Comparison of Efficacies of RWJ-270201, Zanamivir, and Oseltamivir against H5N1, H9N2, and Other Avian Influenza Viruses

The orally administered neuraminidase (NA) inhibitor RWJ-270201 was tested in parallel with zanamivir and oseltamivir against a panel of avian influenza viruses for inhibition of NA activity and replication in tissue culture. The agents were then tested for protection of mice against lethal H5N1 and H9N2 virus infection. In vitro, RWJ-270201 was highly effective against all nine NA subtypes. NA inhibition by RWJ-270201 (50% inhibitory concentration, 0.9 to 4.3 nM) was superior to that by zanamivir and oseltamivir carboxylate. RWJ-270201 inhibited the replication of avian influenza viruses of both Eurasian and American lineages in MDCK cells (50% effective concentration, 0.5 to 11.8 μM). Mice given 10 mg of RWJ-270201 per kg of body weight per day were completely protected against lethal challenge with influenza A/Hong Kong/156/97 (H5N1) and A/quail/Hong Kong/G1/97 (H9N2) viruses. Both RWJ-270201 and oseltamivir significantly reduced virus titers in mouse lungs at daily dosages of 1.0 and 10 mg/kg and prevented the spread of virus to the brain. When treatment began 48 h after exposure to H5N1 virus, 10 mg of RWJ-270201/kg/day protected 50% of mice from death. These results suggest that RWJ-270201 is at least as effective as either zanamivir or oseltamivir against avian influenza viruses and may be of potential clinical use for treatment of emerging influenza viruses that may be transmitted from birds to humans.

本研究将口服给药的神经氨酸酶（neuraminidase，NA）抑制剂RWJ-270201与扎那米韦（zanamivir）、奥司他韦（oseltamivir）平行对照，针对一组禽流感病毒株，评估其对组织培养中NA活性及病毒复制的抑制效果。随后，研究人员对上述受试药物开展小鼠致死性H5N1、H9N2病毒感染的防护实验。体外实验中，RWJ-270201对全部9种NA亚型均展现出强效抑制活性，其NA抑制活性（半数抑制浓度为0.9~4.3 nM）优于扎那米韦与奥司他韦羧酸盐（oseltamivir carboxylate）。RWJ-270201可在犬肾细胞（MDCK）中抑制欧亚谱系与美洲谱系禽流感病毒的复制，其半数有效浓度为0.5~11.8 μM。每日以10 mg/kg体重的剂量给予RWJ-270201的小鼠，可完全抵御甲型流感病毒A/Hong Kong/156/97（H5N1）及A/quail/Hong Kong/G1/97（H9N2）的致死性攻毒。当给药剂量为每日1.0和10 mg/kg时，RWJ-270201与奥司他韦均可显著降低小鼠肺部的病毒滴度，并阻断病毒向脑部的播散。若在暴露于H5N1病毒48小时后开始给药，每日10 mg/kg的RWJ-270201可使50%的小鼠免于死亡。上述实验结果表明，RWJ-270201在抗禽流感病毒方面的疗效至少不逊于扎那米韦或奥司他韦，有望在临床中用于治疗可能由禽传染人类的新型流感病毒。