California Institute for Medical Research, San Jose, California.
Animal Hospital of Smithson Valley, Spring Branch, Texas.
Am J Trop Med Hyg. 2019 Aug;101(2):383-391. doi: 10.4269/ajtmh.19-0023.
is the etiologic agent of Chagas disease (CD), which can result in severe cardiomyopathy. is endemic to the Americas, and of particular importance in Latin America. In the United States and other non-endemic countries, rising case numbers have also been observed. The currently used drugs are benznidazole (BNZ) and nifurtimox, which have limited efficacy during chronic infection. We repurposed itraconazole (ICZ), originally an antifungal, in combination with amiodarone (AMD), an antiarrhythmic, with the goal of interfering with infection. Human pluripotent stem cells (hiPSCs) were differentiated into cardiomyocytes (hiPSC-CMs). Vero cells or hiPSC-CMs were infected with trypomastigotes of the II or I strain in the presence of ICZ and/or AMD. After 48 hours, cells were Giemsa stained, and infection and multiplication were evaluated microscopically. infection and multiplication were evalutated also by electron microscopy. BNZ was used as a reference compound. Cell metabolism in the presence of test substances was assessed. Itraconazole and AMD showed strain- and dose-dependent interference with infection and multiplication in Vero cells or hiPSC-CMs. Combinations of ICZ and AMD were more effective against than the single substances, or BNZ, without affecting host cell metabolism, and better preserving host cell integrity during infection. Our in vitro data in hiPSC-CMs suggest that a combination of ICZ and AMD might serve as a treatment option for CD in patients, but that different responses due to strain differences have to be taken into account.
是恰加斯病（CD）的病原体，可导致严重的心肌病。它在美洲流行，在拉丁美洲尤为重要。在美国和其他非流行国家，也观察到病例数量上升。目前使用的药物是苯硝唑（BNZ）和硝呋替莫，它们在慢性感染期间疗效有限。我们重新利用了伊曲康唑（ICZ），最初是一种抗真菌药，与胺碘酮（AMD）联合使用，目的是干扰感染。人多能干细胞（hiPSCs）分化为心肌细胞（hiPSC-CMs）。在存在 ICZ 和/或 AMD 的情况下，用 II 或 I 株的锥虫感染 Vero 细胞或 hiPSC-CMs。48 小时后，用吉姆萨染色，用显微镜评估感染和增殖情况。还通过电子显微镜评估感染和增殖。使用苯硝唑作为参考化合物。评估测试物质存在时的细胞代谢。伊曲康唑和胺碘酮显示出对 Vero 细胞或 hiPSC-CMs 中感染和增殖的菌株和剂量依赖性干扰。ICZ 和 AMD 的组合比单一物质或苯硝唑更有效，而不影响宿主细胞代谢，并在感染过程中更好地保持宿主细胞完整性。我们在 hiPSC-CMs 中的体外数据表明，ICZ 和 AMD 的组合可能是治疗患者 CD 的一种选择，但由于菌株差异，需要考虑不同的反应。
