Dow G, Smith B
60 Degrees Pharmaceuticals LLC, 1025 Connecticut Ave NW, Suite 1000, Washington DC, 20036, USA.
New Microbes New Infect. 2022 Feb 4;45:100964. doi: 10.1016/j.nmni.2022.100964. eCollection 2022 Jan.
Tafenoquine is active against a broad range of pathogens and accumulates extensively in the lung. We profiled the susceptibility of fungal pathogens to tafenoquine and
Minimum inhibitory concentrations [MICs] of medically important fungal pathogens were determined using conventional assays. The daily maximum tolerated dose [MTD] of tafenoquine was determined in neutropenic mice and the effect of two doses of tafenoquine [MTD and 0.5xMTD] on survival and fungal burden were assessed in and lung infections models.
Mean MICS against panels of yeasts and dimorphic/filamentous fungi were 4.5 and 8.3 ug/mL. The MTD of tafenoquine was 5 mg/kg/day. Against [MIC 16 ug/mL], tafenoquine did not increase survival or decrease fungal burden. Against , [MIC 4 ug/mL], tafenoquine decreased lung fungal burden [by 0.5 logs, < 0.05 at the MTD] in a dose-related manner. Survival in the high-dose [MTD] tafenoquine group was 30% whereas it was 0% in the vehicle group and in most legacy studies.
Tafenoquine exhibited broad spectrum activity against medically important yeasts and fungi and a dose-related antifungal effect in a lung infection model at clinically relevant doses.
他非诺喹对多种病原体具有活性，并在肺中大量蓄积。我们分析了真菌病原体对他非诺喹的敏感性。
使用传统检测方法测定医学上重要真菌病原体的最低抑菌浓度（MIC）。在中性粒细胞减少的小鼠中确定他非诺喹的每日最大耐受剂量（MTD），并在侵袭性肺曲霉病和肺念珠菌病感染模型中评估两剂他非诺喹（MTD和0.5×MTD）对生存和真菌负荷的影响。
针对酵母和双相/丝状真菌的平均MIC分别为4.5和8.3μg/mL。他非诺喹的MTD为5mg/kg/天。针对烟曲霉（MIC 16μg/mL），他非诺喹未提高生存率或降低真菌负荷。针对白色念珠菌（MIC 4μg/mL），他非诺喹以剂量相关的方式降低了肺部真菌负荷（在MTD时降低0.5个对数，P<0.05）。高剂量（MTD）他非诺喹组的生存率为30%，而载体组和大多数传统研究中的生存率为0%。
他非诺喹在临床相关剂量下对医学上重要的酵母和真菌表现出广谱活性，并在肺念珠菌病感染模型中具有剂量相关的抗真菌作用。
