Guiguemde W Armand, Hunt Nicholas H, Guo Jintao, Marciano Annael, Haynes Richard K, Clark Julie, Guy R Kiplin, Golenser Jacob
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Department of Pathology and Bosch Institute, The University of Sydney, Sydney, Australia.
Antimicrob Agents Chemother. 2014 Aug;58(8):4745-54. doi: 10.1128/AAC.01553-13. Epub 2014 Jun 9.
The decreasing effectiveness of antimalarial therapy due to drug resistance necessitates constant efforts to develop new drugs. Artemisinin derivatives are the most recent drugs that have been introduced and are considered the first line of treatment, but there are already indications of Plasmodium falciparum resistance to artemisinins. Consequently, drug combinations are recommended for prevention of the induction of resistance. The research here demonstrates the effects of novel combinations of the new artemisinin derivative, artemisone, a recently described 10-alkylamino artemisinin derivative with improved antimalarial activity and reduced neurotoxicity. We here investigate its ability to kill P. falciparum in a high-throughput in vitro assay and to protect mice against lethal cerebral malaria caused by Plasmodium berghei ANKA when used alone or in combination with established antimalarial drugs. Artemisone effects against P. falciparum in vitro were synergistic with halofantrine and mefloquine, and additive with 25 other drugs, including chloroquine and doxycycline. The concentrations of artemisone combinations that were toxic against THP-1 cells in vitro were much higher than their effective antimalarial concentration. Artemisone, mefloquine, chloroquine, or piperaquine given individually mostly protected mice against cerebral malaria caused by P. berghei ANKA but did not prevent parasite recrudescence. Combinations of artemisone with any of the other three drugs did completely cure most mice of malaria. The combination of artemisone and chloroquine decreased the ratio of proinflammatory (gamma interferon, tumor necrosis factor) to anti-inflammatory (interleukin 10 [IL-10], IL-4) cytokines in the plasma of P. berghei-infected mice. Thus, artemisone in combinations with other antimalarial drugs might have a dual action, both killing parasites and limiting the potentially deleterious host inflammatory response.
由于耐药性导致抗疟治疗效果下降，因此需要不断努力研发新药。青蒿素衍生物是最近引入的药物，被视为一线治疗药物，但已有恶性疟原虫对青蒿素耐药的迹象。因此，推荐联合用药以预防耐药性的产生。本研究展示了新型青蒿素衍生物蒿甲醚的组合效应，蒿甲醚是一种最近描述的具有改善抗疟活性和降低神经毒性的10-烷基氨基青蒿素衍生物。我们在此研究其在高通量体外试验中杀死恶性疟原虫的能力，以及单独使用或与已有的抗疟药物联合使用时保护小鼠免受伯氏疟原虫ANKA株所致致命性脑型疟疾的能力。蒿甲醚在体外对恶性疟原虫的作用与卤泛群和甲氟喹具有协同性，与包括氯喹和强力霉素在内的其他25种药物具有相加性。蒿甲醚组合在体外对THP-1细胞有毒性的浓度远高于其有效的抗疟浓度。单独给予蒿甲醚、甲氟喹、氯喹或哌喹大多能保护小鼠免受伯氏疟原虫ANKA株所致的脑型疟疾，但不能防止寄生虫复发。蒿甲醚与其他三种药物中的任何一种联合使用确实能使大多数小鼠完全治愈疟疾。蒿甲醚和氯喹的组合降低了感染伯氏疟原虫小鼠血浆中促炎（γ干扰素、肿瘤坏死因子）与抗炎（白细胞介素10 [IL-10]、IL-4）细胞因子的比例。因此，蒿甲醚与其他抗疟药物联合使用可能具有双重作用，既能杀死寄生虫，又能限制潜在有害的宿主炎症反应。
