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Effect of repeated doses of netazepide, a gastrin receptor antagonist, omeprazole and placebo on 24?h gastric acidity and gastrin in healthy subjects.

ABSTRACT: AIM:To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24?h gastric pH and plasma gastrin. METHOD:We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100?mg 12?hourly, omeprazole 20?mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25?mg and placebo once daily for 14 days. We measured pH on days 1, 7 and 14 and assayed plasma gastrin on days 1 and 14. We compared treatments by time gastric pH ? 4 during 0-4, 4-9, 9-13 and 13-24?h after the morning dose, and by plasma gastrin. P < 0.05 was significant. RESULTS:Netazepide was well tolerated. On day 7 of the first study, netazepide increased pH significantly only during 9-13?h after the 100?mg dose, whereas omeprazole raised pH significantly during all periods. Both netazepide and omeprazole increased plasma gastrin significantly. Netazepide had linear pharmacokinetics. In the second study, netazepide caused dose-dependent, sustained increases in pH on day 1, but as in the first study, netazepide had little effect on pH on days 7 and 14. Again, netazepide increased plasma gastrin significantly. CONCLUSION:Although repeated doses of netazepide led to tolerance to its effect on pH, the accompanying increase in plasma gastrin is consistent with continued inhibition of acid secretion, via gastrin receptor antagonism and gene up-regulation.

SUBMITTER: Boyce M

PROVIDER: S-EPMC3853527 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Effect of repeated doses of netazepide, a gastrin receptor antagonist, omeprazole and placebo on 24 h gastric acidity and gastrin in healthy subjects.

Boyce Malcolm M Warrington Steve S

British journal of clinical pharmacology 20131101 5

<h4>Aim</h4>To administer repeated oral doses of netazepide to healthy subjects for the first time, to assess safety, tolerability, pharmacokinetics and effect on 24 h gastric pH and plasma gastrin.<h4>Method</h4>We did two randomized, double-blind, parallel group studies. The first compared netazepide 25 and 100 mg 12 hourly, omeprazole 20 mg once daily and placebo for 7 days. On day 7 only, we measured pH and assayed plasma gastrin. The second study compared netazepide 5, 10 and 25 mg and plac ...[more]

PMID: 23432415

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Project description:Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm2, SD 620.7; placebo: +307.8 Ki67+ cells/mm2, SD 640.3; P = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype (TFF2, MUC5B) and certain cancer-associated markers (REG3A, PAX9, MUC1), and decreased expression of intestinal markers MUC2, FABP1, FABP2, and CDX1 No serious adverse events related to study drug occurred. The gastrin/CCK2 receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus.Prevention Relevance: Treatment of patients with Barrett's esophagus with a gastrin/CCK2 receptor antagonist did not have obvious chemopreventive effects.

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Dataset Information

Effect of repeated doses of netazepide, a gastrin receptor antagonist, omeprazole and placebo on 24?h gastric acidity and gastrin in healthy subjects.

Publications

Effect of repeated doses of netazepide, a gastrin receptor antagonist, omeprazole and placebo on 24 h gastric acidity and gastrin in healthy subjects.

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