 citation statements)

References 9 publications

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“…Dependency, both on dose and duration of exposure, is a characteristic of other non-steroidal anti-inflammatory agents . For indomethacin, it is known that intestinal lesions in rats depend on the excretion of the active drug in the bile (Brodie et al, 1970;Duggan et al, 1975). As has been shown by Tocco et al (1975), diflunisal was excreted to some extent in the bile in the rat.…”

Section: Discussionmentioning

confidence: 85%

“…Gastrointestinal effects after single doses The ability of diflunisal and asprin to induce haemorrhage of gastric mucosa and ulcers of the intestine after single doses, was determined using methods described by Brodie et al (1967Brodie et al ( , 1970. Briefly, gastric effects were studied in groups of male Sprague-Dawley rats (125-150 g) which had been starved for 24 h and then given the drug at various doses, or control vehicle, in 0.5% aqueous methylcellulose.…”

Section: Toxicological Studiesmentioning

confidence: 99%

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Pharmacology and toxicology of diflunisal.

Stone¹,

Arman²,

Vj³

et al. 1977

Brit J Clinical Pharma

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1 Diflunisal, a new salicylate, possesses anti-inflammatory, analgesic and antipyretic activity. It was found to be about 7.5-13 times more active than aspirin as an analgesic (Randall-Selitto assay in rats) and as an anti-inflammatory agent (carrageenin foot oedema and adjuvant arthritis in rats). 2 Diflunisal was 1.4 times as active as aspirin as an antipyretic in the rat and about three times as potent in reducing lameness induced by injecting urate crystals into the knee joint of dogs. 3 Diflunisal inhibited adenosine diphosphate, adrenaline and thrombin-induced aggregation of human platelets in vitro. The concentrations required were 18-35 times higher than those needed with aspirin.4 After single doses, both diflunisal and aspirin induced gastric haemorrhages in starved rats. This was evident only after relatively large doses of diflunisal, whereas aspirin induced gastric changes after pharmacologically active amounts. 5 Diflunisal, but not aspirin, after single doses, produced perforations of the small intestine in the rat. The dose levels required were considerably above those that would demonstrate anti-inflammatory and analgesic activity. 6 In oral subacute toxicity studies in rats and dogs of 14 weeks' duration, diflunisal and aspirin produced similar gastric and renal toxicity. Both produced focal oedema, haemorrhage and small ulcers in one or both species. Renal changes were limited to a slight degree of oedema of the papilla in the rat and dog. Diflunisal, but not aspirin, produced intestinal lesions of the small bowel in the rat but not the dog. The changes with either drug were largely limited to the higher levels used (50-200 mg/kg/d).

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Section: Discussionmentioning

confidence: 85%

Section: Toxicological Studiesmentioning

confidence: 99%

Pharmacology and toxicology of diflunisal.

Stone¹,

Arman²,

Vj³

et al. 1977

Brit J Clinical Pharma

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“…Ackerman et al (1 9) demonstrated that l-monthold rats were relatively protected against restraint-induced ulcers if unrestricted suckling is allowed before weaning. Similarly aged rats reared in the presence of their mothers whose nipples were (20). Histologically, mucosal edema and inflammatory cell infiltration with ulceration and cellular necrosis are present.…”

Section: Discussionmentioning

confidence: 99%

Indomethacin Fails to Induce Ulceration in the Gastrointestinal Tract of Newborn and Suckling Rats

Bedrick

Holtzapple

1986

Pediatr Res

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ABSTRACT. Little is known about the role of oral prostaglandins and maintenance of intestinal epithelial cell membrane integrity in suckling animals. The presence of prostaglandins in milk suggests that they may have potential cytoprotective effects. Thus, experiments were performed to determine whether indomethacin causes inflammation in the gastrointestinal tract of suckling animals. Rats were treated with daily intraperitoneal injections of indomethacin (10 mg/kg) starting on the 1st day of life. Unlike adult animals which develop intestinal lesions within 72 h, these rats did not develop intestinal ulcerations until weaning started on days 15 to 16. Indomethacintreated suckling animals prevented from weaning did not develop intestinal lesions until they had access to solid food on day 23. Indomethacin-treated rats had large reductions in jejunal prostaglandin E2 content. In addition, prostaglandin E2 was present in rat milk in relatively large concentration as determined by radioimmunoassay. These studies suggest that exogenous prostaglandins present in milk may protect the intestine of suckling rats from indomethacin-induced inflammation; however, once weaning commences, prostaglandin insufficiency may develop lea& ing to intestinal lesions. We s~eculate that suckling rats treated with indomethacin did-not develop ulcerat6e lesions, despite a marked reduction in intestinal prostaglandin content, possibly due to prostaglandins present in milk. (Pediatr Res 20: 598-601,1986) glandin F,, have also been found in significant amounts, suggesting that milk contains the parent compounds thromboxane A2 and prostacyclin (4-6). They are also found in commercially obtained whole milk and low-fat milk (7), but not in infant formulas (6). Prostaglandin in milk has been demonstrated to be effective in promoting healing of peptic ulcers and in protecting the gastroduodenal mucosa against experimentally induced ulcers (7). In addition, administration of oral prostaglandin E2 to humans has been demonstrated to protect the gastrointestinal mucosa from blood loss induced by indomethacin (8). Thus, considerable information exists about the importance of oral prostaglandins in maintaining integrity of the gastrointestinal epithelial cell membrane in adults. However, very little is known about similar functions of prostaglandins in suckling animals. The presence of prostaglandins in milk suggest that they may play an important role in the function and adaptation of the gastrointestinal tract to extrauterine life. The significance of prostaglandin cytoprotection in the gastrointestinal tract of stressed newborns has not been determined. Exogenous prostaglandin in breast milk could have cytoprotective effects on the gastrointestinal tract. Thus, to evaluate the role of oral prostaglandins in maintenance of gastrointestinal mucosal integrity in suckling animals, experiments were performed in suckling rats to explore whether indomethacin causes inflammation in the immature gastrointestinal tract. A preliminary report has been publish...

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“…1,2) The pathogenesis of NSAID-induced gastric mucosal injury is reported for inhibition of prostaglandin (PG) biosynthesis 3) and depletion of gastric mucosal blood flow. 4,5) A number of studies have highlighted the importance of alterations in mucosal blood flow after NSAID administration.…”

mentioning

confidence: 99%

Mechanism of Superoxide Generation System in Indomethacin-Induced Gastric Mucosal Injury in Rats.

Tanaka¹,

Yuda²,

Yamakawa

2001

Biological & Pharmaceutical Bulletin

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Indomethacin and several other nonsteroidal anti-inflammatory drugs (NSAID) are known to produce gastric mucosal injury.1,2) The pathogenesis of NSAID-induced gastric mucosal injury is reported for inhibition of prostaglandin (PG) biosynthesis 3) and depletion of gastric mucosal blood flow. 4,5) A number of studies have highlighted the importance of alterations in mucosal blood flow after NSAID administration. By this depletion of gastric mucosal blood flow, polymorphonuclear leukocytes (PMN) were infiltlated to gastric mucosal tissue. 6) We clarified these phenomena that PMN infiltlates, generates oxygen radicals and induces direct gastric mucosal injury, and then increasing lipid peroxidation further aggravate damage in previous study. 7) We demonstrated that neutrophil-derived free radicals are also important factors in the gastric mucosal injury induced ischemia-reperfusion in pylorus-ligated rats.8) But the generation system of oxygen free radicals is not clear in the indomethacin induced-gastric mucosal injury. We examined this and report here the mechanism of pathogenesis in this type of injury.Superoxide radicals have several generation systems, with activation of xanthine-xanthine oxidase (XOD) enzyme in vein cellular tissue and activation of NADPH oxidase enzyme in PMN being the main ones. The direct effect of indomethacin on XOD activity in vitro and NADPH oxidase in ex vivo was therefore examined.Cytokines, IL-1 and TNF a are well known to play important roles in inflammation.9) The first step of PMN infiltration into an inflammation site is believed to take place in many cytokines and the growth binding factors IL-1 and TNF a from mast cells and macrophages. We measured cytokines to learn whether indomethacin acts to directly activate the oxygen radical generation system or is a second any effect. MATERIALS AND METHODS AnimalsMale Donryu rats (SPF) 8 weeks old were obtained from Charles River Co., Tokyo, and ICR mice (SPF) 8 weeks old were obtained from SLC Japan Co., Tokyo.Materials Indomethacin, ferricytochrome C (horse heart type III), NADPH Na (type III), NBT and BCIP were obtained from Sigma, and xanthine oxidase solution from Boehringer Mannheim Yamanouchi, Tokyo. Diphenylene iodonium chloride was from ALEXIS Co., U.S.A.; Bio-Rad protein assay was from BIO RAD; anti p47 phox was from Trunsduction Laboratories and mouse IL-1 and the TNF a assay system were obtained from Genzyme. Other chemicals were of reagent grade and were used without purification.Assay of Xanthine Oxidase (XOD) Activity XOD reduced cytochrome c was monitored spectrophotometrically at 550 nm. The reaction mixture consisted of 100 mM potassium phosphate buffer (pH 7.4) (1.2 ml), 0.1 mM cytochrome c (0.2 ml), 5 mM xanthine (0.2 ml) and 0.1 U/ml xanthine oxidase solution (0.2 ml). This mixture was preincubated for 5 min at 37°C and indomethacin was added at a fianl concentration of 0.1, 0.5, 1, 5, or 10 mM. Indomethacin was disorbed by 100% ethanol solution and finally diluted with distilled water at Ͻ1% ethanol concentration.G...

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Indomethacin-induced intestinal lesions in the rat

Cited by 196 publications

References 9 publications

Pharmacology and toxicology of diflunisal.

Pharmacology and toxicology of diflunisal.

Indomethacin Fails to Induce Ulceration in the Gastrointestinal Tract of Newborn and Suckling Rats

Mechanism of Superoxide Generation System in Indomethacin-Induced Gastric Mucosal Injury in Rats.

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