Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate.
Drug repositioning as a route to anti-malarial drug discovery: preliminary investigation of the in vitro anti-malarial efficacy of emetine dihydrochloride hydrate.
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DOI：
10.1186/1475-2875-12-359
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发表时间：
2013-10-09
期刊：
影响因子：
3
通讯作者：
Nirmalan N
中科院分区：
文献类型：
--
作者：
Matthews H;Usman-Idris M;Khan F;Read M;Nirmalan N
药物再利用或重新定位是指将现有药物用于其最初用途以外的疾病。对于像疟疾这样迫切需要活性候选药物的疾病，该战略提供了一条大大缩短传统药物开发管道的途径。最近对恶性疟原虫的专利过期药物库进行了初步的高通量筛选。本研究报告了这些研究中报告的选定化合物的系统和客观的进一步询问，以使其重新定位为新的独立抗疟疾药物或组合伙伴。采用SYBR绿色流式细胞术和微量滴定板法对体外培养的恶性疟原虫K1株进行药物敏感性监测。采用先前描述的固定比例方法来研究药物相互作用。盐酸依美汀水合物是一种先前用于肠道和组织阿米巴病的抗原生动物药物，在恶性疟原虫的多药耐药K1菌株中显示出强效抑制特性（IC 50剂量约为47 nM）。双氢青蒿素与盐酸恩替卡韦对恶性疟原虫K1株的半数抑制浓度（∑ FIC 50，90）在0.88 ~ 1.48之间。这些结果证明了将盐酸依米隆水合物作为一种潜在的独立抗疟疾药物的进一步研究。在测试的固定药物比例中，药物与当前一线双氢青蒿素之间的相互作用范围从相加到轻度拮抗。
Drug repurposing or repositioning refers to the usage of existing drugs in diseases other than those it was originally used for. For diseases like malaria, where there is an urgent need for active drug candidates, the strategy offers a route to significantly shorten the traditional drug development pipelines. Preliminary high-throughput screens on patent expired drug libraries have recently been carried out for Plasmodium falciparum. This study reports the systematic and objective further interrogation of selected compounds reported in these studies, to enable their repositioning as novel stand-alone anti-malarials or as combinatorial partners. SYBR Green flow cytometry and micro-titre plate assays optimized in the laboratory were used to monitor drug susceptibility of in vitro cultures of P. falciparum K1 parasite strains. Previously described fixed-ratio methods were adopted to investigate drug interactions. Emetine dihydrochloride hydrate, an anti-protozoal drug previously used for intestinal and tissue amoebiasis was shown to have potent inhibitory properties (IC50 doses of ~ 47nM) in the multidrug resistant K1 strain of P. falciparum. The sum 50% fractional inhibitory concentration (∑FIC50, 90) of the interaction of emetine dihydrochloride hydrate and dihydroartemisinin against the K1 strains of P. falciparum ranged from 0.88-1.48. The results warrant further investigation of emetine dihydrochloride hydrate as a potential stand-alone anti-malarial option. The interaction between the drug and the current front line dihydroartemisinin ranged from additive to mildly antagonistic in the fixed drug ratios tested.
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