Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
Eur J Pharmacol. 2018 Jan 5;818:191-197. doi: 10.1016/j.ejphar.2017.10.035. Epub 2017 Oct 21.
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 LD) 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 LD). 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.
尽管已经开发出疫苗接种计划和抗病毒药物用于预防和治疗，但流感肺炎仍然是一种常见且使人虚弱的病毒感染。神经氨酸酶抑制剂奥司他韦常用于治疗已确诊的甲型流感病毒感染，但神经氨酸酶抑制剂耐药病毒的出现、治疗窗口期短以及其他竞争性诊断使得其应用变得复杂。PUL-042 是一种处于临床阶段的气溶胶药物，由 Toll 样受体 (TLR) 2/6 和 TLR 9 的合成配体组成。这种针对宿主的固有免疫刺激剂在预防性给予动物时，可广泛预防细菌性、真菌性和病毒性肺炎，包括流感引起的肺炎。本研究评估了 PUL-042 在单独使用或与奥司他韦联合使用时对已建立的流感 A 肺炎的治疗性抗病毒作用。在感染流感肺炎之前或之后的不同时间点，用 PUL-042 气溶胶、奥司他韦或两者联合治疗小鼠。用多次吸入剂量的 PUL-042 气溶胶加口服奥司他韦治疗已建立的、否则致命的流感 A 肺炎（>1LD）可使更多的小鼠存活，而单独使用任何一种药物的治疗效果都较差。单药 PUL-042 还可保护小鼠免受较低病毒接种量（约 1LD）引起的已建立感染。气溶胶化的奥司他韦与 PUL-042 气溶胶联合使用时，可进一步提高生存率。PUL-042 的预防和治疗效果在针对多种流感病毒株时相似。体外流感对人 HBEC3kt 肺上皮细胞的挑战显示，PUL-042 诱导的保护作用与体内观察到的保护作用相当。这些研究为保护易感人群免受流感 A 肺炎提供了新的思路。
