pyrimidinones and Hyperplasia

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 time course and dose response of the neuroendocrine cell hyperplasia in the oxyntic mucosa of the rat was examined after treatment with the potent, long-acting H2-receptor antagonist SK&F 93479 at doses of 0 and 1000 mg/kg orally for 1, 3, 7, and 14 days and at doses of 0, 40, 200, and 1000 mg/kg orally for 1 and 6 months. The number of oxyntic neuroendocrine cells (chromogranin-positive) increased after 7 days of treatment. In the 1- and 6-month studies with doses of 1000 mg/kg, the grading for the number of oxyntic chromogranin-positive cells was 2.5 to 3 times the control levels, and they were distributed mostly throughout the mucosa, whereas at lower doses, which did not produce carcinoid tumours at 2 years, the neuroendocrine cells were distributed in the lower half of the mucosa with 1.5- to 2-fold increases in grades for cell numbers. Increases in cell numbers and cell distribution may be useful factors in the evaluation of the neuroendocrine cell hyperplasia found in, for example, the Zollinger-Ellison syndrome and chronic atrophic gastritis, in which hypergastrinaemia and fundic neuroendocrine cell hyperplasia are present.

Topics: Animals; Chromogranins; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Histamine H2 Antagonists; Hyperplasia; Male; Neurosecretory Systems; Pyrimidinones; Rats; Rats, Inbred Strains

The new long acting histamine H2-receptor antagonist was administered to rats at doses of 1000, 200 and 40 mg/kg body weight. Forestomach lesions of marked focal hyperplasia and hyperkeratosis were observed at a 48% incidence after 1 year daily gavage dosing with 1000 mg/kg. Lesions of this type were not seen in mid- and low-dose groups. The basal epithelium was convoluted and showed frequent mitotic figures. Two cases (4%) showed hyperplastic epithelium penetrating the muscularis mucosae. Recovery high-dose animals left untreated for a further 20-22 weeks were examined by endoscopy and necropsy and showed the hyperplasia and associated hyperkeratosis to be reversible. As penetration of the muscularis mucosae was only present in two cases at 1 year, the reversibility of this stage could not be assessed and the significance of the lesion will be determined by the results of a 2 year carcinogenicity study.

Topics: Animals; Epithelium; Female; Histamine H2 Antagonists; Hyperplasia; Male; Pyrimidinones; Rats; Rats, Inbred Strains; Stomach; Time Factors