The Novel Acid Pump Antagonists for Anti-secretory Actions with Their Peculiar Applications Beyond Acid Suppression

Abstract

Summary The H + /K + -ATPase of gastric parietal cell exchanges luminal K + for cytoplasmic H + , of which outcome is gastric acidification with outflux of hydronium ion (H3O − ). Secretion of gastric acid from the H + / K + -ATPase is stimulated by neuronal sensing and elaborately regulated various neuronal transmitters and hormones, consequently resulting in anchoring of the H + / K + -ATPase in canaliculi membrane of gastric parietal cell. Since hypersecretion of gastric acid or a defect of its barrier function is considered as a principal casual factor in the acid-related diseases such as duodenal and gastric ulcer, reflux esophagitis, and some types of gastritis, the development of anti-secretory agents including PPIs (proton pump inhibitors) and H2-RAs (histamine type 2 receptor antagonists) has revolutionized during the second millennium. Similar considerations applying to design of compounds substituting K + led to the development of acid pump antagonists (APAs), of which advantages are independent of secretory status, no lag time required, reversible in actions allowing "on-demand dosage". Our recent studies revealed that these inhibitors of H + /K + -ATPase could be extensively applied for the selective induction of cancer cell apoptosis, a significant anti-inflammatory and gastroprotective action beyond acid suppression. In the current review, we described the mechanistic regulation of gastric acid secretion with pump inhibitor, the difference and characteristics between PPI and APA based on the molecular mechanism, and their new applications beyond acid suppression.

Novel Application of Proton Pump Inhibitor for the Prevention of Colitis-Induced Colorectal Carcinogenesis beyond Acid Suppression

“…There have been several reports in the literature eliciting the anti-inflammatory actions of PPI beyond its fundamental action of acid suppression-lansoprazole for ischemic-reperfusion intestinal injuries, indomethacin-induced rat enteritis (22) and for a rhinoviral infection (23), heme oxidase-1 induction by omeprazole (11), IL-1β inhibition by v type-ATPase inhibitors, bafilomycin A, or FR 177995 (24), and revaprazan for indomethacin-induced gastropathy (25).…”

The Potential Inhibitory Effect of Revaprazan, an Acid Pump Antagonist, on Anticoagulation with Warfarin

“…Recently, revaprazan was found to control the mitogen-activated protein kinase (MAPK) extracellular signal regulated protein kinases (ERK1/2) signaling in gastric mucosa in addition to suppressive effect of gastric acid secretion. It was also found to be effective in protecting gastric mucosa by increasing protective proteins such as cyclooxygenase-2 resulting in production of prostaglandin as well as vascular endothelial growth factor (VEGF), interleukin (IL)-8 (Yeo et al 2006). In addition to having a protective function in stomach membrane, revaprazan can control inflammation that occurs when the cultured gastric mucosa is infected with Helicobactor pylori (Yeo et al 2006).…”

“…It was also found to be effective in protecting gastric mucosa by increasing protective proteins such as cyclooxygenase-2 resulting in production of prostaglandin as well as vascular endothelial growth factor (VEGF), interleukin (IL)-8 (Yeo et al 2006). In addition to having a protective function in stomach membrane, revaprazan can control inflammation that occurs when the cultured gastric mucosa is infected with Helicobactor pylori (Yeo et al 2006). Compared to rabeprazole, another PPIs, revaparazan showed almost identical results in the post-treatment of endoscopic submucosal dissection, and no additional adverse drug reaction was reported thus far (Kim et al 2010).…”

A Matched Case-Control Study of a Novel Acid-Pump Antagonist and Proton-Pump Inhibitor for the Treatment of Iatrogenic Ulcers Caused by Endoscopic Submucosal Dissection

“…30 However, APA had a weaker effect on the serum gastrin concentration and antral gastrin content than PPIs. 5,31 Therefore, APA would be beneficial for clinical use. This is the first study to demonstrate the efficacy of APA for the treatment of ESD-induced ulcers.…”

“…4 Revaprazan, a new drug, protects the mucosa by inhibiting secretion of pepsinogen and increasing the prostaglandin concentration. 5 In previous study that compared revaprazan with a PPI for the treatment of gastric ulcers, the ulcer healing rates did not differ. After the introduction of endoscopic submucosal dissection (ESD) in the late 1990s, ESD has become widely used as an alternative to surgical resection in patients with early-stage gastric cancer or for adenomas.…”