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Ketoconazole, amphotericin B, and amphotericin B methyl ester: comparative in vitro and in vivo toxicological effects
Abstract:
We investigated a number of parameters for host defense after the in vitro addition of the antifungal agents ketoconazole, amphotericin B (AMB), and amphotericin B methyl ester (AME). Similar assays were repeated before and after patients received the former two drugs. Viability by trypan blue exclusion, adherence by nylon wool columns, chemotaxis by the under-agarose technique, phagocytosis and killing by chemiluminescence, colony counts, and acridine orange direct visualization were assayed. In striking contrast to AMB and AME, ketoconazole demonstrated no significant effect on neutrophils. Adherence in the presence of therapeutic plasma levels of AMB and AME was decreased (P less than or equal to 0.005) at low drug concentrations, whereas at higher concentrations, adherence was increased (P less than 0.001). The chemotactic responses of cells incubated with AMB and AME demonstrated marked suppression. Phagocytic capacity and killing were decreased (P less than or equal to 0.005) with AMB as compared with control assays and assays performed in the presence of ketoconazole and AME. However, no difference were observed between two patients who received AMB and two other treated with ketoconazole.
Insights
Ketoconazole showed no impact on neutrophil host defense, unlike amphotericin B (AMB) and amphotericin B methyl ester (AME). AMB and AME significantly impaired neutrophil adherence, chemotaxis, and killing of fungi.
Area of Science:
- Immunology
- Pharmacology
- Mycology
Background:
- Host defense mechanisms are crucial for combating fungal infections.
- Antifungal agents can potentially modulate immune cell functions.
- Understanding drug effects on neutrophils is vital for patient outcomes.
Purpose of the Study:
- To evaluate the impact of ketoconazole, amphotericin B (AMB), and amphotericin B methyl ester (AME) on neutrophil functions.
- To compare the in vitro and in vivo effects of these antifungal agents on host defense parameters.
- To assess the influence of therapeutic drug levels on neutrophil adherence, chemotaxis, and phagocytic capacity.
Main Methods:
- In vitro assays were performed using neutrophils incubated with ketoconazole, AMB, and AME.
- Neutrophil viability, adherence, chemotaxis, and phagocytosis/killing were measured.
- Assays were repeated in patients receiving ketoconazole or AMB.
- Techniques included trypan blue exclusion, nylon wool adherence, under-agarose chemotaxis, chemiluminescence, colony counts, and acridine orange staining.
Main Results:
- Ketoconazole had no significant effect on neutrophil functions.
- AMB and AME decreased neutrophil adherence at low concentrations but increased it at high concentrations.
- AMB and AME markedly suppressed neutrophil chemotaxis.
- Phagocytic capacity and fungal killing were reduced by AMB compared to controls and other agents.
- No significant differences in host defense were observed between patients treated with AMB and ketoconazole.
Conclusions:
- Ketoconazole does not impair neutrophil-mediated host defense.
- AMB and AME significantly inhibit key neutrophil functions, potentially impacting the immune response to fungal infections.
- Further research is needed to fully elucidate the clinical implications of these findings.