Combination therapy using drugs with different mechanisms of action is the current state of the art in antimalarial treatment. However, except for artemisinin-based combination therapies, only a few other combinations are now available. Increasing concern regarding the emergence and spread of artemisinin resistance in Plasmodium falciparum has led to a need for the development of new antimalarials. Moreover, the efficacy of current available chemoprophylaxis is compromised by drug resistance and noncompliance due to intolerable adverse effects or complicated dosing regimens. Therefore, new antimalarials that are more effective, safer, and more convenient are also urgently needed for malaria chemoprophylaxis. In this study, we assessed the combination of azithromycin and naphthoquine in animal malaria models. A dose-dependent interaction was observed in Peters’ 4-day suppressive test on P. berghei K173-infected mice. Moreover, at inhibition levels of ≥90%, synergistic effects were found for combinations at various ratios. At an optimal dose ratio of 1:1, the combination of azithromycin and naphthoquine acted synergistically even by 4 weeks after the first dose and provided a more effective and sustained prophylaxis than did naphthoquine alone in blood-stage P. berghei K173 and P. cynomolgi bastianelli L challenge models. The ability of the combination to delay and slow down resistance development in P. berghei K173 was also shown. These results showed clear evidence for the benefit of the combination therapy with azithromycin and naphthoquine in animal malaria models, providing some insight for further development of this therapy for malaria treatment and prophylaxis.

中文翻译：

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在动物疟疾模型中评估阿奇霉素和萘喹的组合。

使用具有不同作用机理的药物的联合疗法是抗疟疾治疗的最新技术。但是，除了基于青蒿素的联合疗法外，现在只有几种其他组合可用。对恶性疟原虫中青蒿素耐药性的出现和扩散的关注日益增加导致需要开发新的抗疟药。此外，由于无法忍受的不良反应或复杂的给药方案，药物耐药性和不合规性损害了目前可用的化学预防的功效。因此，迫切需要更有效，更安全，更方便的新型抗疟药来进行疟疾的化学预防。在这项研究中，我们在动物疟疾模型中评估了阿奇霉素和萘喹的组合。在彼得斯对伯氏疟原虫的4天抑制试验中观察到剂量依赖性相互作用K173感染的小鼠。此外，在≥90％的抑制水平下，发现各种比例组合的协同作用。在最佳剂量比为1：1时，阿奇霉素和萘喹的组合甚至在首剂后4周就具有协同作用，并且比单独的萘喹在血阶段伯氏疟原虫K173和食蟹猴 疟原虫中具有更有效和持续的预防作用bastianelli L挑战模型。该组合延迟和减缓伯氏疟原虫抗药性发展的能力还显示了K173。这些结果显示了阿奇霉素和萘喹联合治疗在动物疟疾模型中的益处的明确证据，为进一步开发这种治疗疟疾和预防疟疾的方法提供了一些见识。