Smee Donald F, Hurst Brett L, Wong Min-Hui, Bailey Kevin W, Morrey John D
Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 5600 Old Main Hill, Utah State University, Logan, UT 84322-5600, USA.
Antimicrob Agents Chemother. 2009 May;53(5):2120-8. doi: 10.1128/AAC.01012-08. Epub 2009 Mar 9.
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.
一种对金刚烷胺耐药的甲型流感病毒/鸭/明尼苏达/1525/81（H5N1）毒株是从低致病性北美野生型（对金刚烷胺敏感）病毒培育而来，用于研究细胞培养和小鼠感染的治疗方法。使用了金刚烷胺、奥司他韦（或细胞培养活性形式的奥司他韦羧酸盐）和利巴韦林的双重组合。在马-达二氏犬肾（MDCK）细胞培养中，金刚烷胺-奥司他韦羧酸盐和金刚烷胺-利巴韦林组合在一系列剂量范围内对野生型病毒显示出协同相互作用，但奥司他韦羧酸盐-利巴韦林组合则没有。奥司他韦羧酸盐-利巴韦林组合对金刚烷胺耐药病毒主要表现为相加相互作用。在针对耐药病毒的药物组合中加入金刚烷胺并不能提高活性。野生型和金刚烷胺耐药病毒通过鼻内接种对小鼠具有致死性。对于高达100mg/kg体重/天的金刚烷胺，无法治疗耐药病毒感染，而野生型病毒感染在病毒暴露前4小时开始，每天口服10mg/kg（效果较弱）至100mg/kg/天，分两次给药，持续5天，是可治疗的。药物组合研究表明，用金刚烷胺-奥司他韦或金刚烷胺-利巴韦林组合治疗金刚烷胺耐药病毒感染并不比单独使用奥司他韦或利巴韦林显著更好。相比之下，奥司他韦-利巴韦林（25mg/kg/天和75mg/kg/天组合）治疗可显著降低死亡率。与三种化合物的单一疗法相比，所有三种组合（金刚烷胺，10mg/kg/天与其他化合物20mg/kg/天或40mg/kg/天联合）均使野生型病毒感染的严重程度明显降低。结果表明，金刚烷胺与针对金刚烷胺耐药病毒的组合使用没有益处，但与针对金刚烷胺敏感病毒的组合使用有积极益处。
