Repositioning: the fast track to new anti-malarial medicines?
Repositioning: the fast track to new anti-malarial medicines?
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DOI：
10.1186/1475-2875-13-143
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发表时间：
2014-04-14
期刊：
影响因子：
3
通讯作者：
Wells, Timothy
中科院分区：
文献类型：
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作者：
Lotharius, Julie;Gamo-Benito, Francisco Javier;Wells, Timothy
背景：现有药物的重新定位已被认为是开发新的抗疟疾药物的快速途径。葛兰素史克（GSK）、辉瑞（Pfizer）和阿斯利康（AZ）的化合物库包括在其他治疗领域中已经经历临床研究但未获得批准的药物，以及一组美国食品和药物管理局（FDA）批准的药物和其他生物活性物质，针对恶性疟原虫血液阶段进行测试。最初使用以下方法之一针对恶性疟原虫的红细胞共培养物测试分子以测量增殖抑制：SYBR（R）竖条染料DNA染色测定（3D 7、K1或NF 54菌株）; [H-3]次黄嘌呤放射性同位素掺入测定（3D 7和3D 7A菌株）;或4 '，6-二脒基-2-苯基吲哚（DAPI）DNA成像测定（3D 7和Dd 2菌株）。在审查可用的临床药代动力学和安全性数据后，在伯氏疟原虫四天试验或恶性疟原虫Pf 3D 7（0087/N9）huSCID“人源化”小鼠模型中体内测试具有低μ M活性和合适临床特征的所选化合物。在GSK和Pfizer集中包括的化合物中，3.8%（9/238）具有相关的体外抗疟疾活性，而AZ候选药物库中的6/100化合物具有活性。相比之下，约0.6%（24/3，800）的FDA批准的药物和其他生物活性物质具有活性。在评价现有临床数据后，在恶性疟原虫人源化小鼠模型中检测了4种体外活性研究药物：UK-112，214（PAF-H1抑制剂）、CEP-701（蛋白激酶抑制剂）、CEP-1347（蛋白激酶抑制剂）和PSC-833（p-糖蛋白抑制剂）。仅UK-112，214在体内显示出对恶性疟原虫的显著疗效，尽管在高剂量下（ED 90 131.3 mg/kg [95% CI 112.3，156.7]），并且在给药开始后96小时仍存在寄生虫血症。从AZ库的六个活性，两个化合物（AZ-1和AZ-3）是轻微有效的体内伯氏疟原虫model.Conclusions：重新定位现有的治疗疟疾是一个有吸引力的建议。鉴定了在μ M浓度下具有体外活性的化合物。然而，由于生物利用度差和/或安全性问题，在小鼠或人类中可能无法有效达到治疗浓度。鉴于抗疟疾药物在儿童中的广泛使用，其严格的安全要求使其成为重新定位治疗的一个具有挑战性的领域。
Background: Repositioning of existing drugs has been suggested as a fast track for developing new anti-malarial agents. The compound libraries of GlaxoSmithKline (GSK), Pfizer and AstraZeneca (AZ) comprising drugs that have undergone clinical studies in other therapeutic areas, but not achieved approval, and a set of US Food and Drug Administration (FDA)-approved drugs and other bio-actives were tested against Plasmodium falciparum blood stages.Methods: Molecules were tested initially against erythrocytic co-cultures of P. falciparum to measure proliferation inhibition using one of the following methods: SYBR (R)vertical bar dye DNA staining assay (3D7, K1 or NF54 strains); [H-3] hypoxanthine radioisotope incorporation assay (3D7 and 3D7A strain); or 4',6-diamidino-2-phenylindole (DAPI) DNA imaging assay (3D7 and Dd2 strains). After review of the available clinical pharmacokinetic and safety data, selected compounds with low mu M activity and a suitable clinical profile were tested in vivo either in a Plasmodium berghei four-day test or in the P. falciparum Pf3D7(0087/N9) huSCID 'humanized' mouse model.Results: Of the compounds included in the GSK and Pfizer sets, 3.8% (9/238) had relevant in vitro anti-malarial activity while 6/100 compounds from the AZ candidate drug library were active. In comparison, around 0.6% (24/3,800) of the FDA-approved drugs and other bio-actives were active. After evaluation of available clinical data, four investigational drugs, active in vitro were tested in the P. falciparum humanized mouse model: UK-112,214 (PAF-H1 inhibitor), CEP-701 (protein kinase inhibitor), CEP-1347 (protein kinase inhibitor), and PSC-833 (p-glycoprotein inhibitor). Only UK-112,214 showed significant efficacy against P. falciparum in vivo, although at high doses (ED90 131.3 mg/kg [95% CI 112.3, 156.7]), and parasitaemia was still present 96 hours after treatment commencement. Of the six actives from the AZ library, two compounds (AZ-1 and AZ-3) were marginally efficacious in vivo in a P. berghei model.Conclusions: Repositioning of existing therapeutics in malaria is an attractive proposal. Compounds active in vitro at mu M concentrations were identified. However, therapeutic concentrations may not be effectively achieved in mice or humans because of poor bio-availability and/or safety concerns. Stringent safety requirements for anti-malarial drugs, given their widespread use in children, make this a challenging area in which to reposition therapy.