Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.
Drugs for Neglected Diseases initiative, Geneva, Switzerland.
PLoS Negl Trop Dis. 2019 Jan 16;13(1):e0006320. doi: 10.1371/journal.pntd.0006320. eCollection 2019 Jan.
Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect.
氟苯达唑（FBZ）经肠胃外给药后对丝虫线虫具有高度疗效，并呈现出一种有前途的杀微丝蚴药物候选物，可用于消除盘尾丝虫病和其他丝虫病。在本研究中，研究人员在利什曼原虫感染的沙鼠模型中研究了一种新开发的可生物利用的无定形固体分散体（ASD）FBZ 口服制剂的疗效。FBZ 通过单次（40mg/kg）、重复（2、6 或 15mg/kg，持续 5 或 10 天）口服（OR）剂量或单次皮下（SC）注射（2 或 10mg/kg）给予慢性感染、微丝蚴阳性沙鼠。用 10mg/kg 的 5 次 SC 注射治疗的沙鼠作为阳性对照，未治疗的动物作为阴性对照。OR 剂量后，FBZ 迅速被吸收并清除，暴露量与剂量成正比增加。SC 给予的 FBZ 从注射部位缓慢释放，并且在治疗结束后 8 周的尸检时，血浆水平保持恒定。增加单次 SC 剂量导致暴露量低于剂量比例。在尸检时，所有接受 1x 或 5x 10mg/kg SC FBZ 的动物均清除了所有成虫，而 1x 2mg/kg SC 治疗使成虫负荷减少了 98%。10x 15mg/kg OR FBZ 使成虫负荷减少了 95%，而 1x 40mg/kg 和 5x 15mg/kg OR 使成虫负荷分别减少了 85%和 84%。在所有 SC 治疗方案中，微丝蚴血症在尸检时均完全清除，而所有口服 FBZ 治疗方案均以剂量和时间依赖性方式使微丝蚴血症减少>90%。相应地，来自雌性蠕虫的胚胎图显示 FBZ 剂量和时间依赖性地抑制了胚胎发生。对残留的雌性成虫的组织学分析表明，FBZ 已损坏了体壁、肠，最明显的是子宫和子宫内容物。本研究的结果表明，单次和重复 SC 注射以及重复口服 FBZ 具有极好的杀微丝蚴作用。
