Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model
Efficacy of pyrvinium pamoate against Cryptosporidium parvum infection in vitro and in a neonatal mouse model
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DOI：
10.1128/aac.00207-08
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发表时间：
2008-09-01
影响因子：
4.9
通讯作者：
Sullivan, David J.
中科院分区：
文献类型：
--
作者：
Downey, Autumn S.;Chong, Curtis R.;Sullivan, David J.
对于免疫受损患者的隐孢子虫感染，目前还没有有效的药物治疗方法。在这里，我们研究了未被吸收的驱虫药帕莫酸吡喃对肠道原虫微小隐孢子虫生长的抑制作用。用碱性磷酸酶免疫法测定，吡喃对人肠上皮细胞HCT-8细胞生长抑制作用的浓度为354 nM。在同一试验中，711 mU M帕罗米星和27 mU M氯喹的抑制率均为50%。我们使用新生小鼠模型，在体内测定了帕莫酸吡喃的抗隐孢子虫活性。从感染后3d开始，治疗组小鼠按体重5 mg/kg或12.5 mg/kg/d灌胃，连续4~6d。感染9天后，处死小鼠，通过比较治疗组和未治疗组小鼠粪便涂片中的卵囊数量来确定药物疗效。用苏木精-伊红染色的组织学切片比较回盲肠区域滋养体感染的强度。我们观察到，与未治疗的对照组相比，接受吡喃治疗的小鼠感染强度降低了90%，同时组织病理学也显著降低。基于这些结果，丙氨酸吡酯是一种潜在的候选药物，用于治疗免疫功能正常和免疫功能低下的人的隐孢子虫病。
No effective approved drug therapy exists for Cryptosporidium infection of immunocompromised patients. Here we investigated the nonabsorbed anthelmintic drug pyrvinium pamoate for inhibition of the growth of the intestinal protozoan parasite Cryptosporidium parvum. The concentration of pyrvinium that effected 50% growth inhibition in human enterocytic HCT-8 cells by a quantitative alkaline phosphatase immunoassay was 354 nM. For comparison, in the same assay, 50% growth inhibition was obtained with 711 mu M paromomycin or 27 mu M chloroquine. We used a neonatal mouse model to measure the anti-Cryptosporidium activity of pyrvinium pamoate in vivo. Beginning 3 days after infection, pyrvinium at 5 or 12.5 mg/kg of body weight/day was administered to the treatment group mice for 4 or 6 consecutive days. Nine days after infection, the mice were sacrificed, and drug efficacy was determined by comparing the numbers of oocysts in the fecal smears of treated versus untreated mice. The intensities of trophozoite infection in the ileocecal intestinal regions were also compared using hematoxylin-and-eosin-stained histological slides. We observed a > 90% reduction in infection intensity in pyrvinium-treated mice relative to that in untreated controls, along with a substantial reduction in tissue pathology. Based on these results, pyrvinium pamoate is a potential drug candidate for the treatment of cryptosporidiosis in both immunocompetent and immunocompromised individuals.