Antiviral research
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Antiviral immune responses play as a double edged sword in resolution of infection and pathogenesis of acute lung injury caused by infection with highly pathogenic influenza A viruses. Here we show that type I interferons (IFNs) are important in protection against acute influenza A virus infection not only via their antiviral activity but also via their anti-inflammatory activity. ⋯ Restoration of IL-10 during an ongoing virus infection significantly reduced the levels of proinflammatory cytokines and improved mortality of IFNAR KO mice. These results suggest that type I IFNs are responsible not only for direct resolution of viral load but also for suppression of immunopathology caused by influenza A virus through IL-10 production.
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Severe infections with influenza virus are characterized by acute respiratory distress syndrome (ARDS), a life-threatening disorder in which the alveolocapillary membrane in the lung becomes leaky. This leads to alveolar flooding, hypoxemia and respiratory failure. ⋯ In this paper, we review evidence that lung endothelial activation and vascular leak are a "final common pathway" in severe influenza, as has been reported in bacterial sepsis, and that enhancing endothelial barrier function may improve the outcome of illness. We describe a number of experimental therapies that have shown promise in preventing or reversing increased vascular leak in animal models of sepsis or influenza.
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Randomized Controlled Trial Multicenter Study Comparative Study
Oseltamivir-zanamivir bitherapy compared to oseltamivir monotherapy in the treatment of pandemic 2009 influenza A(H1N1) virus infections.
The emergence of oseltamivir resistance in 2007 highlighted the need for alternative strategies against influenza. To limit the putative emergence of resistant viruses this clinical trial aimed to evaluate the antiviral efficacy and tolerability of oseltamivir-zanamivir (O+Z) bitherapy compared to oseltamivir monotherapy (O). This clinical trial was designed in 2008-2009 and was conducted during the A(H1N1) influenza virus pandemic in 2009-2010. The A(H1N1)pdm09 viruses were reported to be sensitive to oseltamivir and zanamivir but resistant to amantadine. ⋯ The sample size of our study is too limited to be fully informative and we could not detect whether combination therapy (O+Z) improves or reduces the effectiveness of oseltamivir in the treatment of influenza A(H1N1)pdm09 virus infection in community patients. Additional studies are needed to improve the antiviral treatment of patients infected with influenza virus.
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The combined effect of rimantadine and oseltamivir in a prophylactic context (therapy beginning 4 h pre-virus infection) and therapeutic context (therapy started at 24 h post-viral inoculation) course on influenza H3N2 virus infection in mice was studied. In the prophylactic course 5 and 10 mg/kg/day rimantadine with 0.2 and 0.4 mg/kg/day (25:1 dose ratio) oseltamivir showed a protection index (PI) of 79.6% and 75%, respectively and a mean survival time (MST) of 13.1 and 12.9 days. The individual effects of the same doses ranged from 0% to 33.3% PI and 8.2 to 10.3 days MST, respectively. ⋯ Monotherapy protection was from 9.1% to a maximum of 56.5%, MST being prolonged only by 1.3-4.2 days compared to 7.5 days in the PBS control group. Lung viral titers were decreased 1445-fold for the most efficacious combination groups and a significant reduction in lung parameters was observed. These data emphasize that prophylactic and therapeutic courses using a combination of oseltamivir and rimantadine have a significant protective effect in mice experimentally infected with drug-sensitive influenza virus A (H3N2).
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The highly lethal filoviruses, Ebola and Marburg cause severe hemorrhagic fever in humans and non-human primates. To date there are no licensed vaccines or therapeutics to counter these infections. Identifying novel pathways and host targets that play an essential role during infection will provide potential targets to develop therapeutics. ⋯ Investigation of the mechanism of action of the compound revealed that it had antioxidant properties. Specifically, compound NSC 62914 was found to act as a scavenger of reactive oxygen species, and to up-regulate oxidative stress-induced genes. However, four known antioxidant compounds failed to inhibit filovirus infection, thus suggesting that the mechanistic basis of the antiviral function of the antioxidant NSC 62914 may involve modulation of multiple signaling pathways/targets.