Effects of Double Combinations of Amantadine, Oseltamivir, and Ribavirin on Influenza A (H5N1) Virus Infections in Cell Culture and in Mice
Effects of Double Combinations of Amantadine, Oseltamivir, and Ribavirin on Influenza A (H5N1) Virus Infections in Cell Culture and in Mice
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DOI：
10.1128/aac.01012-08
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发表时间：
2009-05-01
影响因子：
4.9
通讯作者：
Morrey, John D.
中科院分区：
文献类型：
--
作者：
Smee, Donald F.;Hurst, Brett L.;Morrey, John D.
金刚烷胺耐药流感病毒A/Duck/MN/1525/81(H5N1)是从低致病性的北美野生型(金刚烷胺敏感)病毒发展而来的，用于研究细胞培养和小鼠感染的治疗。使用金刚烷胺、奥司他韦(或细胞培养活性形式，羧酸奥司他韦)和利巴韦林的双重组合。在Madin-Darby犬肾(MDCK)细胞培养中，金刚烷胺-奥司他韦和金刚烷胺-利巴韦林在一定剂量范围内显示出抗野生型病毒的协同作用，而奥司他韦-利巴韦林则没有。抗金刚烷胺耐药病毒的奥司他韦-利巴韦林联合作用主要表现为相加作用。金刚烷胺在抗耐药病毒药物组合中的存在并没有改善活性。野生型和金刚烷胺抗性病毒经鼻内滴注对小鼠均有致死作用。金刚烷胺的剂量超过100 mg/kg体重/天不能治疗耐药病毒感染，而野生型病毒感染可以用10~100 mg/kg/天的口服剂量治疗，从病毒暴露前4h开始，每天两次，连续5天。药物联合研究表明，金刚烷胺-奥司他韦或金刚烷胺-利巴韦林联合治疗金刚烷胺耐药病毒感染的效果并不明显优于单独使用奥司他韦或利巴韦林。相比之下，奥司他韦-利巴韦林(25毫克/公斤/天和75毫克/公斤/天)治疗显著降低了死亡率。与单独使用这三种化合物相比，所有三种组合(金刚烷胺，10毫克/公斤/天与其他化合物以20或40毫克/公斤/天组合)在野生型病毒感染方面的严重程度都显著减轻。结果表明，金刚烷胺在联合抗金刚烷胺耐药病毒中缺乏益处，但在联合抗金刚烷胺敏感病毒中有积极的益处。
An amantadine-resistant influenza A/Duck/MN/1525/81 (H5N1) virus was developed from the low-pathogenic North American wild-type (amantadine-sensitive) virus for studying treatment of infections in cell culture and in mice. Double combinations of amantadine, oseltamivir (or the cell culture-active form, oseltamivir carboxylate), and ribavirin were used. Amantadine-oseltamivir carboxylate and amantadine-ribavirin combinations showed synergistic interactions over a range of doses against wild-type virus in Madin-Darby canine kidney (MDCK) cell culture, but oseltamivir carboxylate-ribavirin combinations did not. Primarily additive interactions were seen with oseltamivir carboxylate-ribavirin combinations against amantadine-resistant virus. The presence of amantadine in drug combinations against the resistant virus did not improve activity. The wild-type and amantadine-resistant viruses were lethal to mice by intranasal instillation. The resistant virus infection could not be treated with amantadine up to 100 mg/kg body weight/day, whereas the wild-type virus infection was treatable with oral doses of 10 (weakly effective) to 100 mg/kg/day administered twice a day for 5 days starting 4 h prior to virus exposure. Drug combination studies showed that treatment of the amantadine-resistant virus infection with amantadine-oseltamivir or amantadine-ribavirin combinations was not significantly better than using oseltamivir or ribavirin alone. In contrast, the oseltamivir-ribavirin (25-and 75-mg/kg/day combination) treatments produced significant reductions in mortality. The wild-type virus infection was markedly reduced in severity by all three combinations (amantadine, 10 mg/kg/day combined with the other compounds at 20 or 40 mg/kg/day) compared to monotherapy with the three compounds. Results indicate a lack of benefit of amantadine in combinations against amantadine-resistant virus, but positive benefits in combinations against amantadine-sensitive virus.