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Notes: Background: There are no published comparative studies on the effect of low-dose H2-antagonists on pentagastrin-stimulated gastric acid secretion. Methods: Twenty-four healthy subjects were dosed with either famotidine 10 mg, ranitidine 75 mg or placebo in a balanced three-period cross-over design. The subjects were studied in groups of 12, simultaneously, under identical controlled environmental conditions. Gastric juice was aspirated in 15-min aliquots during sub-maximal (0.6 μg . h/kg) intravenous pentagastrin stimulation in the third and fourth hours (early period) and the eighth and ninth hours (late period) after oral dosing. The hydrogen ion (H+) content of gastric juice was measured ex vivo, by titrating to pH 7 known volumes of gastric aspirate against 0.1 m sodium hydroxide, using a versatile microprocessor-controlled auto-titration unit. Gastric acid output during the period of interest was calculated by adding the hydrogen ion content of 15-min aliquots collected during that period. The geometric mean of the cumulative pentagastrin-stimulated gastric acid output during the early and late periods was determined for the subjects dosed with either famotidine, ranitidine or placebo. Comparisons were performed by ANOVA. Results: During the early period (2–4 h post-dose), when the subjects were given placebo, mean gastric acid output was 46.6 mmol, decreasing by 76% to 11.3 mmol (P〈0.001) when treated with famotidine and by 76% to 11.1 mmol (P〈0.001) when treated with ranitidine. During the late period (7–9 h post-dose), when the subjects were dosed with placebo, mean gastric acid output was 41.2 mmol, decreasing by 38% to 25.7 mmol (P〈0.001) when treated with famotidine and by 27% to 30.0 mmol (P=0.007) when treated with ranitidine. The difference between the inhibitory effects of famotidine and ranitidine on gastric acid output were non-significant during either period. Conclusions: Low-dose famotidine and ranitidine, intended for over-the-counter use, inhibit stimulated gastric acid secretion profoundly in the third and fourth hours after an oral dose. Modest effects are still detectable up to 9 h after dosing.