Chemical and Bioassay Techniques to Authenticate Quality of the Anti-Leishmanial Drug Miltefosine
Chemical and Bioassay Techniques to Authenticate Quality of the Anti-Leishmanial Drug Miltefosine
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DOI：
10.4269/ajtmh.14-0586
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发表时间：
2015-06-01
影响因子：
3.3
通讯作者：
Croft, Simon L.
中科院分区：
文献类型：
--
作者：
Kaur, Harparkash;Seifert, Karin;Croft, Simon L.
米替福新是一种有效的口服治疗内脏利什曼病（VL）的药物，于2005年5月被印度、尼泊尔和孟加拉国政府选择用于消除VL。然而，在孟加拉国的患者中报告了异常高的治疗失败率，给予米替福新仿制品（“Miltefos”，Popular Pharmaceuticals Ltd.）在2008年期间，领导世界卫生组织（世卫组织）采购该制剂进行质量检测。Miltefos（TM）胶囊的质子（H-1）和磷（P-31）核磁共振（NMR）分析没有给出Impavido（R）的峰，Impavido（R）是来自Aeterna Zentaris的质量有保证的VL治疗产品。胶囊的内容物产生了米替福新的预期峰（质子化母离子的m/z 408.33和碎片离子的m/z 183.99加上mtz 124.8），这在MiltefosTM胶囊中不存在。此外，使用体外杜氏利什曼原虫细胞内无鞭毛体-巨噬细胞模型进行测试，对于来自胶囊和米替福新标准品的提取物，分别产生2.55至4.06 μ g/mL和3.02至5.92 μ g/mL的EC 50值。在该测定中，即使在浓度高达100 μ g/mL时，也鉴定出Miltefos（TM）胶囊缺乏显著的抗利什曼原虫活性。Miltefos（TM）胶囊通过三种方法NMR和质谱分析和生物测定被归类为伪造的（不存在所述的活性药物成分）。
Miltefosine, an effective oral treatment of visceral leishmaniasis (VL), was selected in May 2005, by the governments of India, Nepal, and Bangladesh for the elimination of VL. However, abnormally high treatment failure rates reported in patients in Bangladesh, given a miltefosine generic product ("Miltefos", Popular Pharmaceuticals Ltd.) during 2008, led the World Health Organization (WHO) to procure this formulation for quality testing. Proton (H-1) and phosphorous (P-31) nuclear magnetic resonance (NMR) analyses of the Miltefos (TM) capsules did not give the peaks defined for Impavido (R) the quality assured VL treatment product from Aeterna Zentaris. Contents of capsules of Impavido (R) yielded expected peaks for miltefosine (m/z 408.33 for the protonated parent ion and m/z 183.99 plus mtz 124.8 the fragment ions) that were absent in the Miltefos (TM) capsules. Furthermore, testing using an in vitro Leishmania donovani intracellular amastigote-macrophage model, yielded EC50 values of between 2.55 and 4.06 mu g/mL and 3.02 to 5.92 mu g/mL for extracts from the Impavido (R) capsules and the miltefosine standard, respectively. Lack of significant anti-leishmanial activity of Miltefos (TM) capsules was identified in this assay even at concentrations up to 100 mu g/mL. Capsules of Miltefos (TM) were classified as falsified (absence of stated active pharmaceutical ingredient) by three methods NMR and mass spectrometry analysis and bioassay.