Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease.
Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease.
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DOI：
10.1128/aac.01909-17
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发表时间：
2018-04
影响因子：
4.9
通讯作者：
Hope W
中科院分区：
文献类型：
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作者：
Nixon GL;McEntee L;Johnson A;Farrington N;Whalley S;Livermore J;Natal C;Washbourn G;Bibby J;Berry N;Lestner J;Truong M;Owen A;Lalloo D;Charles I;Hope W
目前隐球菌脑膜炎的治疗选择受到毒性、全球供应和耐药性出现的限制。迫切需要开发在中枢神经系统内具有杀真菌作用并且优选可口服生物利用的其他抗真菌剂。苯并咪唑类药物具有广谱抗寄生虫活性，而且还具有体外抗真菌活性，包括新型隐球菌。杨森制药公司将氟苯达唑（苯并咪唑）重新配制为无定形固体药物纳米分散体，以开发一种口服生物药物，用于治疗盘尾丝虫病等被忽视的热带疾病。我们研究了氟苯达唑治疗隐球菌性脑膜炎的体外活性、构效关系以及体内外药效学。氟苯达唑对新型隐球菌具有有效的体外活性，根据欧洲抗菌药物敏感性测试委员会 (EUCAST) 方法，其众数 MIC 为 0.125 毫克/升。计算机模型提供了对氟苯达唑与隐球菌 β-微管蛋白结合的残基的深入了解。在隐球菌脑膜炎的中空纤维感染模型中，快速杀菌活性是明显的。固体药物纳米分散体在大脑中药物暴露较高的小鼠中具有口服生物利用度。与媒介物处理的对照组相比，口服最大剂量的氟苯达唑（12毫克/公斤体重/天）导致真菌负荷减少~2 log10CFU/g。氟苯达唑在兔子中具有口服生物利用度，但在脑脊液 (CSF) 或大脑中没有可量化的药物浓度，并且在 CSF 或大脑中没有显示出抗真菌活性。这些研究为苯并咪唑支架治疗隐球菌性脑膜炎的进一步研究和开发提供了依据。
Current therapeutic options for cryptococcal meningitis are limited by toxicity, global supply, and emergence of resistance. There is an urgent need to develop additional antifungal agents that are fungicidal within the central nervous system and preferably orally bioavailable. The benzimidazoles have broad-spectrum antiparasitic activity but also have in vitro antifungal activity that includes Cryptococcus neoformans. Flubendazole (a benzimidazole) has been reformulated by Janssen Pharmaceutica as an amorphous solid drug nanodispersion to develop an orally bioavailable medicine for the treatment of neglected tropical diseases such as onchocerciasis. We investigated the in vitro activity, the structure-activity-relationships, and both in vitro and in vivo pharmacodynamics of flubendazole for cryptococcal meningitis. Flubendazole has potent in vitro activity against Cryptococcus neoformans, with a modal MIC of 0.125 mg/liter using European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology. Computer models provided an insight into the residues responsible for the binding of flubendazole to cryptococcal β-tubulin. Rapid fungicidal activity was evident in a hollow-fiber infection model of cryptococcal meningitis. The solid drug nanodispersion was orally bioavailable in mice with higher drug exposure in the cerebrum. The maximal dose of flubendazole (12 mg/kg of body weight/day) orally resulted in an ∼2 log10CFU/g reduction in fungal burden compared with that in vehicle-treated controls. Flubendazole was orally bioavailable in rabbits, but there were no quantifiable drug concentrations in the cerebrospinal fluid (CSF) or cerebrum and no antifungal activity was demonstrated in either CSF or cerebrum. These studies provide evidence for the further study and development of the benzimidazole scaffold for the treatment of cryptococcal meningitis.