title: Randomised trial of the effect of a gastrin/CCK2receptor antagonist on esomeprazole-induced hypergastrinaemia: evidence against rebound hyperacidity.
abstract: OBJECTIVE
  Hypergastrinaemia induced by proton pump inhibitor (PPI) therapy may cause ECL-cell and parietal-cell hyperplasia and rebound hyperacidity and dyspepsia after PPI withdrawal. The aim of the study was to assess the effect of different dosage-regimens of netazepide, a gastrin/CCK2receptor antagonist, on PPI-induced hypergastrinaemia and elevated chromogranin A (CgA).
  
  
  METHODS
  Six groups of eight healthy subjects participated in a randomised, double-blind study of esomeprazole 40 mg daily for 28 days, in combination with netazepide 1, 5 or 25 mg or placebo, daily, during the last 14 days of esomeprazole or during 14 days after treatment withdrawal. Fasting serum gastrin and plasma CgA were measured during treatment and after withdrawal, as biomarkers of acid suppression and ECL-cell activity, respectively. Dyspepsia was monitored throughout the study.
  
  
  RESULTS
  Esomeprazole increased gastrin and CgA. Netazepide increased gastrin, but not CgA, and inhibited dose dependently the CgA response to esomeprazole. Gastrin and CgA returned to baseline within 2-3 days of esomeprazole withdrawal; netazepide did not shorten that time. There was no rebound dyspepsia after esomeprazole withdrawal.
  
  
  CONCLUSIONS
  Esomeprazole and netazepide each increase gastrin, consistent with a secondary effect of gastric acid suppression, but by different mechanisms. Esomeprazole-induced hypergastrinaemia stimulates ECL cells and thereby increases CgA. Netazepide-induced hypergastrinaemia does not increase CgA, because netazepide blocks gastrin/CCK2receptors on ECL cells. Co-administration of netazepide 5 mg abolishes the effect of esomeprazole-induced hypergastrinaemia on ECL cells. The quick return to baseline of gastrin and CgA and absence of dyspepsia after esomeprazole withdrawal do not support the concept of rebound hyperacidity.
authors: Hammersmith Medicines Research, Cumberland Avenue, London, NW10 7EW, UK. mboyce@hmrlondon.com.
authors: Malcolm
authors: http://orcid.org/0000-0001-8807-612X
authors: M
authors: Boyce
authors: Hammersmith Medicines Research, Cumberland Avenue, London, NW10 7EW, UK.
authors: Frans
authors: F
authors: van den Berg
authors: Hammersmith Medicines Research, Cumberland Avenue, London, NW10 7EW, UK.
authors: Toni
authors: T
authors: Mitchell
authors: Hammersmith Medicines Research, Cumberland Avenue, London, NW10 7EW, UK.
authors: Kate
authors: K
authors: Darwin
authors: Hammersmith Medicines Research, Cumberland Avenue, London, NW10 7EW, UK.
authors: Steve
authors: S
authors: Warrington
mesh_terms: D000328:Adult; D000368:Aged; D000897:Anti-Ulcer Agents / Q000009:adverse effects*; D001570:Benzodiazepinones / Q000627:therapeutic use*; D053379:Chromogranin A / Q000097:blood; D004311:Double-Blind Method; D004415:Dyspepsia / Q000517:prevention & control; D064098:Esomeprazole / Q000009:adverse effects*; D005260:Female; D005745:Gastric Acidity Determination; D005755:Gastrins / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D054328:Proton Pump Inhibitors / Q000009:adverse effects*; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000897:Anti-Ulcer Agents; D001570:Benzodiazepinones; D053379:Chromogranin A; D005755:Gastrins; D010671:Phenylurea Compounds; D054328:Proton Pump Inhibitors; D043887:Receptor, Cholecystokinin B; C104428:YF 476; D064098:Esomeprazole
keywords: Chromogranin A; ECL cell; Esomeprazole; Gastric acid; Gastrin; Gastrin/CCK2 receptor antagonist; Netazepide