Branquinho Renata Tupinambá, de Mello Carlos Geraldo Campos, Oliveira Maykon Tavares, Reis Levi Eduardo Soares, Vieira Paula Mello de Abreu, Saúde-Guimarães Dênia Antunes, Mosqueira Vanessa Carla Furtado, de Lana Marta
Programa de Pós-Graduação em Ciências Farmacêuticas, Escola de Farmácia, Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
Programa de Pós-Graduação em Ciências Biológicas, Núcleo de Pesquisa em Ciências Biológicas (NUPEB), Universidade Federal de Ouro Preto, Minas Gerais, Brazil.
Antimicrob Agents Chemother. 2020 Mar 24;64(4). doi: 10.1128/AAC.01937-19.
Chagas disease remains neglected, and current chemotherapeutics present severe limitations. Lychnopholide (LYC) at low doses loaded in polymeric poly(d,l-lactide)--polyethylene glycol (PLA-PEG) nanocapsules (LYC-PLA-PEG-NC) exhibits anti- efficacy in mice infected with a partially drug-resistant strain. This study reports the efficacy of LYC-PLA-PEG-NC at higher doses in mice infected with a strain resistant to benznidazole (BZ) and nifurtimox (NF) treated at both the acute phase (AP) and the chronic phase (CP) of infection by the oral route. Mice infected with the VL-10 strain were treated by the oral route with free LYC (12 mg/kg of body weight/day), LYC-PLA-PEG-NC (8 or 12 mg/kg/day), or BZ at 100 mg/kg/day or were not treated (controls). Treatment efficacy was assessed by hemoculture (HC), PCR, enzyme-linked immunosorbent assay (ELISA), heart tissue quantitative PCR (qPCR), and histopathology. According to classical cure criteria, treatment with LYC-PLA-PEG-NC at 12 mg/kg/day cured 75% (AP) and 88% (CP) of the animals, while at a dose of 8 mg/kg/day, 43% (AP) and 43% (CP) were cured, showing dose-dependent efficacy. The negative qPCR results for heart tissue and the absence of inflammation/fibrosis agreed with the negative results obtained by HC and PCR. Thus, the mice treated with the highest dose could be considered 100% cured, in spite of a low ELISA reactivity in some animals. No cure was observed in animals treated with free LYC or BZ or the controls. These results are exceptional in terms of experimental Chagas disease chemotherapy and provide evidence of the outstanding contribution of nanotechnology in mice infected with a strain totally resistant to BZ and NF at both phases of infection. Therefore, LYC-PLA-PEG-NC has great potential as a new treatment for Chagas disease and deserves further investigations in clinical trials.
恰加斯病仍然未得到足够重视，并且目前的化学疗法存在严重局限性。低剂量的lychnopholide（LYC）负载于聚（d，l-丙交酯）-聚乙二醇（PLA-PEG）聚合物纳米胶囊（LYC-PLA-PEG-NC）中，对感染部分耐药菌株的小鼠具有抗虫效果。本研究报告了高剂量的LYC-PLA-PEG-NC在感染对苯硝唑（BZ）和硝呋替莫（NF）耐药菌株的小鼠中，通过口服途径在感染急性期（AP）和慢性期（CP）进行治疗的效果。感染VL-10菌株的小鼠通过口服途径接受游离LYC（12毫克/千克体重/天）、LYC-PLA-PEG-NC（8或12毫克/千克/天）、100毫克/千克/天的BZ治疗，或不接受治疗（对照组）。通过血液培养（HC）、聚合酶链反应（PCR）、酶联免疫吸附测定（ELISA）、心脏组织定量聚合酶链反应（qPCR）和组织病理学评估治疗效果。根据经典治愈标准，12毫克/千克/天的LYC-PLA-PEG-NC治疗使75%（AP）和88%（CP）的动物治愈，而在8毫克/千克/天的剂量下，43%（AP）和43%（CP）的动物被治愈，显示出剂量依赖性疗效。心脏组织的qPCR阴性结果以及无炎症/纤维化与HC和PCR获得的阴性结果一致。因此，尽管在一些动物中ELISA反应性较低，但接受最高剂量治疗的小鼠可被视为100%治愈。在接受游离LYC或BZ治疗的动物或对照组中未观察到治愈情况。就实验性恰加斯病化疗而言，这些结果非常出色，并为纳米技术在感染对BZ和NF完全耐药菌株的小鼠感染的两个阶段中的杰出贡献提供了证据。因此，LYC-PLA-PEG-NC作为恰加斯病的新治疗方法具有巨大潜力，值得在临床试验中进一步研究。
