体外和体内评估莫能菌素（AAD 1566）对人体肠道线虫感染的实验室模型的疗效。
In vitro and in vivo efficacy of Monepantel (AAD 1566) against laboratory models of human intestinal nematode infections.
机构信息
Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland.
出版信息
PLoS Negl Trop Dis. 2011 Dec;5(12):e1457. doi: 10.1371/journal.pntd.0001457. Epub 2011 Dec 27.
BACKGROUND
Few effective drugs are available for soil-transmitted helminthiases and drug resistance is of concern. In the present work, we tested the efficacy of the veterinary drug monepantel, a potential drug development candidate compared to standard drugs in vitro and in parasite-rodent models of relevance to human soil-transmitted helminthiases.
METHODOLOGY
A motility assay was used to assess the efficacy of monepantel, albendazole, levamisole, and pyrantel pamoate in vitro on third-stage larvae (L3) and adult worms of Ancylostoma ceylanicum, Necator americanus and Trichuris muris. Ancylostoma ceylanicum- or N. americanus-infected hamsters, T. muris- or Ascaris suum-infected mice, and Strongyloides ratti-infected rats were treated with single oral doses of monepantel or with one of the reference drugs.
PRINCIPAL FINDINGS
Monepantel showed excellent activity on A. ceylanicum adults (IC(50) = 1.7 µg/ml), a moderate effect on T. muris L3 (IC(50) = 78.7 µg/ml), whereas no effect was observed on A. ceylanicum L3, T. muris adults, and both stages of N. americanus. Of the standard drugs, levamisole showed the highest potency in vitro (IC(50) = 1.6 and 33.1 µg/ml on A. ceylanicum and T. muris L3, respectively). Complete elimination of worms was observed with monepantel (10 mg/kg) and albendazole (2.5 mg/kg) in A. ceylanicum-infected hamsters. In the N. americanus hamster model single 10 mg/kg oral doses of monepantel and albendazole resulted in worm burden reductions of 58.3% and 100%, respectively. Trichuris muris, S. ratti and A. suum were not affected by treatment with monepantel in vivo (following doses of 600 mg/kg, 32 mg/kg and 600 mg/kg, respectively). In contrast, worm burden reductions of 95.9% and 76.6% were observed following treatment of T. muris- and A. suum infected mice with levamisole (200 mg/kg) and albendazole (600 mg/kg), respectively.
CONCLUSIONS/SIGNIFICANCE: Monepantel reveals low or no activities against N. americanus, T. muris, S. ratti and A. suum in vivo, hence does not qualify as drug development candidate for human soil-transmitted helminthiases.
背景
目前针对土壤传播性蠕虫病，可用的有效药物寥寥无几，且药物耐药性令人担忧。本研究旨在对比标准药物，评估兽用药物莫能菌素在体外和与人类土壤传播性蠕虫病相关的寄生虫-啮齿动物模型中的疗效，将其作为一种有潜力的药物开发候选药物。
方法
使用运动性测定法评估莫能菌素、阿苯达唑、左旋咪唑和噻嘧啶在体外对第三期幼虫（L3）和Ancylostoma ceylanicum、Necator americanus 和 Trichuris muris 成虫的疗效。使用单次口服剂量的莫能菌素或一种参考药物对感染Ancylostoma ceylanicum 或 N. americanus 的仓鼠、感染 T. muris 或 Ascaris suum 的小鼠以及感染 Strongyloides ratti 的大鼠进行治疗。
主要发现
莫能菌素对 A. ceylanicum 成虫（IC50=1.7 µg/ml）具有极好的活性，对 T. muris L3 具有中等活性（IC50=78.7 µg/ml），而对 A. ceylanicum L3、T. muris 成虫和 N. americanus 的两个阶段均无作用。在标准药物中，左旋咪唑在体外的活性最高（IC50 分别为 1.6 和 33.1 µg/ml，对 A. ceylanicum 和 T. muris L3）。莫能菌素（10 mg/kg）和阿苯达唑（2.5 mg/kg）完全消除了感染 Ancylostoma ceylanicum 的仓鼠体内的蠕虫。在 N. americanus 仓鼠模型中，单次口服 10 mg/kg 莫能菌素和阿苯达唑可分别使蠕虫负荷减少 58.3%和 100%。莫能菌素（600 mg/kg、32 mg/kg 和 600 mg/kg 剂量）对感染 Trichuris muris、Strongyloides ratti 和 Ascaris suum 的大鼠无体内作用。相比之下，感染 Trichuris muris 和 Ascaris suum 的小鼠经左旋咪唑（200 mg/kg）和阿苯达唑（600 mg/kg）治疗后，蠕虫负荷分别减少了 95.9%和 76.6%。
结论/意义：莫能菌素在体内对 N. americanus、T. muris、S. ratti 和 A. suum 的活性低或无，因此不适合作为人类土壤传播性蠕虫病的药物开发候选药物。
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