Gastroprotective Mechanism of Lafutidine, a Novel Anti-ulcer Drug with Histamine H2-Receptor Antagonistic Activity

Abstract

Lafutidine (CAS 118288-08-7, FRG-8813) is a novel histamine H2-receptor antagonist with gastroprotective activity. The aim of this study was to investigate the property of the gastro-protective activity of lafutidine by examining the effect on ammonia-induced change in transmucosal potential difference (PD), basal gastric mucosal blood flow (GMBF) and noxious agent-induced cell damage. Intragastrical application of lafutidine accelerated the recovery of the PD reduction after exposure of the mucosa to 0.25% ammonia solution and the accelerating effect was abolished by chemical deafferentation, but not with indometacin, a cyclooxygenase inhibitor. The application of capsaicin, as a reference compound, significantly promoted the recovery of the ammonia-induced PD reduction and this effect was not altered with indometacin. Lafutidine given intragastrically caused a sustained increase in GMBF in a dose-dependent fashion, which was also completely inhibited in the deafferentated rats. In vitro studies revealed that, in contrast to 16,16-dimethyl prostaglandin E2, lafutidine did not protect isolated gastric superficial epithelial cells from ethanol- or ammonia-induced damage. In conclusion, the gastroprotection of lafutidine is induced by promoting the restitution of the damaged mucosa after a noxious agent, not by directly protecting the epithelial cells and this effect may be caused through the mechanism of capsaicin-sensitive afferent nerves.

Capsaicin as New Orally Applicable Gastroprotective and Therapeutic Drug Alone or in Combination with Nonsteroidal Anti-Inflammatory Drugs in Healthy Human Subjects and in Patients

“…Even the new drug "Lafutidine" a Histamin-2-receptor (H 2 R) blocking compound, that was developed in the medical treatment of GI mucosal damage and marketed in Japan (Ajioka et al 2000(Ajioka et al , 2002Onodera et al 1999;Takeuchi 2006) showed typical capsaicin actions at the target organ.…”

Formulation development and in vitro and in vivo evaluation of gastroretentive floating drug delivery system of Lafutidine

“…[2] It is absorbed in the small intestine, reaches gastric cells via the systemic circulation, and rapidly binds to gastric cell histamine H2 receptors, resulting in immediate inhibition of gastric acid secretion. [3] Lafutidine has been shown to increase the gastric mucosal blood flow [4] and gastric mucus secretion [5,6] also accelerate sepithelial restitution in rats. Lafutidine has a receptor binding affinity, which is 2-80 times higher than famotidine, ranitidine and cimetidine.…”

Protective Effects of Gastric Mucus

“…An earlier study demonstrated that lafutidine does not influence the impaired healing of epithelial wounds in RGM1 cells under in vitro conditions without neuronal innervations (Murashima et al, 2009), again confirming the importance of sensory neurons in the healing-promoting action of this agent. Several studies show that luminal lafutidine stimulates capsaicin-sensitive afferent nerves via presumably direct diffusion rather than after its absorption from intestine followed by via circulation, suggesting the rapid local diffusion reaching to the afferents before H 2 -receptor blockade from the circulation (Onodera et al, 1999b;Nagahama et al, 2003). Second-generation H 2 -receptor antagonists such as lafutidine are thought to facilitate capsaicin-sensitive sensory afferent nerves and exert gastroprotective effects through CGRP and in part via NO release in the stomach.…”