Antisecretory effects of YF476, gastrin/CCK-B receptor antagonist, in beagle dogs with gastric fistula

Takemoto, Yukihiro; Nishida, Akito; Yuki, Hidenobu; Takinami, Yusuke; Miyata, Keiji; Yamaguchi, Tokio

doi:10.1016/s0021-5198(19)45376-6

Cited by 2 publications

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“…82 However, most other CCK 2 RAs have had problems with potency, selectivity for the CCK 2 versus CCK 1 R, solubility or oral bioavailability. Netazepide, a benzodiazepine derivative, has been the most studied CCK 2 RA [83][84][85] with main results as follows.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology

Chen

Hagen

Boyce

et al. 2023

J Neuroendocrinology

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The physiology of gastric acid secretion is one of the earliest subjects in medical literature and has been continuously studied since 1833. Starting with the notion that neural stimulation alone drives acid secretion, progress in understanding the physiology and pathophysiology of this process has led to the development of therapeutic strategies for patients with acid‐related diseases. For instance, understanding the physiology of parietal cells led to the developments of histamine 2 receptor blockers, proton pump inhibitors (PPIs), and recently, potassium‐competitive acid blockers. Furthermore, understanding the physiology and pathophysiology of gastrin has led to the development of gastrin/CCK2 receptor (CCK2R) antagonists. The need for refinement of existing drugs in patients have led to second and third generation drugs with better efficacy at blocking acid secretion. Further understanding of the mechanism of acid secretion by gene targeting in mice has enabled us to dissect the unique role for each regulator to leverage and justify the development of new targeted therapeutics for acid‐related disorders. Further research on the mechanism of stimulation of gastric acid secretion and the physiological significances of gastric acidity in gut microbiome is needed in the future.

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Section: Preclinical Studiesmentioning

confidence: 99%

Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology

Chen

Hagen

Boyce

et al. 2023

J Neuroendocrinology

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“…Many gastrin/CCK-2 receptor antagonists have been described [27,28], but none has been developed as a medicine [29], mainly because of problems with potency, selectivity and oral bioavailability. In non-clinical studies, netazepide (YF476) is a potent, highly selective and competitive gastrin/CCK-2 receptor antagonist, and has good oral bioavailability [30][31][32]. Activity persists during repeated dosing [33].…”

Section: Introductionmentioning

confidence: 99%

Correction: Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

Moore¹,

Boyce²,

Steele³

et al. 2013

PLoS ONE

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Introduction: Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia. Aim:To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs. Methods:We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.Results: Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at followup. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected. Conclusion:The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.

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Antisecretory effects of YF476, gastrin/CCK-B receptor antagonist, in beagle dogs with gastric fistula

Cited by 2 publications

References 0 publications

Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology

Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology

Correction: Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

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