Studies on the cytoprotective and antisecretory activity of ebrotidine. A review

Gastric mucosa is exposed to various aggressive factors such as stress, ulcerogenic drugs including acetyl-salicylic acid(ASA)-like agents, ethanol, bacteria, particularly Helicobacter pylori (Hp), and various endogenous irritants such as acid-pepsin secretion and bile salts. The maintenance of the mucosal barrier depends upon the activation of the pre-epithelial (mucus-alkali secretion), epithelial (surface-active phospholipids and rapid mucosal restitution) and post-epithelial (mucosal microcirculation, sensory nerves and mast cells) components of mucosal defense. Ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]- 4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamid e, CAS 100981-43-9, FI-3542) is the first of a new generation of H2-receptor antagonists with both antisecretory and cytoprotective activities. Its inhibitory action is similar to that of ranitidine and approximately tenfold greater than cimetidine, and is accompanied by a small and transient increase in plasma gastrin levels. In contrast to ranitidine and other H2-receptor antagonists, ebrotidine exerts a unique cytoprotection against injury by various ulcerogens such as ethanol, ammonia, lipopolysaccharides (LPS), stress and ASA or acidified taurocholate. The mechanism of this protection by ebrotidine is not clear, but it has been shown to stimulate mucus secretion, to increase the quality of adherent mucus gel and to increase gastric mucosal blood flow (GBF), possibly due to enhanced mucosal formation of prostaglandin E2 (PGE2) and nitric oxide (NO). The cytoprotective effects of ebrotidine were observed in rats and confirmed also in humans with gastric lesions induced by ethanol or ASA. Ebrotidine also exerts anti-Helicobacter pylori (Hp) effects by interfering with surface receptors of epithelial cells and inhibiting urease, protease and lipase activity, and by counteracting the noxious effects of Hp-related substances such as ammonia and lipopoly-saccharides (LPS).