抗利什曼原虫药物对利什曼原虫的体外活性依赖于宿主细胞。
In vitro activity of anti-leishmanial drugs against Leishmania donovani is host cell dependent.
机构信息
London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
出版信息
J Antimicrob Chemother. 2010 Mar;65(3):508-11. doi: 10.1093/jac/dkp500. Epub 2010 Jan 20.
OBJECTIVES
To evaluate the in vitro activity of anti-leishmanial drugs against intracellular Leishmania donovani amastigotes in different types of macrophages.
METHODS
Mouse peritoneal macrophages (PEMs), mouse bone marrow-derived macrophages (BMMPhi), human peripheral blood monocyte-derived macrophages (PBM Phi) and differentiated THP-1 cells were infected with L. donovani. Cultures were incubated with sodium stibogluconate, amphotericin B deoxycholate (Fungizone), miltefosine or paromomycin sulphate over six concentrations in 3-fold serial dilutions for 5 days. Analysis was based on percentage inhibition of infected macrophages and EC(50)/EC(90) values estimated using sigmoidal curve-fitting.
RESULTS
The rank order of drug activity was the same in the different macrophage populations: amphotericin B > miltefosine > sodium stibogluconate > paromomycin. However, significant (P < 0.05) differences were observed between populations. Amphotericin B was more active in PEMs and BMM Phi (EC(50) 0.02-0.06 microM) compared with PBM Phi and differentiated THP-1 cells (EC(50) 0.08-0.40 microM) and miltefosine was more active in PBM Phi (EC(50) 0.16-0.74 microM) compared with PEMs and BMM Phi (EC(50) 2.60-7.67 microM). Sodium stibogluconate displayed highest activity in PBM Phi (EC(50) 1.38-1.89 microg Sb(v)/mL), followed by PEMs (EC(50) 21.75-27.79 microg Sb(v)/mL) and BMM Phi and differentiated THP-1 cells (EC(50) 28.96-112.77 microg Sb(v)/mL). Paromomycin showed highest activity in PBM Phi (EC(50) 80.03-104.38 microM) and PEMs (EC(50) 75.42-201.63 microM).
CONCLUSIONS
In vitro activity of anti-leishmanial drugs is host cell dependent. This has implications for: (i) the evaluation of in vitro drug activity; (ii) the evaluation of drug susceptibility of clinical isolates; and (iii) the standardization of anti-leishmanial drug assays.
目的
评估抗利什曼原虫药物对不同类型巨噬细胞内利什曼原虫无鞭毛体的体外活性。
方法
用利什曼原虫感染小鼠腹腔巨噬细胞（PEM）、小鼠骨髓来源巨噬细胞（BMMPhi）、人外周血单核细胞衍生的巨噬细胞（PBM Phi）和分化的 THP-1 细胞。在 6 个浓度下，用 3 倍系列稀释法孵育 5 天，用钠葡庚糖酸盐、两性霉素 B 去氧胆酸盐（两性霉素 B）、米替福新或硫酸巴龙霉素。分析基于受感染巨噬细胞的百分比抑制率和使用 S 形曲线拟合估计的 EC（50）/EC（90）值。
结果
药物活性的等级顺序在不同的巨噬细胞群体中相同：两性霉素 B > 米替福新 > 钠葡庚糖酸盐 > 硫酸巴龙霉素。然而，不同群体之间存在显著差异（P < 0.05）。两性霉素 B 在 PEM 和 BMM Phi 中的活性更高（EC（50）0.02-0.06 μM），而在 PBM Phi 和分化的 THP-1 细胞中的活性较低（EC（50）0.08-0.40 μM），米替福新在 PBM Phi 中的活性更高（EC（50）0.16-0.74 μM），而在 PEM 和 BMM Phi 中的活性较低（EC（50）2.60-7.67 μM）。葡庚糖酸钠在 PBM Phi 中的活性最高（EC（50）1.38-1.89 μg Sb（v）/mL），其次是 PEM（EC（50）21.75-27.79 μg Sb（v）/mL）、BMM Phi 和分化的 THP-1 细胞（EC（50）28.96-112.77 μg Sb（v）/mL）。硫酸巴龙霉素在 PBM Phi 和 PEM 中的活性最高（EC（50）80.03-104.38 μM）和（EC（50）75.42-201.63 μM）。
结论
抗利什曼原虫药物的体外活性依赖于宿主细胞。这对以下方面有影响：（i）体外药物活性的评估；（ii）临床分离株药物敏感性的评估；（iii）抗利什曼原虫药物测定的标准化。
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