Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322-5600, USA.
Antimicrob Agents Chemother. 2010 Jan;54(1):126-33. doi: 10.1128/AAC.00933-09. Epub 2009 Nov 9.
Favipiravir (T-705 [6-fluoro-3-hydroxy-2-pyrazinecarboxamide]) and oseltamivir were combined to treat influenza virus A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), and A/Duck/MN/1525/81 (H5N1) infections. T-705 alone inhibited viruses in cell culture at 1.4 to 4.3 microM. Oseltamivir inhibited these three viruses in cells at 3.7, 0.02, and 0.16 microM and in neuraminidase assays at 0.94, 0.46, and 2.31 nM, respectively. Oral treatments were given twice daily to mice for 5 to 7 days starting, generally, 24 h after infection. Survival resulting from 5 days of oseltamivir treatment (0.1 and 0.3 mg/kg/day) was significantly better in combination with 20 mg/kg of body weight/day of T-705 against the H1N1 infection. Treatment of the H3N2 infection required 50 mg/kg/day of oseltamivir for 7 days to achieve 60% protection; 25 mg/kg/day was ineffective. T-705 was >or=70% protective at 50 to 100 mg/kg/day but inactive at 25 mg/kg/day. The combination of inhibitors (25 mg/kg/day each) increased survival to 90%. The H5N1 infection was not benefited by treatment with oseltamivir (<or=100 mg/kg/day for 7 days). T-705 was 30 to 70% protective at 25 to 100 mg/kg/day. Survival improved slightly with combination treatments. Increased activity was seen against H5N1 infection by starting treatments 2 h before infection. Oseltamivir was ineffective at <or=40 mg/kg/day. T-705 was 100% protective at 40 and 80 mg/kg/day and inactive at 20 mg/kg/day. Combining ineffective doses (20 mg/kg/day of T-705 and 10 to 40 mg/kg/day of oseltamivir) afforded 60 to 80% protection and improved body weights during infection. Thus, synergistic responses were achieved with low doses of T-705 combined with oseltamivir. These compounds may be viable candidates for combination treatment of human influenza infections.
联合使用法匹拉韦（T-705 [6-氟-3-羟基-2-吡嗪甲酰胺]）和奥司他韦治疗甲型流感病毒 A/NWS/33（H1N1）、A/Victoria/3/75（H3N2）和 A/Duck/MN/1525/81（H5N1）感染。T-705 单独作用时，在细胞培养物中的抑制浓度为 1.4 至 4.3 μM。奥司他韦在细胞中以 3.7、0.02 和 0.16 μM 的浓度以及以 0.94、0.46 和 2.31 nM 的浓度抑制这三种病毒在神经氨酸酶测定中的活性。感染后一般 24 小时开始，每天两次给予小鼠口服治疗，持续 5 至 7 天。奥司他韦治疗 5 天（0.1 和 0.3 mg/kg/天）与 T-705（20 mg/kg/体重/天）联合治疗可显著提高 H1N1 感染的存活率。治疗 H3N2 感染需要 7 天每天 50 mg/kg 的奥司他韦才能达到 60%的保护率；25 mg/kg/天无效。T-705 以 50 至 100 mg/kg/天的剂量具有 >或=70%的保护作用，但 25 mg/kg/天的剂量无效。抑制剂联合治疗（每天 25 mg/kg/天）可将存活率提高至 90%。奥司他韦治疗（7 天每天 100 mg/kg 以下）对 H5N1 感染无益处。T-705 以 25 至 100 mg/kg/天的剂量具有 30 至 70%的保护作用。联合治疗略有改善。在感染前 2 小时开始治疗，可增强对 H5N1 感染的活性。奥司他韦的有效剂量为 <或=40 mg/kg/天。T-705 以 40 和 80 mg/kg/天的剂量具有 100%的保护作用，以 20 mg/kg/天的剂量无效。联合使用无效剂量（20 mg/kg/天的 T-705 和 10 至 40 mg/kg/天的奥司他韦）可提供 60%至 80%的保护作用，并改善感染期间的体重。因此，低剂量 T-705 与奥司他韦联合使用可产生协同反应。这些化合物可能是治疗人类流感感染的联合治疗的候选药物。
