metiamide and Agranulocytosis

Drug-induced agranulocytosis is relatively rare. It is a heterogeneous disorder in pathogenetic terms, not surprisingly in view of its idosyncratic nature. Indeed, one drug might cause agranulocytosis by different mechanisms in different patients. Recent investigations suggest that there are at least three mechanisms by which it can be produced, namely differences in drug pharmacokinetics, abnormal sensitivity of myeloid precursors, and adverse immune responses to drug administration. Genetic factors are important and could act via any of the above. Examples have been reported where one drug has been shown to cause damage at different levels of neutrophil development in one patient, and others where the drug acted at different sites in different patients. Any drug is potentially capable of toxicity and should be viewed with suspicion in the appropriate context. Drug-induced agranulocytosis is usually a self-limiting condition (provided toxic drugs are withdrawn) with complete resolution within two weeks. However, the mortality rate during the acute phase is high, and therefore prompt supportive therapy with isolation and broad-spectrum antibiotics for infection are mandatory during periods of severe neutropenia. The place of granulocyte transfusions in this disorder has not yet been established, and needs to be decided in each individual case.

Topics: Agranulocytosis; Autoantibodies; Blood Transfusion; Cimetidine; Female; Granulocytes; Hematopoiesis; Humans; Kinetics; Metiamide; Phenothiazines; Sweden

Topics: Agranulocytosis; Chemical Phenomena; Chemistry; Duodenal Ulcer; Gastric Juice; Guanidines; Histamine H1 Antagonists; Humans; Imidazoles; Metiamide; Peptic Ulcer; Receptors, Drug; Stomach Ulcer

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

Topics: Agranulocytosis; Female; Guanidines; Humans; Imidazoles; Metiamide; Middle Aged; Thiourea

Topics: Agranulocytosis; Bone Marrow; Celiac Disease; Diarrhea; Gastric Juice; Histamine; Humans; Male; Metiamide; Middle Aged; Secretory Rate; Thiourea; Urticaria Pigmentosa

Topics: Administration, Oral; Agranulocytosis; Guanidines; Histamine H1 Antagonists; Humans; Imidazoles; Infusions, Parenteral; Male; Metiamide; Middle Aged; Peptic Ulcer Hemorrhage; Thiourea