Gastrin Receptor Antagonist Research Articles

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice.

Proton pump inhibitor use is associated with an increased risk of gastric cancer, which may be mediated by hypergastrinemia. Spasmolytic polypeptide-expression metaplasia (SPEM) has been proposed as a precursor of gastric cancer. We have examined the effects of the gastrin receptor antagonist netazepide (NTZ) or vehicle on the gastric corpus mucosa of H+/K+ATPase beta subunit knockout (KO) and wild-type (WT) mice. The gastric corpus was evaluated by histopathology, immunohistochemistry (IHC), in situ hybridization (ISH) and whole-genome gene expression analysis, focusing on markers of SPEM and neuroendocrine (NE) cells. KO mice had pronounced hypertrophy, intra- and submucosal cysts and extensive expression of SPEM and NE cell markers in the gastric corpus, but not in the antrum. Numerous SPEM-related genes were upregulated in KO mice compared to WT mice. NTZ reduced hypertrophia, cysts, inflammation and NE hyperplasia. However, NTZ neither affected expression of SPEM markers nor of SPEM-related genes. In conclusion, NTZ prevented mucosal hypertrophy, cyst formation and NE cell hyperplasia but did not affect SPEM. The presence of SPEM seems unrelated to the changes caused by hypergastrinemia in this animal model.

Preventive and therapeutic strategies of pharmaco-correction gastropathy induced by nonsteroidal anti-inflammatory drugs

Today the problem of prevention and treatment of gastropathy associated with nonsteroidal anti-inflammatory drugs has not lost its relevance. In order to reduce the ulcerogenicity of non-steroidal anti-inflammatory drugs, it is classically accepted to supplement the therapy scheme with preparations of other pharmacological groups - antacids, alginates, M-cholinoblockers, gastrin receptor antagonists, H2-histamine blockers, proton pump inhibitors, synthetic analogues of prostaglandins or stimulators of their synthesis, reparants, gastroprotectors. Nowadays, it was suggested I was suggested the use of drugs which have pharmacological properties polyvector (vinboron, thiotriazoline et al.). Also, the scientists started of combined preparations “NSAIDs + drugs other pharmacological groups” - indotril (indomethacin + thiotriazoline) diklokor (diclofenac + quercetin) Artrotek (diclofenac sodium + misoprostol) dueksis (ibuprofen + famotidine) vimovo (naproxen + esomeprazole) aksorid (ketoprofen + omeprazole) tioaspekard (thiotriazoline + ACK) aspifat (ACK + sucralfate), Alka-Zelttser® (ACK + sodium bicarbonate), and others. The second direction is preventing and improving NSAID gastrotoxicity protrudes improving existing non-steroidal drugs - modification of gaseous molecules (NO, H2S, CO), amino acid derivatives, modulators “effector function” of afferent terminals n. vagus (amtolmetina guatsil) то pairing with nanoparticles biometals (Zn-ibuprofen, Zn-naproxen, Zn-indomethacin). (For citation: Hladkykh FV. Preventive and therapeutic strategies of pharmaco-correction gastropathy induced by nonsteroidal anti-inflammatory drugs. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(4):14-23. doi: 10.17816/RCF15414-23).

The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival

The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.

Joseph Rudinger memorial lecture: Unexpected functions of angiotensin converting enzyme, beyond its enzymatic activity.

Angiotensin converting enzyme (ACE) is a well-known enzyme, largely studied for its action on hypertension, as it produces angiotensin II from angiotensin I. This paper describes two original behaviours of ACE. We showed that ACE could hydrolyse gastrin, a neuropeptide from the gastrointestinal tract, releasing the C-terminal amidated dipeptide H-Asp-Phe-NH2 . This dipeptide is believed to be involved in the gastrin-induced acid secretion in the stomach. This hypothetic mechanism of action of gastrin resulted in a strategy to rationally design gastrin receptor antagonists. Beyond, we showed that the brain renin angiotensin system (RAS) could be activated by a new characterized peptide named acein, resulting in stimulation of dopamine release within the striatum. This new and original 'receptor-like' activity for brain membrane-bound ACE is quite significant taking into account the role of dopamine in the brain, particularly in neurodegenerative diseases. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Advances and Current Concepts in the Medical Management of Gastroenteropancreatic Neuroendocrine Neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous group of tumors presenting as localised or metastatic disease and in a subset with distinct clinical syndromes. Treatment is aimed at controlling the functional syndrome, eradicating the tumor, and/or preventing further tumor growth. Surgery is the treatment of choice in removing the primary tumor and/or reducing tumor burden but cannot be applied to all patients. Somatostatin analogs (SS-analogs) obtain control of functional syndromes in the majority of GEP-neuroendocrine tumors (NETs); phase III trials have shown that SS-analogs can be used as first-line antiproliferative treatment in patients with slow-growing GEP-NETs. The role of the recently approved serotonin inhibitor, telotristat ethyl, and gastrin receptor antagonist, netazepide, is evolving. Streptozotocin-based chemotherapy has been used for inoperable or progressing pancreatic NENs but the orally administered combination of capecitabine/temozolomide is becoming more popular due to its better tolerability and potential effect in other GEP-NENs. Phase III trials have shown efficacy of molecular targeted therapies in GEP-NETs and of radionuclide treatment in patients with midgut carcinoid tumors expressing somatostatin receptors. Most patients will develop disease progression necessitating further therapeutic options. A combination of currently available treatments along with the molecular signature of each tumor will guide future treatment.

The gastrin receptor antagonist netazepide (YF476) in patients with type 1 gastric enterochromaffin-like cell neuroendocrine tumours: review of long-term treatment.

Netazepide (YF476) is a recently developed, orally active gastrin receptor antagonist that, in short trials in patients with type 1 gastric enterochromaffin-like cell neuroendocrine tumours, has been shown to induce a significant reduction in the number and size of tumours as well as serum chromogranin A (CgA). The aim of this review is to evaluate the long-term effect and safety of netazepide. Five patients previously treated with netazepide in an open-label trial were offered continuous treatment with netazepide 25 mg once daily. Upper endoscopy was performed every 6 months. The tumours were counted and measured, and tissue samples were obtained from the flat corpus mucosa. Enterochromaffin-like cell hyperplasia was classified according to Solcia and colleagues and volume density of CgA immunoreactive (IR) cells was calculated. Fasting serum CgA and fasting serum gastrin were measured every 3 months. All tumours regressed completely in three of five patients; time until total disappearance was 3, 9 and 12 months. In the other two patients, the number of tumours was reduced from 13 to 5 and from 14 to 3. Serum CgA showed a rapid and sustained decrease (P<0.001). The mean reduction in serum CgA was 4.1±0.5 nmol/l. Similarly, volume density of CgA IR cells in the flat corpus mucosa decreased (P<0.001), with the mean change being 2.0±0.4%. Serum gastrin and volume density of gastrin IR cells in the antral part of the stomach remained unchanged (P=0.2 and 0.7, respectively). Long-term administration of netazepide is effective and safe.

Skeletal effects of a gastrin receptor antagonist in H+/K+ATPase beta subunit KO mice.

Epidemiological studies suggest an increased fracture risk in patients taking proton pump inhibitors (PPIs) for long term. The underlying mechanism, however, has been disputed. By binding to the gastric proton pump, PPIs inhibit gastric acid secretion. We have previously shown that proton pump (H(+)/K(+)ATPase beta subunit) KO mice exhibit reduced bone mineral density (BMD) and inferior bone strength compared with WT mice. Patients using PPIs as well as these KO mice exhibit gastric hypoacidity, and subsequently increased serum concentrations of the hormone gastrin. In this study, we wanted to examine whether inhibition of the gastrin/CCK2 receptor influences bone quality in these mice. KO and WT mice were given either the gastrin/CCK2 receptor antagonist netazepide dissolved in polyethylene glycol (PEG) or only PEG for 1year. We found significantly lower bone mineral content and BMD, as well as inferior bone microarchitecture in KO mice compared with WT. Biomechanical properties by three-point bending test also proved inferior in KO mice. KO mice receiving netazepide exhibited significantly higher cortical thickness, cortical area fraction, trabecular thickness and trabecular BMD by micro-CT compared with the control group. Three-point bending test also showed higher Young's modulus of elasticity in the netazepide KO group compared with control mice. In conclusion, we observed that the gastrin receptor antagonist netazepide slightly improved bone quality in this mouse model, suggesting that hypergastrinemia may contribute to deteriorated bone quality during acid inhibition.

Follow-up of patients with ECL cell-derived tumours

Objectives: To review the presentation, treatment and outcome of patients with type 1 gastric carcinoid tumours.Material and methods: We retrospectively reviewed medical records and re-evaluated histopathological specimens of 26 patients with type 1 gastric carcinoids treated at a single tertiary referral centre from 1993 to 2013, with median time of follow-up 52.5 months (IQR 90.8).Results: Seven patients (27%) had single tumours and 19 patients (73%) multiple tumours at the time of diagnosis. The median number of tumours and median diameter of largest tumour were 2.5 (IQR 3.2) and 6.0 mm (IQR 9.5) respectively. Median serum gastrin was 321.0 pmol/l (IQR 604.0) and median serum chromogranin A 7.7 nmol/l (IQR 5.3). Three patients had metastatic disease at the time of diagnosis and two developed metastases during follow-up. Patients with metastatic disease had larger primary tumours than the others (20.0 mm (IQR 28.5) vs. 5.0 mm (IQR 5.5), p = 0.04). There was a positive correlation between age and tumour size (r = 0.44, p = 0.03) and between serum chromogranin A and serum gastrin at diagnosis (r = 0.76, p = 0.001). Patients were either treated with surgery (n = 8 (31%)), a long-acting somatostatin analogue and/or gastrin receptor antagonist (n = 10 (39%)) for a period of time, or were observed without treatment (n = 8 (31%) with close endoscopic follow up.Conclusions: Although gastric carcinoids have an overall good prognosis, a significant proportion develops metastatic disease. As partial and total gastrectomy is associated with major side effects, treatment with long-acting a somatostatin analogue or gastrin antagonist should be considered.

Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids

BackgroundGastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and...

Role of p38 Signaling Pathway in Pentagastrin-Regulated Cell Proliferation of Colorectal Carcinoma Cell Line HT-29

Objective: To investigate the effects and mechanisms of p38 signaling pathway in pentagastrin-regulated cell proliferation of colorectal carcinoma cell line HT-29. Methods: HT-29 cell line of colorectal carcinoma was in vitro incubated and divided into the control group, pentagastrin group, proglumide group, and pentagastrin + proglumide group. MTT reduction assay was performed to detect the proliferation status of HT-29 cell line and determine the optimal dosage of pentagastrin and proglumide. Annexin V-fluorescein isothiocyanate flow cytometry was used to detect the proliferation index (PI) and apoptosis rate (AR) of HT-29 cells. Reverse transcriptase polymerase chain reaction was performed to detect the mRNA expression of the pentagastrin receptor/cholecystokinin-B receptor (CCK-BR) and p38. The protein and phosphorylation levels of p38 were estimated by western blotting. Results: RT-PCR detection showed that CCK-BR mRNA was expressed in the HT-29 cell line. Pentagatrin improved HT-29 cell proliferation in dosage of 6.25 - 100 mg/L, and the optimal dosage of pentagastrin was 25.0 mg/L. Proglumide had no significant effect on the proliferation of HT-29 cells, but significantly inhibited the proliferation of HT-29 cells stimulated by pentagastrin when the dosage of proglumide was 8.0 - 128.0 mg/L, and the optimal dosage was 32.0 mg/L. The AR in the pentagastrin group was significantly lower than that in the control group and in the pentagastrin + proglumide group. The PI in the pentagastrin group was significantly higher than that in the control group and in the pentagastrin + proglumide group. P38 phosphorylation level in the pentagastrin group was significantly lower than that in the control group, and in the pentagastrin + proglumide group. There were no significant differences in the mRNA and protein expression of p38 in the control, pentagastrin, proglumide and pentagastrin + proglumide groups. Conclusion: Pentagastrin can improve proliferation of the CRC cell line HT-29 and inhibit apoptosis via the p38 signal transduction pathway. This mechanism may be associated with suppressed p38 protein phosphorylation level due to inhibition of proglumide, a gastrin receptor antagonist.

ChemInform Abstract: Highly Diastereoselective Reaction of α‐Diazoesters with Aryl Alcohols and Isatin Imines: Rapid Access to Oxindole‐Derived α‐Alkoxy‐β‐Amino Acid Derivatives with Two Adjacent Quaternary Carbon Centers.

A stereoselective synthesis of oxindole-derived α-alkoxy-β-amino acid derivatives was achieved in high yield with excellent diastereoselectivity through the three-component reaction of methyl 2-diazoarylacetate, aryl alcohols, and isatin-derived ketimines by using Rh2(OAc)4 (1 mol-%) as the catalyst. The products are very useful for the synthesis of analogues of the gastrin receptor antagonist AG-041R, spirooxindolyl β-lactams, the oxindole-derived side chain of Taxol, and natural product cytoxazone and aminopyrrolo[2,3-b]indoline derivatives.

Abstract 349: Gastrin and D1 Dopamine Receptor Interact to Induce Natriuresis and Diuresis

Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl. Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells. We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension. In Wistar-Kyoto (WKY) rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (CCK B R; CI-988) or D 1 -like receptor antagonist (SCH23390). Similarly, the natriuretic and diuretic effects of fenoldopam, a D 1 -like receptor agonist, were blocked by SCH23390, as well as by CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats (SHRs). The gastrin/D 1 -like receptor interaction was also confirmed in RPT cells. In RPT cells from WKY but not SHRs, stimulation of either D 1 -like or gastrin receptor inhibited Na + -K + -ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988. In RPT cells from WKY and SHRs, CCK B R and D 1 receptor (D 1 R) co-immunoprecipitated, which was increased after stimulation of either D 1 R or CCK B R in RPT cells from WKY rats; stimulation of one receptor increased RPT cell membrane expression of the other receptor, effects that were not observed in SHRs. These data suggest that there is a synergism between CCK B R and D 1 -like receptors to increase sodium excretion. An aberrant interaction between the renal CCK B R and D 1 -like receptors (e.g., D 1 R) may play a role in the pathogenesis of hypertension.

Highly Diastereoselective Reaction of α‐Diazoesters with Aryl Alcohols and Isatin Imines: Rapid Access to Oxindole‐Derived α‐Alkoxy‐β‐amino Acid Derivatives with Two Adjacent Quaternary Carbon Centers

AbstractA stereoselective synthesis of oxindole‐derived α‐alkoxy‐β‐amino acid derivatives was achieved in high yield with excellent diastereoselectivity through the three‐component reaction of methyl 2‐diazoarylacetate, aryl alcohols, and isatin‐derived ketimines by using Rh2(OAc)4 (1 mol‐%) as the catalyst. The products are very useful for the synthesis of analogues of the gastrin receptor antagonist AG‐041R, spirooxindolyl β‐lactams, the oxindole‐derived side chain of Taxol, and natural product cytoxazone and aminopyrrolo[2,3‐b]indoline derivatives.

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

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

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

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. 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. 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. 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.

Effects and mechanisms of ceramide signaling pathway in gastrin-inhibited cell apoptosis of large intestinal cancer

Objective To investigate the effects and mechanisms of ceramide signaling pathway in gastrin-inhibited cell apoptosis of large intestinal cancer.Methods Gastrin group and proglumide group were divided into five different densities with concentration gradient of gastrin and proglumide being 6.25,12.50,25.00,50.00,100.00 mg/L and 8.00,16.00,32.00,64.00,128.00 mg/L,respectively.The changes of proliferation of the HT-29 cells were detected by methyl thiazol tetrazolium (MTT) assay,and the optimal concentrations of gastrin and proglumide were determined.The changes of apoptosis rate of HT-29 cells were detected by using flow cytometry.The mRNA expression levels of gastrin receptor/cholecystokinin-B receptor (CCK-BR),ceramide,p38,B lymphocytes/leukemia-2 (bcl-2) and bcl-2 associated X protein (bax) were detected by using reverse transcriptase-polymerase chain reaction (RT-PCR).The protein expression levels of bcl-2,bax and ceramide,and p38 phosphorylation levels were detected by using Western blotting.Results Gastrin could promote the proliferation of HT-29 cells,and the optimal concentration was 25 mg/L (F =31.36,P ＜ 0.05).Proglumide could significantly inhibit the proliferation of HT-29 cells stimulated by gastrin,and the optimal concentration was 32 mg/L (F =24.31,P ＜ 0.05).The apoptosis rate of the gastrin group was significantly lower than in the control group and the gastrin + proglumid group (q =4.23,4.06,P ＜0.05).The mRNA and protein expression of bax and the levels of phosphorylated ceramide protein and phosphorylated p38 protein in the gastrin group were significantly lower than in the control group,the proglumid group,and the gastrin + proglumid group (q =5.50,6.00,7.50; 6.50,7.00,8.50; 8.00,8.50,10.00; 4.60,4.90,6.53,P＜0.05).On the contrary,the mRNA and protein expression of bcl-2 in the gastrin group was significantly higher than in the control group,the proglumid group,and the gastrin + proglumid group (q =4.95,4.24,7.07; 7.07,6.36,7.78,P ＜ 0.05).Conclusion Gastrin could inhibit the apoptosis of HT-29 cells by down-regulate the phosphorylation levels of ceramide and p38 protein,thus up-regulate bcl-2 and down-regulate bax through the ceramide signaling transduction pathway,while the effect can be restrained by gastrin receptor antagonist proglumide. Key words: Colorectal cancer; Gastrin ; Ceramide ; p38 ; B lymphocytes/leukemia-2 ; Bcl-2 associated X protein

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

IntroductionAutoimmune 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.AimTo assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.MethodsWe 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.ResultsNetazepide 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 follow-up. 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.ConclusionThe 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.Trial RegistrationEuropean Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24 ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5

Abstract 554: Gastrin and D 1 Dopamine Receptor Interact to Induce Natriuresis and Diuresis

Oral NaCl produces a greater natriuresis and diuresis as compared with an intravenous infusion of the same amount of NaCl, indicating the existence of a gastro-renal axis. Gastrin is the major gastrointestinal hormone, which could be taken up by the renal proximal tubule (RPT) cells. We hypothesized that gastrin and dopamine receptors in the kidney interact to synergistically increase sodium excretion, an impaired interaction may be involved in the pathogenesis of hypertension. In Wistar-Kyoto (WKY) rats, infusion of gastrin induced a natriuresis and diuresis, which was abrogated in the presence of CI-988, a gastrin receptor (CCK B R) antagonist, as well as SCH 23390, a D 1 -like receptor antagonist. Similarly, the natriuretic and diuretic effect of fenoldopam, a D 1 -like receptor agonist, was blocked by SCH23390 , as well as CI-988. However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats (SHRs). The gastrin/D 1 -like receptor interaction was also confirmed in RPT cells. In RPT cells from WKY but not SHRs, stimulation of either D 1 -like receptor or gastrin receptor inhibited Na + -K + -ATPase activity, an effect that was blocked by the presence of SCH23390 or CI-988. In RPT cells from WKY and SHRs, CCK B R and D 1 R co-immunoprecipitated, which were increased after stimulation of either D 1 R or CCK B R receptor in WKY cells, but not in SHR cells. Stimulation of one receptor increased RPT cell membrane expression of another receptor. The data suggest that there is a synergism between CCK B R and D 1 -like receptor to increase sodium excretion. Aberrant interaction between the renal CCK B R and D 1 -like receptors (e.g., D 1 R) may play a role in the pathogenesis of hypertension.

The Gastrin Receptor Antagonist Netazepide (YF476) Prevents Oxyntic Mucosal Inflammation Induced byHelicobacter PyloriInfection in Mongolian Gerbils

Long-term Helicobacter pylori infection causes gastritis leading to hypergastrinemia and predisposes to gastric cancer. Our aim was to assess the role of gastrin in oxyntic mucosal inflammation in H.pylori-infected Mongolian gerbils by means of the gastrin receptor antagonist netazepide (YF476). We studied 60 gerbils for 18months and left five animals uninfected (control group), inoculated 55 with H.pylori, and treated 28 of the infected animals with netazepide (Hp+YF476 group). Twenty-seven infected animals were given no treatment (Hp group). We measured plasma gastrin and intraluminal pH. H.pylori detection and histologic evaluations of the stomach were carried out. All 55 inoculated animals were H.pylori positive at termination. Eighteen animals in the Hp group had gastritis. There was a threefold increase in mucosal thickness in the Hp group compared to the Hp+YF476 group, and a threefold increase in oxyntic neuroendocrine cells in the Hp group compared to the Hp+YF476 group (p<.05). All animals in the Hp+YF476 group had macro- and microscopically normal findings in the stomach. Plasma gastrin was higher in the Hp group than in the control group (172±16pmol/L vs 124±5pmol/L, p<.05) and highest in the Hp+YF476 group (530±36pmol/L). Intraluminal pH was higher in the Hp group than in the Hp+YF476 group (2.51 vs 2.30, p<.05). The gastrin antagonist netazepide prevents H.pylori-induced gastritis in Mongolian gerbils. Thus, gastrin has a key role in the inflammatory reaction of the gastric mucosa to H.pylori infection in this species.

Treatment of gastric carcinoids type 1 with the gastrin receptor antagonist netazepide (YF476) results in regression of tumours and normalisation of serum chromogranin A

Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers. To assess the effect of netazepide on type 1 GC. Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks. Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment. The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.