title: Mucosal protective agents prevent exacerbation of NSAID-induced small intestinal lesions caused by antisecretory drugs in rats.
abstract: Antisecretory drugs such as histamine H₂-receptor antagonists and proton pump inhibitors are commonly used for the treatment of upper gastrointestinal mucosal lesions induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, it has recently been reported that these drugs exacerbate NSAID-induced small intestinal lesions in rats. Unfortunately, there are few effective agents for the treatment of this complication. We examined the effects of mucosal protective agents (MPAs) (misoprostol, irsogladine, and rebamipide) and mucin of porcine stomach on diclofenac-induced intestinal lesions and the exacerbation of the lesions by ranitidine or omeprazole. The effects of the drugs on intestinal motility and mucus distribution/content were also examined. Male Wistar rats (180-220 g) were used. Each drug was administered orally under fed conditions. Diclofenac (1-10 mg/kg) produced multiple lesions in the small intestine dose-dependently. Both ranitidine (30 mg/kg) and omeprazole (100 mg/kg) significantly increased the intestinal lesions induced by low doses (3 and 6 mg/kg) of diclofenac. Misoprostol (0.03-0.3 mg/kg), irsogladine (3-30 mg/kg), and rebamipide (30-300 mg/kg), as well as mucin (30-300 mg/kg) inhibited the formation of intestinal lesions caused by a high dose (10 mg/kg) of diclofenac alone and prevented the exacerbation of diclofenac-induced lesions by antisecretory drugs. Diclofenac (10 mg/kg) markedly increased the intestinal motility and decreased the mucosal mucus, and the decrease of mucus was significantly inhibited by the MPAs. These results indicate the usefulness of the MPAs for the treatment of intestinal lesions induced by NSAIDs alone or by coadministration with antisecretory drugs, and suggest that mucus plays an important role in the protection of intestinal mucosa by the MPAs.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics, Division of Pathological Science, Kyoto Pharmaceutical University, Kyoto, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satoh
authors.forename: Kikuko
authors.initials: K
authors.lastname: Amagase
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D000897:Anti-Ulcer Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004008:Diclofenac / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005752:Gastric Mucins / Q000008:administration & dosage / Q000627:therapeutic use; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007410:Intestinal Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016595:Misoprostol / Q000008:administration & dosage / Q000627:therapeutic use; D009093:Mucus / Q000187:drug effects / Q000378:metabolism; D009853:Omeprazole / Q000009:adverse effects / Q000627:therapeutic use; D020011:Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D015363:Quinolones / Q000008:administration & dosage / Q000627:therapeutic use; D011899:Ranitidine / Q000009:adverse effects / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D034421:Sus scrofa; D014227:Triazines / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D005752:Gastric Mucins; D005765:Gastrointestinal Agents; D020011:Protective Agents; D054328:Proton Pump Inhibitors; D015363:Quinolones; D014227:Triazines; D016595:Misoprostol; D004008:Diclofenac; D011899:Ranitidine; D009853:Omeprazole; C052785:rebamipide; D000409:Alanine; C041836:irsogladine