W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Baltimore Polytechnic Institute High School, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.00394-18. Print 2018 Sep.
Many previous and preclinical malaria drug studies have relied on low-parasite-number drug inhibition numerically compared to the untreated controls. In contrast, human malaria drug studies measure the high-parasite-density killing near 100 million/ml. Here we compared the single-dose pharmacodynamic properties of artesunate and the 4-aminoquinolines pyronaridine, chloroquine, and amodiaquine in a ANKA-green fluorescent protein GFP-luciferase-based murine malaria blood-stage model. Pyronaridine exhibited dose-dependent killing, achieving parasite reductions near 5 to 6 logs at 48 h, with complete cure at 10 mg/kg of body weight compared to artesunate, which exhibited a 48-h dose-dependent killing with a 2-log drop at the noncurative 250-mg/kg dose. Chloroquine, which was noncurative, and amodiaquine, which was partially curative, had nearly the same initial dose-independent killing, with a lag phase of minimal parasite reduction at all doses between 6 and 24 h, followed by a 2.5-log reduction at 48 h. In experiments with drug-treated, washed infected blood transfer to naive mice, chloroquine and amodiaquine showed fewer viable parasites at the 24-h transfer than at the 8-h transfer, measured by a prolonged return to parasitemia, despite a similar parasite log reduction at these time points, in contrast to the correlation of the parasite log reduction to viable parasites with artesunate and pyronaridine. Artesunate in combination with pyronaridine exhibited an initial parasite reduction similar to that achieved with pyronaridine, while with chloroquine or amodiaquine, the reduction was similar to that achieved with artesunate. Single-oral-dose pyronaridine was much more potent than artesunate, chloroquine, and amodiaquine during the initial decline in parasites and cure.
许多以前和临床前疟疾药物研究都依赖于低寄生虫数药物抑制数值与未处理对照相比。相比之下，人类疟疾药物研究测量接近 1 亿/ml 的高寄生虫密度杀伤。在这里，我们比较了青蒿琥酯和 4-氨基喹啉类药物咯萘啶、氯喹和阿莫地喹在基于 ANKA-绿色荧光蛋白 GFP-荧光素酶的鼠疟血液期模型中的单剂量药效特性。咯萘啶表现出剂量依赖性杀伤，在 48 小时内实现接近 5 到 6 个对数的寄生虫减少，在 10mg/kg 体重时完全治愈，而青蒿琥酯在 250mg/kg 非治愈剂量时表现出 48 小时剂量依赖性杀伤，下降 2 个对数。氯喹无疗效，阿莫地喹部分有效，初始无剂量依赖性杀伤几乎相同，在所有剂量下，在 6 至 24 小时之间，寄生虫减少的潜伏期非常短，然后在 48 小时时减少 2.5 个对数。在药物处理、洗涤感染血液转移到幼稚小鼠的实验中，氯喹和阿莫地喹在 24 小时转移时比在 8 小时转移时显示出更少的存活寄生虫，这是通过延长寄生虫血症的恢复来测量的，尽管在这些时间点，寄生虫的对数减少与青蒿琥酯和咯萘啶相似，但与青蒿琥酯和咯萘啶相比，寄生虫的对数减少与存活寄生虫相关。青蒿琥酯与咯萘啶联合应用时，最初的寄生虫减少与咯萘啶相似，而与氯喹或阿莫地喹联合应用时，减少与青蒿琥酯相似。单口服剂量的咯萘啶在寄生虫和治愈的最初下降期间比青蒿琥酯、氯喹和阿莫地喹更有效。
