ABslRAcrThe histamine H,-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 m@g/ 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 doserelated and time-dependent neuroendocrine ECLcell hyperplasia was correlated with the sustained elevated hypergastrinemia. A 2 l-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 m a g 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. INTRODUC~IONThe development of the histamine H,-receptor antagonist cimetidine represented a major therapeutic advance in the therapy of peptic ulcer disease.A second generation of more potent, longer-acting H,-antagonists to produce a more sustained blockade of parietal cell stimulation and the development of the irreversible H+/K+ ATPase inhibitor omeprazole demonstrated the ability of such compounds to induce previously unreported gastric enterochromaffin-like (ECL)-cell carcinoid tumors in the rat (1, 5, 13). Despite the long latent period for tumor development (>80 weeks), it has subsequently been possible to demonstrate early neuroendocrine cell hyperplasia (7, 18) with associated hypergastrinemia (9,18) and activation of histidine decarboxylase activity (1 8). Although shorter-acting H,-antagonists such as cimetidine, ranitidine, and oxmetidine have not induced ECL-cell focal hyperplasias or carcinoid tumors in 2-year rat oncogenicity studies, a lower degree of hypergastrinemia and diffuse ECLcell hyperplasia have been demonstrated in shorterterm studies (18). The present report details the short-and long-term gastrin changes associated with SK&F 93479 treatment in rodents, and relates these changes to the ,pharmacological effects of this and other carcinoid-inducing (omeprazole) and non-tumorigenic (oxmetidine) compounds. 93479 was synthesized by SK&F Research Ltd. and was prepared as the acidic aqueous solution of the -A, trihydrochloride salt. The pH of the dosing solution was adjusted to pH 4.0 on measurement days for gastric acid sec...
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