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Influenza pathogenesis comprises a complex cascade of impaired cellular processes resulting from the viral replication and exaggerated immune response accompanied by reactive oxygen species (ROS) burst and oxidative stress, destructing membranous structures and tissues. By classical virological and biochemical methods we compared and evaluated the therapeutic effects of 2.5mg/kg/day of the antiviral drug - oseltamivir (OS), 500mg/kg/day of the immune modulator - isoprinosine (IP) and 500mg/kg/day of the antioxidant agent ellagic acid (EA) with a focus on their combined activities in influenza H3N2 virus-infected mice. The survival, lung pathology and titers, as well as the oxidative stress biomarker thiobarbituric acid reactive substances (TBARS) in the lungs, liver and blood plasma, correlated to the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione reductase (GR) were assessed. We found that the viral inhibitor applied together with the immune modulator and the antioxidant exhibited strong therapeutic effects on the survival of the influenza-challenged mice. That effect was mostly pronounced for the triple combination - protection index (PI) of 75.2%, mean survival time (MST) extended by 5.8 days compared to the PBS control and significant reduction of the lung titers by 1.38 Δlg; 2.3 scores lower lung pathology and 8 times reduction of the accumulated TBARS in the lungs and liver on the 5 -th day p.i. The enzymatic assays revealed that this combination demonstrated very good protection against the damaging superoxide radicals (83% efficiency of SOD, in comparison to healthy controls 100%). The double combinations of OS with IP and EA also showed protective effects according to the virological analysis - PI of 53.1% and 54.5%. Ten times higher GR activity was observed when the combination EA+OS and monotherapy of EA were applied (96% in comparison to healthy controls 100%). The best antioxidant effect in blood plasma was observed in the EA+IP group - 4 times reduction in the TBARS-content compared to infected controls but it did not have any efficacy on the survival and lung injury., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

This study compares the antioxidant capacities in vitro of several synthetic and natural compounds applied and researched for influenza treatment - oseltamivir, isoprinosine, ellagic acid, vitamin E and vitamin C. Three chemical systems are utilized for the generation of reactive oxygen species (ROS) at pH 7.4 and pH 8.5: (1) Fenton's (Fe 2+ +H 2 O 2 ) for OH and -OH species (2) H 2 O 2 (3) NADH-phenazinemethosulfat, for superoxide radicals (O 2 - ). The kinetics was evaluated by lucigenin-enhanced chemiluminescence. The calculated constants of inhibition k 7 describe the antioxidant capacity at the moment of oxidative burst. Their values do not necessarily correspond to the calculated total antioxidant activity. The obtained results revealed that the synthetic anti-influenza drugs (oseltamivir and isoprinosine) as well as ellagic acid possess pronounced scavenging properties mostly against superoxide radicals, comparable and higher than that of traditional natural antioxidants. Quantitative analysis of the antioxidant effects of the examined synthetic substances was performed. The results compared the corresponding effect of the average physiological concentrations and the applied therapeutic antioxidant dose. With these experiments we registered new aspects of their therapeutic activities, due to antioxidant properties against hydroxyl, superoxide radicals and H 2 O 2 oxidation., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)