Saraiva Victor B, Gibaldi Daniel, Previato José O, Mendonça-Previato Lucia, Bozza Marcelo T, Freire-De-Lima Célio G, Heise Norton
Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro-RJ, 21944-970, Brazil.
Antimicrob Agents Chemother. 2002 Nov;46(11):3472-7. doi: 10.1128/AAC.46.11.3472-3477.2002.
The increased resistance of the protozoan parasite Trypanosoma cruzi to nitro derivatives is one of the major problems for the successful treatment of Chagas' disease. In the present study, we have tested the effects of 1-O-hexadecylphosphocholine (miltefosine) against strains of T. cruzi that are partially resistant (strain Y) and highly resistant (strain Colombiana) to the drugs in clinical use. As expected, epimastigotes of strain Colombiana showed higher levels of resistance to benznidazole than those of strain Y. However, the level of resistance to miltefosine was the same for both strains. This alkylphospholipid was also extremely toxic against intracellular amastigotes of both strains. This ether-lipid analogue induced in a dose-dependent manner the production of tumor necrosis factor alpha and nitric oxide (NO) radicals by infected and noninfected macrophages, suggesting that miltefosine may activate macrophages in vitro. Nevertheless, the cytotoxic effect of miltefosine against intracellular amastigotes was independent of the amount of NO produced by the infected macrophages since the same dose-response curves for miltefosine were observed when the NO production was blocked by the NO synthase inhibitor N(G)-monomethyl-L-arginine monoacetate. Preliminary in vivo studies with BALB/c mice infected with strain Y indicated that oral miltefosine promoted survival and reduced the parasitemia to levels comparable to those observed when benznidazole was used. Four months after treatment, no parasites were detected in the blood or spleen tissue sections maintained in culture. Together, these results support the hypothesis that miltefosine may be used for the treatment of Chagas' disease, including cases caused by resistant strains of T. cruzi.
原生动物寄生虫克氏锥虫对硝基衍生物耐药性增加是恰加斯病成功治疗的主要问题之一。在本研究中，我们测试了1-O-十六烷基磷酰胆碱（米替福新）对临床使用药物部分耐药（Y株）和高度耐药（哥伦比亚株）的克氏锥虫菌株的作用。正如预期的那样，哥伦比亚株的前鞭毛体对苯硝唑的耐药水平高于Y株。然而，两株对米替福新的耐药水平相同。这种烷基磷脂对两株的细胞内无鞭毛体也极具毒性。这种醚脂类似物以剂量依赖的方式诱导感染和未感染的巨噬细胞产生肿瘤坏死因子α和一氧化氮（NO）自由基，表明米替福新可能在体外激活巨噬细胞。然而，米替福新对细胞内无鞭毛体的细胞毒性作用与感染巨噬细胞产生的NO量无关，因为当NO合酶抑制剂N(G)-单甲基-L-精氨酸单乙酸酯阻断NO产生时，观察到米替福新的剂量反应曲线相同。对感染Y株的BALB/c小鼠进行的初步体内研究表明，口服米替福新可提高生存率，并将寄生虫血症降低到与使用苯硝唑时观察到的水平相当。治疗四个月后，在培养的血液或脾脏组织切片中未检测到寄生虫。总之，这些结果支持以下假设：米替福新可用于治疗恰加斯病，包括由克氏锥虫耐药菌株引起的病例。
