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Interference by antimalarial drugs with the in-vitro production of reactive nitrogen intermediates by murine
P G Kremsner1, S Neifer, T Rasenack
1Landesinstitut für Tropenmedizin, Berlin, Germany.
Abstract:
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.
Insights
Antimalarial drugs impact reactive nitrogen intermediates (RNI) production by macrophages, crucial for malaria defense. Some drugs inhibit RNI, while others enhance it, affecting immune response.
Area of Science:
- Immunology
- Pharmacology
- Infectious Diseases
Background:
- Macrophages produce reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI) as key defense mechanisms.
- Reactive nitrogen intermediates (RNI) are recognized as a crucial component of the host's initial defense against malaria.
Purpose of the Study:
- To investigate the in-vitro effects of various antimalarial drugs on RNI production by murine macrophages.
- To assess the impact of these drugs on ROI production induced by phorbol myristate acetate.
Main Methods:
- Murine macrophages were stimulated with interferon-gamma (IFN-gamma) and/or malaria antigen.
- Drug effects on RNI production were measured at concentrations relevant to therapeutic dosages.
- ROI production was induced by phorbol myristate acetate.
Main Results:
- Chloroquine and quinine significantly inhibited RNI production in a dose-dependent manner.
- Artelinate showed significant inhibition of IFN-gamma-induced RNI, while clindamycin had no effect.
- Halofantrine significantly enhanced IFN-gamma-induced RNI production; ROI production remained unaffected by all tested drugs.
Conclusions:
- Antimalarial drugs exhibit varied effects on macrophage-derived RNI production in vitro.
- These findings suggest a potential influence of antimalarial drugs on the host's immune response to malaria, warranting further clinical investigation.