Gastric ECL-cell hyperplasia and carcinoids in rodents following chronic administration of H2-antagonists SK&F 93479 and oxmetidine and omeprazole. 1988

G R Betton, and C S Dormer, and T Wells, and P Pert, and C A Price, and P Buckley
Smith Kline & French Research Ltd., Welwyn, Hertfordshire, England.

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.

UI MeSH Term Description Entries
D006965 Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from HYPERTROPHY, which is an increase in bulk without an increase in the number of cells. Hyperplasias
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008297 Male Males
D009853 Omeprazole A 4-methoxy-3,5-dimethylpyridyl, 5-methoxybenzimidazole derivative of timoprazole that is used in the therapy of STOMACH ULCERS and ZOLLINGER-ELLISON SYNDROME. The drug inhibits an H(+)-K(+)-EXCHANGING ATPASE which is found in GASTRIC PARIETAL CELLS. H 168-68,Omeprazole Magnesium,Omeprazole Sodium,Prilosec,H 168 68,H 16868,Magnesium, Omeprazole,Sodium, Omeprazole
D011744 Pyrimidinones Heterocyclic compounds known as 2-pyrimidones (or 2-hydroxypyrimidines) and 4-pyrimidones (or 4-hydroxypyrimidines) with the general formula C4H4N2O. Pyrimidinone,Pyrimidone,Pyrimidones
D002273 Carcinogens Substances that increase the risk of NEOPLASMS in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. Carcinogen,Oncogen,Oncogens,Tumor Initiator,Tumor Initiators,Tumor Promoter,Tumor Promoters,Initiator, Tumor,Initiators, Tumor,Promoter, Tumor,Promoters, Tumor
D002276 Carcinoid Tumor A usually small, slow-growing neoplasm composed of islands of rounded, oxyphilic, or spindle-shaped cells of medium size, with moderately small vesicular nuclei, and covered by intact mucosa with a yellow cut surface. The tumor can occur anywhere in the gastrointestinal tract (and in the lungs and other sites); approximately 90% arise in the appendix. It is now established that these tumors are of neuroendocrine origin and derive from a primitive stem cell. (From Stedman, 25th ed & Holland et al., Cancer Medicine, 3d ed, p1182) Argentaffinoma,Carcinoid,Carcinoid, Goblet Cell,Argentaffinomas,Carcinoid Tumors,Carcinoids,Carcinoids, Goblet Cell,Goblet Cell Carcinoid,Goblet Cell Carcinoids,Tumor, Carcinoid,Tumors, Carcinoid
D004759 Enterochromaffin Cells A subtype of enteroendocrine cells found in the gastrointestinal MUCOSA, particularly in the glands of PYLORIC ANTRUM; DUODENUM; and ILEUM. These cells secrete mainly SEROTONIN and some neuropeptides. Their secretory granules stain readily with silver (argentaffin stain). Argentaffin Cells,5-HT-Containing Enterochromaffin Cells,Serotonin-Containing Enterochromaffin Cells,5 HT Containing Enterochromaffin Cells,5-HT-Containing Enterochromaffin Cell,Argentaffin Cell,Cell, Enterochromaffin,Cells, Enterochromaffin,Enterochromaffin Cell,Enterochromaffin Cell, 5-HT-Containing,Enterochromaffin Cell, Serotonin-Containing,Enterochromaffin Cells, 5-HT-Containing,Enterochromaffin Cells, Serotonin-Containing,Serotonin Containing Enterochromaffin Cells,Serotonin-Containing Enterochromaffin Cell
D005260 Female Females
D005744 Gastric Acid Hydrochloric acid present in GASTRIC JUICE. Hydrochloric Acid, Gastric,Acids, Gastric,Acids, Gastric Hydrochloric,Gastric Acids,Gastric Hydrochloric Acid,Gastric Hydrochloric Acids,Hydrochloric Acids, Gastric

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