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Abstract：
Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials conducted across various malaria-endemic areas. A co-formulated combination of naphthoquine and azithromycin has also shown high clinical efficacy for malaria prophylaxis in Southeast Asia. Developing new combination therapies using naphthoquine will provide additional arsenal responses to the growing threat of artemisinin resistance. Furthermore, due to its long half-life, the possible interaction of naphthoquine with other drugs also needs attention. However, studies on its pharmacodynamic interactions with other drugs are still limited. In this study, the in vitro interactions of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen were evaluated in the asexual stage of Plasmodium falciparum 3D7. By using the combination index analysis and the SYBR Green I-based fluorescence assay, different interaction patterns of selected drugs with naphthoquine were revealed. Curcumin showed a slight but significant synergistic interaction with naphthoquine at lower effect levels, and no antagonism was observed across the full range of effect levels for all tested ratios. Atovaquone showed a potency decline when combined with naphthoquine. For ivermectin, a significant antagonism with naphthoquine was observed at a broad range of effect levels below 75% inhibition, although no significant interaction was observed at higher effect levels. Ketotifen interacted with naphthoquine similar to ivermectin, but significant antagonism was observed for only one tested ratio. These findings should be helpful to the development of new naphthoquine-based combination therapy and the clinically reasonable application of naphthoquine-containing therapies.
OBJECTIVE: Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.
OBJECTIVE: Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.
摘要：
萘酚喹是抗疟疾联合治疗的有希望的候选药物。它与青蒿素的组合在各个疟疾流行地区进行的临床试验中显示出优异的疗效。萘酚喹和阿奇霉素的共同配制组合在东南亚的疟疾预防中也显示出很高的临床疗效。使用萘酚喹开发新的联合疗法将为青蒿素耐药性日益增长的威胁提供额外的武器库反应。此外，由于其半衰期长，萘酚喹与其他药物的可能相互作用也需要注意。然而,关于其与其他药物的药效学相互作用的研究仍然有限。在这项研究中,萘酚喹与伊维菌素的体外相互作用，atovaquone,姜黄素,和酮替芬在恶性疟原虫3D7的无性阶段进行了评估。通过组合指数分析和基于SYBRGreenI的荧光测定法，揭示了所选药物与萘酚喹的不同相互作用模式。姜黄素与萘酚喹在较低的作用水平下表现出轻微但显著的协同作用，对于所有测试的比率，在整个作用水平范围内均未观察到拮抗作用。与萘酚喹联用时，阿托伐喹的效力下降。对于伊维菌素，在低于75%抑制的广泛作用水平下观察到萘酚喹的显著拮抗作用，尽管在较高的效应水平下没有观察到显著的相互作用。酮替芬与萘酚喹的相互作用类似于伊维菌素，但只有一个测试比例观察到显著的拮抗作用。这些发现应有助于开发新的以萘酚喹为基础的联合疗法以及含萘酚喹的疗法的临床合理应用。
目的：抗疟药物之间的药效学相互作用不仅对开发新的抗疟药物组合疗法至关重要，而且对临床合理使用抗疟药物也很重要。在这项研究中观察到的姜黄素和萘酚喹之间的显着协同作用表明了进一步开发新的抗疟药联合疗法的潜在价值。在萘酚喹存在下，阿托伐醌效力下降的发现提醒了在含有萘酚喹的治疗后，阿托伐醌-丙胍的治疗或预防失败的可能风险。观察到萘酚喹和伊维菌素之间的拮抗作用，引起了人们对含萘酚喹的疗法在部署了伊维菌素大规模药物管理的疟疾流行地区的适用性的关注。考虑到当一线青蒿素为基础的联合治疗无效时，阿托伐醌-丙胍作为主要替代药物的作用，以及在疟疾流行国家广泛实施伊维菌素大规模药物管理，上述发现对于涉及含萘酚喹治疗的抗疟药物的适当临床应用具有重要意义.
目的：抗疟药物之间的药效学相互作用不仅对开发新的抗疟药物组合疗法至关重要，而且对临床合理使用抗疟药物也很重要。在这项研究中观察到的姜黄素和萘酚喹之间的显着协同作用表明了进一步开发新的抗疟药联合疗法的潜在价值。在萘酚喹存在下，阿托伐醌效力下降的发现提醒了在含有萘酚喹的治疗后，阿托伐醌-丙胍的治疗或预防失败的可能风险。观察到萘酚喹和伊维菌素之间的拮抗作用，引起了人们对含萘酚喹的疗法在部署了伊维菌素大规模药物管理的疟疾流行地区的适用性的关注。考虑到当一线青蒿素为基础的联合治疗无效时，阿托伐醌-丙胍作为主要替代药物的作用，以及在疟疾流行国家广泛实施伊维菌素大规模药物管理，上述发现对于涉及含萘酚喹治疗的抗疟药物的适当临床应用具有重要意义.
