gastrins and oxmetidine

Gastric acid secretion was measured in six healthy volunteers following the intravenous administration (over 30 min.) of oxmetidine 200 mg, 400 mg and 800 mg in a randomized double blind trial for 12 hours. Gastric aspirates were fractionated into hourly aliquots and pH, volume, gastric acidity and gastric acid output were determined. Total gastric acid output over 12 hours was significantly reduced from 24.4 mmol/12 h (median) after placebo to 13.5 mmol/12 h, 11.8 mmol/12 h and 7.7 mmol/12 h after oxmetidine 200 mg, 400 mg and 800 mg respectively. An inhibition of at least 90% was achieved with all doses of oxmetidine and this lasted dose-dependently for 4 to 6 hours. A rise in pH to greater than 5 occurred during the 2nd or 3rd hour after dosing which lasted for 2-5 hours depending on the dose administered. Mean hourly pH was dose-dependently significantly higher for 4-6 hours following oxmetidine treatment than after placebo. A significant reduction in gastric acidity after oxmetidine infusion was also observed while the reduction in volume output calculated for 12 hours was not statistically significant. No significant rises in serum gastrin levels were observed with the oxmetidine doses used. Three out of the six subjects tested showed an increase in serum prolactin levels in response to the highest dose of oxmetidine but this was not statistically significant. The results of the present study have shown that the administration of 400 mg oxmetidine did not cause a longer pH elevation greater than 5 than 200 mg, while with 800 mg side effects were observed in one of the six subjects studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Gastric Acid; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Humans; Imidazoles; Injections, Intravenous; Male; Prolactin

The histamine H2-receptor antagonist SK&F 93479 induced gastric neuroendocrine (carcinoid) ECL-cell tumor formation in 6/34 male and 8/37 female rats treated for 22-24 months at 1,000 mg/kg/day po. Focal ECL-cell hyperplasia was present in 21/34 males and 15/37 females, with local infiltration through the muscularis mucosae in half these cases. No focal hyperplasias or carcinoids were present after 200 mg/kg/day po treatment. Investigative studies showed evidence for marked and sustained hypergastrinemia increasing on chronic dosing which was capable of restoring gastric acid secretion and pH to near control values. Using morphometric analysis of immunoperoxidase anti-chromogranin A stained sections, a dose-related and time-dependent neuroendocrine ECL-cell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 21-month mouse oncogenicity study showed no focal neuroendocrine cell hyperplasia or carcinoid tumor induction, but a diffuse neuroendocrine cell hyperplasia and an increase in multifocal glandular hyperplasia of the oxyntic mucosa was observed in mice treated with 1,000 mg/kg SK&F 93479 po. The morphological changes observed in both rat and mouse were considered to be secondary to the hypergastrinemia resulting from the pharmacological suppression of gastric acid secretion by SK&F 93479. These changes were also observed to a more marked degree following omeprazole treatment and were only slight following oxmetidine treatment in the rat.

Topics: Animals; Carcinogens; Carcinoid Tumor; Enterochromaffin Cells; Female; Gastric Acid; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Hydrogen-Ion Concentration; Hyperplasia; Imidazoles; Male; Mice; Omeprazole; Pyrimidinones; Rats; Stomach Neoplasms

The effect of 2-[2-(5-methyl-4-imidazolmethylthio)-ethyl-amino]-5-(3,4- methylendioxybenzyl)-4-pyrimidone dihydrochloride (oxmetidine) as continuous i.v. infusion over 11 1/2 h was tested with the doses of 12.5, 25 and 50 mg/h following an infusion of 200 mg over 30 min. In eight healthy male volunteers the parameters of gastric acid secretion were examined over 12 h as well as plasma oxmetidine and serum gastrin concentrations. Basal acid secretion was dose-dependently reduced from 53.1 mmol/12 h to minimally 3.2 mmol/12 h. A pH greater than or equal to 5 was reached for each volunteer under each dose, but even with the highest dose (50 mg/h) of oxmetidine a suppression of acid secretion up to the end of the 12-h experiment could not be observed.

Topics: Adult; Gastric Acid; Gastric Acidity Determination; Gastrins; Histamine H2 Antagonists; Humans; Imidazoles; Infusions, Parenteral; Male; Time Factors

The antisecretory potency of oxmetidine was compared with that of ranitidine for its action against gastric acid secretion induced by histamine and by 2-deoxy-D-glucose (2DG) in the conscious gastric-fistula dog. Oxmetidine, administered i.v. during histamine stimulation, was nearly as effective as ranitidine, with a similar duration of action, but it was about twice as potent as ranitidine against 2DG-stimulated acid secretion. In experiments with bombesin, both oxmetidine and ranitidine significantly decreased gastric acid secretion to a similar extent, without affecting plasma gastrin levels.

Topics: Animals; Bombesin; Deoxyglucose; Dogs; Gastric Acid; Gastric Mucosa; Gastrins; Histamine; Histamine H2 Antagonists; Imidazoles; Ranitidine; Stimulation, Chemical

It has been previously suggested that antral pH governs the density of antral G- and D-cells. Therefore, we investigated the effect of acid neutralization by an antacid (magaldrat; in vivo neutralization capacity of 144 mval/day) and the effect of suppression of gastric acid secretion by an H2-receptor blocker (oxmetidine, 400 mg/day) on the density of both cell types in healthy volunteers and duodenal ulcer patients. Four weeks after antacid treatment antral G-cell density decreased significantly in both groups, while antral D-cells decreased only in volunteers. Basal serum gastrin was not altered, whereas the integrated postprandial serum gastrin response and antral gastrin concentration was significantly reduced in volunteers but not in ulcer patients. None of the parameters investigated was changed by oxmetidine treatment. Considering the short-lasting effect on acid neutralization induced by the antacid dosage used in this study and the inability of oxmetidine treatment to influence volume densities and secretory activities of antral G- and D-cells it is concluded that mechanisms other than a change of antral pH may account for the results obtained during antacid treatment.

Topics: Adult; Aluminum Hydroxide; Antacids; Duodenal Ulcer; Female; Gastric Mucosa; Gastrins; Histamine H1 Antagonists; Humans; Imidazoles; Magnesium; Magnesium Hydroxide; Male; Middle Aged; Pyloric Antrum