Effect of netazepide, a gastrin/CCK₂ receptor antagonist, on gastric acid secretion and rabeprazole‐induced hypergastrinaemia in healthy subjects

Abstract

AIMSTo compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia. METHODSThirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal. RESULTSAll treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia. CONCLUSIONSNetazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like (ECL) cells, which express gastrin/CCK2 receptors and release chromogranin A (CgA) into the circulation when stimulated by gastrin. • In non-clinical studies, acid suppression by a proton pump inhibitor (PPI) causes hypergastrinaemia which results in ECL cell growth and, after PPI withdrawal, rebound hyperacidity. Netazepide is an orally active, selective gastrin/CCK2 receptor antagonist, which suppresses acid production and prevents the trophic effects of PPI-induced hypergastrinaemia.• In healthy subjects, oral netazepide causes dose-dependent, persistent inhibition of gastric acid secretion, which leads to increased serum gastrin. WHAT THIS STUDY ADDS• In healthy subjects, netazepide and the PPI rabeprazole were similarly effective at suppressing pentagastrin-stimulated gastric acid secretion and increasing serum gastrin.• Rabeprazole increased plasma CgA, a sign of ECL cell hyperactivity, whereas netazepide reduced plasma CgA, a sign of ECL cell hypoactivity. Netazepide also prevented the increase in CgA resulting from rabeprazole-induced hyp...

Response: Randomised trial of the effect of a gastrin/CCK2 receptor antagonist on esomeprazole-induced hypergastrinaemia: evidence against rebound hyperacidity

“…Tapering the dose of a PPI rather than stopping it abruptly is based on the concept that abrupt withdrawal leads to rebound hyperacidity and dyspepsia secondary to persistent PPI-induced hypergastrinaemia, and that tapering minimises withdrawal symptoms [2]. Although we demonstrated neither rebound hyperacidity [3] nor persistent hypergastrinaemia [1] after abrupt cessation of PPI treatment in healthy subjects, we did not suggest that those negative findings should prompt any change in the clinical management of patients receiving a PPI. Rather, we stated that PPI withdrawal should be studied further in an adequately powered trial in patients on long-term PPI treatment.…”

Netazepide, a gastrin/cholecystokinin‐2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis

“…While patients were off‐treatment for a mean of 14 (range 8–19) months, the number of tumours, size of the largest tumour, circulating CgA and tumour biomarkers all increased again. Circulating CgA is a valid biomarker of ECL‐cell activity in patients with type 1 gastric NETs and in healthy subjects . Type 1 gastric NETs are derived from ECL cells, which are also the source of the increased circulating CgA in CAG patients .…”

“…In animal models [24] and healthy subjects [27], acid suppression by netazepide leads to a secondary increase in serum gastrin, which is 'harmless' because the gastrin/CCK 2 receptors are blocked. Netazepide did not increase serum gastrin further in the CAG patients, confirming that they had achlorhydria as a result of parietal-cell atrophy.…”

“…It caused dose‐dependent, persistent inhibition of pentagastrin‐induced gastric acid secretion and prevented the increase in plasma CgA – a biomarker of ECL‐cell hyperactivity – resulting from proton pump inhibitor‐induced hypergastrinaemia. Furthermore, netazepide reduced baseline plasma CgA – a sign of ECL‐cell hypoactivity .…”

Новая Группа Антисекреторных Средств — Калий-Конкурентные Ингибиторы Протонового Насоса

“…Âàaeíûìè ñâîéñòâàìè äàííîãî ñîåäèíåíèÿ ÿâëÿåòñÿ ïðåäîòâðàùåíèå ðàçâèòèÿ ãèïåðòðîôèè ýíòåðîõðîìàôôèíîïîäîáíûõ êëåòîê íà ôîíå ïðèìåíåíèÿ ÈÏÍ è ïîäàâëåíèå âîñïàëåíèÿ ñëèçèñòîé îáîëî÷êè aeåëóäêà ïðè èíôèöèðîâàíèè H. ðylori, ïðîäåìîíñòðèðîâàííîå íà ìîíãîëüñêèõ ïåñ÷àíêàõ [5]. Òàêaeå áûëî ïðîâåäåíî íåñêîëüêî êëè-íè÷åñêèõ èññëåäîâàíèé íåòàçåïèäà íà çäîðîâûõ äîáðîâîëüöàõ, â ðåçóëüòàòå êîòîðûõ áûëî ïðîäåìîíñòðèðîâàíî ñòîéêîå (áîëåå 24 ÷) ñíèaeåíèå áàçàëüíîé è ñòèìóëèðîâàííîé ïèùåé ñåêðåöèè ñîëÿíîé êèñëîòû, ñðàâíèìîå ïî ýôôåêòèâíîñòè ñ ïðèìåíåíèåì ðàáåïðàçîëà, è ïðåäîòâðàùåíèå ãèïåðòðîôèè âñëåäñòâèå ãèïåðãàñòðèíåìèè [4].  íàñòîÿùåå âðåìÿ íàòåçåïèä ïðîõîäèò êëèíè÷åñêèå èññëåäîâàíèÿ ïðè ãèïåðïëàçèÿõ ýíòåðîõðîìàôôèíîïîäîáíûõ êëåòîê [8].…”