Interference by antimalarial drugs with the in-vitro production of reactive nitrogen intermediates by murine macrophages.
The production of reactive oxygen intermediates (ROI) by host macrophages has long been recognized as an important defense mechanism against microorganisms. More recently, reactive nitrogen intermediates (RNI), also produced by activated macrophages, have been shown to be part of the host's first line of defense against malaria. In the present in-vitro study we have investigated the effects of antimalarial drugs on RNI production by murine macrophages stimulated by interferon-gamma (IFN-gamma) and/or malaria antigen, and on ROI production induced by phorbol myristate acetate. At concentrations exceeding the peak serum levels achieved with therapeutic dosages, chloroquine, in a dose-dependent manner, inhibited IFN-gamma- and malaria antigen-induced RNI production. Quinine, at a concentration of 10 mg/L also caused a significant reduction in IFN-gamma and malaria antigen-induced RNI synthesis; this concentration was well within the therapeutic range. High concentrations of artelinate significantly inhibited IFN-gamma-induced RNI production but clindamycin had no effect on RNI synthesis. In contrast, halofantrine, in concentrations attainable with therapeutic dosages, significantly enhanced IFN-gamma-induced RNI production. ROI production by murine macrophages was unaffected by the antimalarial drugs over the same concentration ranges. It remains to be determined whether these in-vitro effects of antimalarial drugs on RNI production also influence the clinical and parasitological response in patients with malaria.
Kremsner
P G
PG
Landesinstitut für Tropenmedizin, Berlin, Germany.
Neifer
S
S
Rasenack
T
T
Bienzle
U
U
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009573:Nitrites / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism*; D011803:Quinine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
D000962:Antimalarials; D009573:Nitrites; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D002738:Chloroquine; D011803:Quinine; D009584:Nitrogen