Abstract
Lafutidine is a newly developed antiulcer drug, having histamine H2 receptor antagonistic and mucosal protective activity. This compound showed a potent and long-lasting inhibition on tiotidine binding and histamine-induced cyclic-3,5-adenosine monophosphate production in CHO cells expressing human H2 receptors. The duration of the antisecretory activity in dogs and rats was substantially longer than that of famotidine or cimetidine. Lafutidine prevented gastric lesions as induced by a variety of noxious agents, and structure-activity relationships reveal that the presence of furfurylsulfinyl, pyridyl and amide moiety are chemically important for the gastroprotective activity. The mucosal protective effect of lafutidine was attenuated by pretreatment with the antagonist of calcitonin gene-related peptide (CGRP8-37) and the blocker of nitric oxide (NO) production, NG-nitro-L-arginine, as well as chemical ablation of capsaicin-sensitive sensory neurons, suggesting that this action appears through capsaicin-sensitive afferent neurons and is mediated by CGRP and NO. Lafutidine also exhibits a protective activity against the experimentally-induced mucosal lesions in digestive tissues other than the stomach; including acid reflux esophagitis; indomethacin-induced small intestinal lesions; colonic inflammation induced by dextran sulfate sodium. Furthermore, lafutidine also promotes healing of gastric ulcers and reduces the ulcer relapse after discontinuation of the treatment. Given the above results, we conclude that lafutidine has a protective action throughout the gastrointestinal tract from the esophagus to large intestine, and these pharmacological effects are mediated by both the histamine H2 receptor antagonism and facilitation of the sensory neuronal mechanism involving CGRP and NO.
Keywords: lafutidine, histamine h2 receptor antagonist, capsaicin-sensitive afferent neurons, gastric acid secretion
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