Gastrointestinal ulcerations induced by anti-inflammatory drugs in rats

Abstract

Aspirin, diclofenac, diflunisal, ibuprofen and indomethacin were given orally or intravenously to fasted or fed rats. The resulting gastric and intestinal damage was assessed using standard methods. The same drugs were administered to rats with biliary fistulas, and the fraction of drug excreted in bile was quantified using HPLC methods. We found that gastric damage occurred only in the fasted animals and was found to be dose-dependent and related to the amount (r = 0.871) and solubility (r = 0.909) of the individual drug. As far as acute gastric toxicity is concerned, neither the potency of a drug as an inhibitor of cyclo-oxygenase nor the fraction of unchanged or conjugated agent excreted in bile appeared to be relevant. Secondly, ulcerations of the small intestine occurred in fed animals only. The degree of damage was related to the amount of unchanged or conjugated drug excreted in bile and cyclo-oxygenase inhibitory potency (r = 0.873). The administered dose (within the range investigated) and drug solubility appeared not to contribute to intestinal toxicity. It is concluded that, in the rat, acute gastric and intestinal toxicity of non-steroidal anti-inflammatory drugs are due to different mechanisms. Whereas gastric toxicity is strongly influenced by the amount of drug dissolved under the pH conditions in the stomach, intestinal toxicity appears to depend on biliary excretion and enterohepatic circulation of a drug as well as on its potency as an inhibitor of prostaglandin synthesis.

Culture Supernatants of Lactobacillus acidophilus and Bifidobacterium adolescentis Repress Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug by Suppressing Unbalanced Growth of Aerobic Bacteria and Lipid Peroxidation

“…BFMeT induces small intestinal ulcers in rats like other NSAIDs (2,30,36). Recently, we reported that BFMeT induced ileal ulcers in specific pathogen-free rats but no ulcers in germ-free rats or gnotobiotic rats monoassociated with L. acidophilus and B. adolescentis, and that antibiotic treatment, which decreases the total number of bacteria, inhibited ulcer formation (36).…”

“…When NSAIDs are administered to rats, ulcers are observed in the small intestine (2,30,36). Therefore, NSAID-induced small intestinal ulceration in rats may be a useful animal model for human ulcers.…”

Role of Intestinal Bacteria in Ileal Ulcer Formation in Rats Treated with a Nonsteroidal Antiinflammatory Drug

“…hepatic circulation of NSAIDs and their metabolites (2,9,29). The gastric and duodenal or ileal damage caused by NSAID toxicity are explained by different factors such as acid and pepsin or intestinal bacteria, respectively (3,26).…”

Some pharmacological actions of Myrica rubra part 1: Effect on experimentally-induced gastric ulcers, inflammation and haemorrhoids in rats

“…Furthermore, an additional physical mechanism such as binding of the proanthocyanidins to the gastric mucosa proteins cannot be ruled out since procyanidins can bind to bovine serum albumin (Saito et al., 1998). On the other hand, indomethacin-induced ulcers seemed to involve inhibition of gastric prostaglandins derived mainly via COX-1, with some involvement of COX-2 (El-Bayer et al, 1985;Beck et al, 1990;Iseki, 1995;Wallace, 1997;Schmassmann et al, 1998). Stress-induced ulcers are believed to result from an increase in gastric acid secretion (Kitagawa et al, 1979;Marrone, 1984), a decrease in gastric PGE 2 production (Moody, 1976;Arakawa et al, 1981) and disturbed microcirculation in the gastric mucosa (Murakami et al, 1985).…”

“…Stress-indomethacin ulcers were induced in male Wistar rats by a modification of the methods described by Senay and Levine (1967), Levine (1971), Bhargava et al (1975), Beck et al (1990) and Schmassmann et al (1998). In brief, all animals were fasted for 48 h from food only with the respective drinking liquids ad libitum.…”