metiamide and Neutropenia

We studied the effect of the H2-receptor antagonists, cimetidine and metiamide, on in vitro myeloid colony formation by bone marrow cells from seven normal volunteers and two patients with a cimetidine-associated neutropenia. A cimetidine concentration of 500 microgram/ml produced 50% inhibition of normal granulocyte-macrophage colony formation, and 1000 microgram/ml of cimetidine completely suppressed proliferation. The inhibitory effect of metiamide occurred at lower concentrations: 50% inhibition at 250 microgram/ml and 95% inhibition at 350 microgram/ml. Cimetidine had a similar inhibitory effect on colony formation by recovery marrow from the two patients with cimetidine-associated neutropenia. Treatment of autologous and allogeneic marrows with patients' acute phase sera and cimetidine failed to show evidence of antibody-mediated suppression of granulopoiesis. Our results indicate that at sufficiently high concentrations, cimetidine and metiamide inhibit human bone marrow myeloid colony formation in vitro. These findings are consistent with the hypothesis that H2-receptor antagonists may produce neutropenia in a dose-related fashion by injury to granulocytic progenitor cells in vivo.

Topics: Adult; Aged; Agranulocytosis; Bone Marrow; Cells, Cultured; Cimetidine; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Female; Granulocytes; Guanidines; Hematopoiesis; Humans; Male; Metiamide; Middle Aged; Neutropenia

A new group of drugs, the histamine2 (H2)-receptor antagonists, act on receptors in the stomach to reduce acid secretion when this is stimulated by histamine, pentagastrin, the vagus nerve or food. The reduction in acid secretion is profound and may approach the degree of reduction brought about by gastric surgery. The H2-receptor antagonist metiamide, administered orally, has been used successfully in the treatment of duodenal ulcer and the Zollinger-Ellison syndrome, but it has been shown to cause agranulocytosis. Trials are in process with an analogue, cimetidine (Tagamet, SKF), which has a different chemical structure from metiamide and has not caused haematological changes in animals or man. These drugs offer the prospect of successful medical management of duodenal ulcer, while a study of their effects on H2-receptors elsewhere in the body may reveal other therapeutic benefits.

Topics: Depression, Chemical; Duodenal Ulcer; Gastric Juice; Histamine H1 Antagonists; Humans; Intestinal Absorption; Metiamide; Neutropenia; Receptors, Histamine; Zollinger-Ellison Syndrome