Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations.
Investigating antimalarial drug interactions of emetine dihydrochloride hydrate using CalcuSyn-based interactivity calculations.
复制标题
DOI：
10.1371/journal.pone.0173303
复制
发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Nirmalan NJ
中科院分区：
文献类型：
--
作者：
Matthews H;Deakin J;Rajab M;Idris-Usman M;Nirmalan NJ
广泛采用青蒿素类复方疗法有助于降低疟疾死亡率。联合治疗具有一系列优点，包括协同作用、毒性降低和延迟耐药性获得的发生。不幸的是，抗疟联合治疗受到具有不同靶向途径的有效药物库枯竭的限制。为了快速发现抗疟疾药物，我们以前曾采用药物重新定位来确定抗阿米巴药物，盐酸恩替卡韦水合物，作为重新定位用于抗疟疾的潜在候选药物。尽管与其抗阿米巴效力（ED 50 26-32 μ M）相比，其体外抗疟效力（ED 50 47 nM）增加了1000倍，但该化合物的实际使用受到剂量依赖性毒性（呕吐和心脏毒性）的限制。协同伴侣药物的鉴定将提供剂量减少的机会，从而增加治疗窗。缺乏可靠和标准化的方法，使抗疟药的协同潜力的体外定义是一个主要的缺点。在这里，我们使用等值线图和组合指数数据生成的CalcuSyn软件分析（Biosoft v2.1），以定义药物的相互作用，在一个客观的，自动化的方式。该方法基于Chou和Talalay提出的中位效应原理，最初使用已知的协同组合（阿托伐醌-氯胍）验证用于抗疟应用。该组合用于进一步理解SYBR绿色活力与药物在较高抑制水平下的细胞杀灭作用与细胞抑制作用之间的关系。我们在这里报告使用优化的Chou Talalay方法来定义盐酸恩替卡韦水合物和阿托伐醌之间的协同抗疟药物相互作用。新的发现提出了一种潜在的途径，利用这种负担得起的天然产品的纳摩尔抗疟功效。
The widespread introduction of artemisinin-based combination therapy has contributed to recent reductions in malaria mortality. Combination therapies have a range of advantages, including synergism, toxicity reduction, and delaying the onset of resistance acquisition. Unfortunately, antimalarial combination therapy is limited by the depleting repertoire of effective drugs with distinct target pathways. To fast-track antimalarial drug discovery, we have previously employed drug-repositioning to identify the anti-amoebic drug, emetine dihydrochloride hydrate, as a potential candidate for repositioned use against malaria. Despite its 1000-fold increase in in vitro antimalarial potency (ED50 47 nM) compared with its anti-amoebic potency (ED50 26–32 uM), practical use of the compound has been limited by dose-dependent toxicity (emesis and cardiotoxicity). Identification of a synergistic partner drug would present an opportunity for dose-reduction, thus increasing the therapeutic window. The lack of reliable and standardised methodology to enable the in vitro definition of synergistic potential for antimalarials is a major drawback. Here we use isobologram and combination-index data generated by CalcuSyn software analyses (Biosoft v2.1) to define drug interactivity in an objective, automated manner. The method, based on the median effect principle proposed by Chou and Talalay, was initially validated for antimalarial application using the known synergistic combination (atovaquone-proguanil). The combination was used to further understand the relationship between SYBR Green viability and cytocidal versus cytostatic effects of drugs at higher levels of inhibition. We report here the use of the optimised Chou Talalay method to define synergistic antimalarial drug interactivity between emetine dihydrochloride hydrate and atovaquone. The novel findings present a potential route to harness the nanomolar antimalarial efficacy of this affordable natural product.