Summary
Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most prescribed drugs worldwide and have now probably overtaken Helicobacter pylori as the most common cause of gastrointestinal injury in Western countries. Further understanding of the pathogenesis of NSAID-induced ulcers is important to enable the development of novel and effective preventive strategies.

Aims  To provide an update on recent advances in our understanding of the cellular and molecular mechanisms involved in the development of NSAID-induced ulcers.

Methods  A Medline search was performed to identify relevant literature using search terms including ‘nonsteroidal anti-inflammatory drugs, aspirin, gastric ulcer, duodenal ulcer, pathogenesis, pharmacogenetics’.

Results  The mechanisms of NSAID-induced ulcers can be divided into topical and systemic effects and the latter may be prostaglandin-dependent (through COX inhibition) or prostaglandin-independent. Genetic factors may play an important role in determining individual predisposition.

Conclusions  The pathogenesis of NSAID-induced peptic ulcers is complex and multifactorial. Recent advances in cellular and molecular biology have highlighted the importance of various prostaglandin-independent mechanisms. Pharmacogenetic studies may provide further insights into the pathogenetic mechanisms of NSAID-induced ulcers and help identify patients at increased risk.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2009.04086.x

Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers

Pathogenesis of NSAID-induced gastric damage: Importance of cyclooxygenase inhibition and gastric hypermotility

The dramatic success of pharmacological acid suppression in healing peptic ulcers and managing patients with gastroesophageal reflux disease (GERD) has been reflected in the virtual abolition of elect

Acid Suppression Therapy: Where Do We Go from Here?

Aspirin causes gastroduodenal ulcers and complications. Food bioactive compounds could exert beneficial effects in the gastrointestinal tract. We evaluated whether apple polyphenol extract (APE) reduced aspirin-induced injury to the rat gastric mucosa. Rats were treated with APE (10(-4) m catechin equivalent) before oral aspirin (200 mg/kg). Cyclo-oxygenase-2 (COX-2), transforming growth factor-alpha (TGF alpha) and heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) mRNA and protein expression were assessed by RT-PCR and Western blot analysis, respectively; malondialdehyde (MDA) was determined by HPLC; gastric secretion was evaluated in pylorus-ligated rats. APE decreased acute and chronic aspirin injury both macroscopically and microscopically (approximately 50 % decrease in lesion score; P < 0.05). Aspirin up-regulated mRNA and protein expression of COX-2 and HB-EGF, but not of TGF alpha; APE reduced aspirin-induced mRNA and protein over-expression of COX-2 and HB-EGF; aspirin significantly increased gastric MDA and this effect was counteracted by APE pre-treatment. APE did not significantly affect gastric acid secretion. In conclusion, APE reduces aspirin-induced gastric injury independently of acid inhibition. We speculate that APE might be of therapeutic use in the prophylaxis of aspirin-related gastropathy.

/pdf/apple-polyphenol-extracts-prevent-aspirin-induced-damage-to-6roa6jmh0r.pdf

Apple polyphenol extracts prevent aspirin-induced damage to the rat gastric mucosa.

The effect of irsogladine maleate, a widely used antiulcer drug in Japan, on indomethacin-induced small intestinal lesions was examined in rats. Animals without fasting were given indomethacin (10 mg/kg, s.c.) and sacrificed 24 h later. Irsogladine (1–10 mg/kg) or 16,16-dimethyl prostaglandin E2 (dmPGE2 0.03 mg/kg) was given p.o. twice, 0.5 before and 6 h after indomethacin, while ampicillin (800 mg/kg) was given twice, 18 and 0.5 h before. Indomethacin caused severe lesions in the small intestine, mainly the jejunum and ileum, accompanied by intestinal hypermotility, the up-regulation of inducible nitric oxide synthase (iNOS) expression, and an increase of myeloperoxidase (MPO) activity as well as enterobacterial invasion in the mucosa. These events were all prevented by both dmPGE2 and ampicillin, except the intestinal hypermotility which was only prevented by dmPGE2. Likewise, irsogladine also significantly and dose-dependently prevented these lesions at >1 mg/kg. This agent alone increased mucus secretion and significantly suppressed the decreased mucus response to indomethacin, resulting in a suppression of the bacterial invasion as well as the increase in MPO activity and iNOS expression. The protective effect of irsogladine was mimicked by isobutylmethylxanthine, a nonselective inhibitor of phosphodiesterase (PDE), as well as rolipram, a selective PDE4 inhibitor. These results suggest that irsogladine protects the small intestine against indomethacin-induced lesions, and this effect may be associated with the increased mucus secretion, probably due to the inhibitory actions of PDE, resulting in suppression of enterobacterial invasion and iNOS expression.

Prophylactic Effect of Irsogladine Maleate Against Indomethacin-Induced Small Intestinal Lesions in Rats

アスピリン経口投与による胃粘膜におけるcox-2誘導機序 : cox-2発現とpg枯渇の関連性

PROBLEM TO BE SOLVED: To provide a safer prophylactic or treating agent for inflammatory enteropathy causing less side effect SOLUTION: Lafutidine, an optical isomer thereof, a lafutidine derivative or their physiologically permissible salts is (are) incorporated in the prophylactic or treating agent for inflammatory enteropathy as an effective ingredient COPYRIGHT: (C)2004,JPO

孝治竹内

Papers

アスピリン経口投与による胃粘膜におけるcox-2誘導機序 : cox-2発現とpg枯渇の関連性

Prophylactic or treating agent for inflammatory enteropathy

消化管傷害性の低いNSAIDsの開発 - COX-2選択的阻害薬とNO遊離型NSAIDs -

孝治 竹内

Papers

アスピリン経口投与による胃粘膜におけるcox-2誘導機序 : cox-2発現とpg枯渇の関連性

Prophylactic or treating agent for inflammatory enteropathy

消化管傷害性の低いNSAIDsの開発 - COX-2選択的阻害薬とNO遊離型NSAIDs -

孝治竹内