title: Effect of repeated doses of netazepide, a gastrin receptor antagonist, omeprazole and placebo on 24 h gastric acidity and gastrin in healthy subjects.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: Hammersmith Medicines Research, Central Middlesex Hospital, London, UK.
authors: Malcolm
authors: M
authors: Boyce
authors: Steve
authors: S
authors: Warrington
mesh_terms: D000328:Adult; D001570:Benzodiazepinones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D005260:Female; D005745:Gastric Acidity Determination; D005755:Gastrins / Q000097:blood*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D009853:Omeprazole / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D013997:Time Factors; D055815:Young Adult
chemical_list: D001570:Benzodiazepinones; D005755:Gastrins; D010671:Phenylurea Compounds; D054328:Proton Pump Inhibitors; D043887:Receptor, Cholecystokinin B; C104428:YF 476; D009853:Omeprazole
keywords: gastric pH; gastrin receptor antagonist; netazepide (YF476); plasma gastrin