tacrolimus and Stomach-Ulcer

Topics: Carcinoma, Hepatocellular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma, Primary Effusion; Male; Middle Aged; Pleural Effusion; Stomach Ulcer; Tacrolimus

Topics: Arthritis, Juvenile; Child, Preschool; Epstein-Barr Virus Infections; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Prednisolone; Stomach Ulcer; Tacrolimus

The effect of tacrolimus (FK506) on peptic ulcer was evaluated using pyloric ligation (PL) model in rats. Tacrolimus was administered orally at different doses (1, 2 and 3 mg/kg) and it showed a gastric ulcer healing effect in a dose dependent manner. Gastric volume, total and free acidity and ulcerative index parameters were reduced in the tacrolimus treated rats as compared to pyloric ligated rats. The higher dose (3 mg/kg) treated group produced significant results similar to that of the ranitidine (50 mg/kg) treated group. Pretreatment with tacrolimus also produced significant (p<0.05) reduction in TBARS, total calcium, TNF-alpha, IL-8 and MPO whereas it showed an increase in GSH level at higher dose. The anti-secretory and anti-ulcerative effect of tacrolimus may be due to immunosuppressive actions by inhibition of calcineurin and the oxidative pathway. It can be concluded that tacrolimus can play an important role in the treatment of peptic ulcer disorder to improve the quality of life.

Topics: Administration, Oral; Animals; Depression, Chemical; Disease Models, Animal; Dose-Response Relationship, Drug; Gastric Acid; Immunosuppressive Agents; Ligation; Male; Peptic Ulcer; Pyloric Antrum; Rats; Rats, Wistar; Stomach Ulcer; Tacrolimus

Nitric oxide (NO) is a potent cytoprotective substance of gastric mucosa. FK506, an immunosuppressive drug, shows anti-gastric ulcer effects equivalent to famotidine, an H2 blocker, in rats. This study was designed to evaluate the cytoprotective mechanism of FK506 on gastric mucosa in relation to the changes in NO synthase activity.. Gastric lesions were induced in rats by water immersion stress. Changes in NO synthase activity during water immersion stress treatment, and effects of FK506 on NO synthase activity were determined enzymatically. Gastric mucosal interleukin (IL)-1 beta and IL-2 were measured by immunoradiometric assay. Gastric mucosal blood flow was measured by hydrogen gas clearance technique.. FK506 mitigated gastric lesions developed by water immersion stress. Stress-induced lesions were exacerbated by NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthase, while sodium nitroprusside, a NO donor, mitigated the lesions. Water immersion stress increased NO synthase activity in the early phase (0.5 h after stress treatment) and decreased it in the late phase (6 h after). Decrease in NO synthase activity in the late phase was significantly mitigated by FK506, though it did not affect changes in NO synthase activity in the early phase. Water immersion stress increased gastric mucosal IL-1 beta and IL-2 contents 6 h after stress treatment, and these increases were prevented by FK506. FK506 itself did not affect gastric mucosal blood flow. L-NMMA treatment significantly decreased gastric mucosal blood flow. In contrast, gastric mucosal blood flow was significantly increased by sodium nitroprusside.. Increase in NO synthase activity might contribute to cytoprotection, and a decrease in activity might be a harmful factor for the gastric mucosa. Preservation of NO synthase activity by FK506 might be involved in FK506's protective effects on the gastric mucosa.

Topics: Animals; Anti-Ulcer Agents; Gastric Mucosa; Immersion; Interleukin-1; Interleukin-2; Male; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological; Tacrolimus

We examined the effects of FK506, an immunosuppressive agent, on the genesis of water immersion stress-induced gastric lesions in rats. Using high-performance liquid chromatography, four kinds of prostaglandins, ie, 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and prostaglandin D2, were detected, and no leukotrienes were detected in gastric mucosa in rats without stress. After 6 hr of stress, gastric lesions developed with decreases in all prostaglandin contents, and the emergence of peptide leukotrienes was observed. Intramuscular administration of FK506 (0.1, 0.25, 0.5, 1.0, and 2.0 mg/kg) reduced lesion index dose-dependently. Administration of FK506 at doses over 0.25 mg/kg decreased all prostaglandin contents, but did not affect the increase in leukotriene contents. Pretreatment with famotidine or omeprazole reduced lesion index, and the protective effects were equivalent to those of 1.0 mg/kg of FK506, although FK506 did not affect gastric secretion during water-immersion stress. Water-immersion stress did not change the activities of xanthine oxidase in either stomach or serum. Polyoxyethylene-modified superoxide dismutase did not prevent gastric lesions. Water-immersion stress significantly increased myeloperoxidase activity in gastric mucosa, and FK506 reduced the increase in myeloperoxidase activity induced by stress. From our results, other factors besides gastric acid secretion and tissue eicosanoid contents, such as chemoattractant factor, might also be involved in the genesis of water-immersion stress-induced gastric lesions in rats.

Topics: Animals; Famotidine; Gastric Mucosa; Immersion; Leukotrienes; Male; Omeprazole; Peroxidase; Polyethylene Glycols; Prostaglandins; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological; Superoxide Dismutase; Tacrolimus; Xanthine Oxidase

The mechanism of nonsteroidal antiinflammatory drug-induced intestinal ulcers is not clearly understood. To evaluate whether immunosuppressants have a preventive effect against indomethacin-induced gastrointestinal damage, we investigated the effects of prednisolone, cyclosporin, and the newly developed immunosuppressant FK-506 in intracolonically indomethacin-treated rats: 24 mg/kg of indomethacin, administered intracolonically for two days, caused gastric ulcers and two types of small intestinal ulcers (longitudinal ulcers and scattered small ulcers). Pretreatment with intraperitoneal immunosuppressants reduced the size of gastric ulcers. Both cyclosporin (10 mg/kg) and FK-506 (1 mg/kg, 2 mg/kg) treatments significantly reduced the incidence and the length of the longitudinal ulcers of the small intestine when compared to the vehicle-treated controls, whereas prednisolone (20 mg/kg) did not show any preventive effect. Furthermore, the number of small scattered ulcers of the small intestine was significantly reduced by the high dose of FK-506 (2 mg/kg), but not by cyclosporin or prednisolone. These findings indicate that immunosuppressants have protective and antiinflammatory effects in indomethacin-induced gastroenteropathy, suggesting that cytokines may be important mediators in the pathogenesis of enteropathy induced by nonsteroidal antiinflammatory drugs.

Topics: Animals; Cyclosporine; Duodenal Ulcer; Immunosuppressive Agents; Indomethacin; Intestine, Small; Male; Prednisolone; Rats; Rats, Wistar; Stomach Ulcer; Tacrolimus

Topics: Animals; Anti-Ulcer Agents; Hydrochloric Acid; Immunosuppressive Agents; Male; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Stress, Physiological; Tacrolimus