Combined aerosolized Toll-like receptor ligands are an effective therapeutic agent against influenza pneumonia when co-administered with oseltamivir.
Combined aerosolized Toll-like receptor ligands are an effective therapeutic agent against influenza pneumonia when co-administered with oseltamivir.
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DOI：
10.1016/j.ejphar.2017.10.035
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发表时间：
2018-01-05
影响因子：
5
通讯作者：
Markesich D
中科院分区：
文献类型：
--
作者：
Leiva-Juarez MM;Kirkpatrick CT;Gilbert BE;Scott B;Tuvim MJ;Dickey BF;Evans SE;Markesich D
尽管制定了预防和治疗的疫苗接种计划和抗病毒药物，但流行性肺炎仍然是一种常见的、使人衰弱的病毒感染。神经氨酸酶抑制剂奥司他韦经常用于甲型流感病毒感染，但神经氨酸酶抑制剂耐药病毒的出现、短暂的治疗窗口期和相互竞争的诊断使其使用复杂化。pull -042是由toll样受体（TLR） 2/6和TLR 9的合成配体组成的临床阶段气溶胶药物。这种以宿主为靶点的先天免疫兴奋剂，在预防性地给予动物时，对细菌、真菌和病毒性肺炎（包括由流感引起的肺炎）具有广泛的保护作用。本研究评估了单独给药或与奥司他韦联合给药时，pul042对甲型流感肺炎的抗病毒治疗效果。小鼠在感染流感肺炎之前或之后的不同时间点接受pul042气雾剂、奥司他韦或两者同时治疗。多剂量吸入PUL-042气雾剂加口服奥司他韦治疗已确定的致命性甲型流感肺炎（bbb1ld100），比单独使用任何一种药物治疗的小鼠存活率更高。单剂pu -042也可以保护小鼠免受低病毒接种（约1 LD20）后的既定感染。雾化奥司他韦与pu -042气雾剂联合使用可进一步提高生存率。pu -042对多种流感病毒株的预防和治疗效果相似。体外流感对人HBEC3kt肺上皮细胞的攻击显示，pull -042诱导的抗感染保护作用与在体内观察到的效果相当。这些研究为保护易感人群免受甲型流感肺炎的手段提供了新的见解。
Influenza pneumonia remains a common and debilitating viral infection despite vaccination programs and antiviral agents developed for prophylaxis and treatment. The neuraminidase inhibitor oseltamivir is frequently prescribed for established influenza A virus infections, but the emergence of neuraminidase inhibitor resistant viruses, a brief therapeutic window and competing diagnoses complicate its use. PUL-042 is a clinical stage, aerosol drug comprised of synthetic ligands for Toll-like receptor (TLR) 2/6 and TLR 9. This host-targeted, innate immune stimulant broadly protects against bacterial, fungal and viral pneumonias, including those caused by influenza, when given prophylactically to animals. This study evaluated the therapeutic antiviral effects of PUL-042 against established influenza A pneumonia, when given alone or in combination with oseltamivir. Mice were treated with PUL-042 aerosol, oseltamivir or both at varying time points before or after challenge with influenza pneumonia. Treating established, otherwise lethal influenza A pneumonia (>1 LD100) with multiple inhaled doses of PUL-042 aerosol plus oral oseltamivir resulted in greater mouse survival than treatment with either drug alone. Single agent PUL-042 also protected mice against established infections following challenges with lower viral inocula (approximately 1 LD20). Aerosolized oseltamivir further enhanced survival when co-delivered with PUL-042 aerosol. The prophylactic and therapeutic benefits of PUL-042 were similar against multiple strains of influenza virus. In vitro influenza challenge of human HBEC3kt lung epithelial cells revealed PUL-042-induced protection against infection that was comparable to that observed in vivo. These studies offer new insights into means to protect susceptible populations against influenza A pneumonia.
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DOI：
10.1038/nri3665
发表时间：
2014-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.4049/jimmunol.1002122
发表时间：
2011-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Duggan JM;You D;Cleaver JO;Larson DT;Garza RJ;Guzmán Pruneda FA;Tuvim MJ;Zhang J;Dickey BF;Evans SE
通讯作者：
Evans SE
影响因子：
11.8
作者：
Stephenson, Iain;Democratis, Jane;Zambon, Maria
通讯作者：
Zambon, Maria
影响因子：
6.4
作者：
Gubareva, LV;Kaiser, L;Hayden, FG
通讯作者：
Hayden, FG
影响因子：
20.3
作者：
Leiva-Juarez, Miguel M.;Ware, Hayden H.;Evans, Scott E.
通讯作者：
Evans, Scott E.