Antiulcer Effect of Lafutidine on Indomethacin-Induced Gastric Antral Ulcers in Refed Rats

Abstract

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.

Potent and Long-Lasting Action of Lafutidine on the Human Histamine H₂ Receptor

“…In addition to its antisecretory action, lafutidine is reported to exert a gastroprotective effect, which does not result from its antisecretory action, and also to promote mucin synthesis [10, 17]. The former effect was revealed to be mediated by capsaicin-sensitive sensory neurons [8, 9, 18]. However, there are no reports concerning direct interaction of lafutidine with the human H 2 R. Although the above-mentioned effects are beneficial, since lafutidine is an H 2 R antagonist, it is essential to determine the direct interaction of lafutidine with the human H 2 R. Herein, we describe, for the first time, the interaction of lafutidine with human H 2 Rs expressed in CHO cells.…”

Protective Effects of Gastric Mucus

“…Figure 13 demonstrates that after administration of lafutidine there is thickening of the surface mucus gel layer. In other studies using experimental animals, lafutidine has been shown to possess gastroprotective properties, such as strengthening the mucus gel layer, apart from its antisecretory activity (Ichikawa et al, 1994a;Onodera et al, 1999a;Sato et al, 2003). …”

“…The action of CGRP is in part mediated by endogenous NO. The gastroprotective action of lafutidine has been reduced or abolished by treatment with tetrodotoxin, CGRP 8-37 , or chemical defunctionalisation of afferent nerves (Mimaki et al, 2002;Onodera et al, 1999a), indicating that capsaicin-sensitive nerves contribute significantly to the mechanisms underlying the actions of lafutidine (Nishihara et al, 2002). Moreover, lafutidine has been shown to significantly increase CGRP release in both experimental animal models and humans (Harada & Okajima, 2007;Nishihara et al, 2002;Ikawa et al, 2006;Shimatani et al, 2006).…”

An open-label, randomized, cross-over bioequivalence study of lafutidine 10 mg under fasting condition

“…famotidine, ranitidine, and cimetidine) [7] . In addition, lafutidine exerts gastroprotective effects independent of its antisecretory action [8,9] . Lafutidine has been shown to increase the gastric mucosal blood flow [9] and gastric mucus secretion [10,11] and to accelerate epithelial restitution in rats.…”