The inhibitory effects of a positive inotropic quinolinone derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)- quinolinone (OPC-8212), on bone-marrow progenitor cells and peripheral lymphocytes.
3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (OPC-8212) is a quinolinone derivative with positive inotropic properties. In order to elucidate the effect of OPC-8212 on the haemopoietic system we studied its in vitro effect on bone-marrow progenitor cells (granulocyte/monocyte colony-forming units [CFU-GM] and erythroid burst-forming units [BFU-E]), on the proliferation and secretion of granulocyte/monocyte colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma) by peripheral lymphocytes, and on GM-CSF secretion by fibroblasts from healthy individuals. The dose-effect relations of OPC-8212 on CFU-GM proliferation and on lymphocytic GM-CSF secretion showed no effect at very low drug concentrations, with a threshold at the lower end of the therapeutic range and highly significant dose-dependent inhibition at concentrations above that threshold. BFU-E, peripheral lymphocyte proliferation and lymphocytic IFN-gamma secretion were depressed, although to a lesser extent, in a linear dose-dependent fashion. OPC-8212 did not affect GM-CSF secretion by one strain of fibroblasts but reduced it at higher concentrations in assays with another strain of cells. We conclude that direct toxic effects on bone-marrow progenitor cells, in combination with the inhibition of cytokines involved in the regulation of haemopoiesis in certain susceptible individuals, may be responsible for idiosyncratic reactions to OPC-8212.
Busch
F W
FW
Department of Internal Medicine, University of Tübingen, FRG.
Tillmann
A
A
Becker
E W
EW
Owsianowski
M
M
Berg
P A
PA
D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D002316:Cardiotonic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects*; D011719:Pyrazines; D011804:Quinolines / Q000633:toxicity*; D012867:Skin / Q000166:cytology
D002316:Cardiotonic Agents; D011719:Pyrazines; D011804:Quinolines; C041667:vesnarinone; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor