Prophylactic and therapeutic combination effects of rimantadine and oseltamivir against influenza virus A (H3N2) infection in mice

Simeonova, Lora; Gegova, G; Galabov, Angel S.

doi:10.1016/j.antiviral.2012.05.004

Cited by 10 publications

(5 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…vir against new and emerging strains of influenza is frequently tested in mice and other animal species and is used as a predictor for efficacy in humans (12)(13)(14)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)), but we demonstrate here that evaluation of antiviral efficacy in in vitro assays as well as in vivo analyses in other animal species should be assessed collectively to ensure that an accurate understanding of antiviral efficacy for humans will be predicted.…”

Section: Discussionmentioning

confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

View full text Add to dashboard Cite

During the first wave of the 2009 pandemic, caused by a H1N1 influenza virus (pH1N1) of swine origin, antivirals were the only form of therapeutic available to control the proliferation of disease until the conventional strain-matched vaccine was produced. Oseltamivir is an antiviral that inhibits the sialidase activity of the viral neuraminidase (NA) protein and was shown to be effective against pH1N1 viruses in ferrets. Furthermore, it was used in humans to treat infections during the pandemic and is still used for current infections without reported complication or exacerbation of illness. However, in an evaluation of the effectiveness of oseltamivir against pH1N1 infection, we unexpectedly observed an exacerbation of disease in virus-infected mice treated with oseltamivir, transforming an otherwise mild illness into one with high morbidity and mortality. In contrast, an identical treatment regime alleviated all signs of illness in mice infected with the pathogenic mouse-adapted virus A/WSN/33 (H1N1). The worsened clinical outcome with pH1N1 viruses occurred over a range of oseltamivir doses and treatment schedules and was directly linked to a reduction in NA enzymatic activity. Our results suggest that the suppression of NA activity with antivirals may exacerbate disease in a host-dependent manner by increasing replicative fitness in viruses that are not optimally adapted for replication in that host. IMPORTANCEHere, we report that treatment of pH1N1-infected mice with oseltamivir enhanced disease progression, transforming a mild illness into a lethal infection. This raises a potential pitfall of using the mouse model for evaluation of the therapeutic efficacy of neuraminidase inhibitors. We show that antiviral efficacy determined in a single animal species may not represent treatment in humans and that caution should be used when interpreting the outcome. Furthermore, increased virulence due to oseltamivir treatment was the effect of a shift in the hemagglutinin (HA) and neuraminidase (NA) activity balance. This is the first study that has demonstrated that altering the HA/NA activity balance by reduction in NA activity can result in an increase in virulence in any animal model from nonpathogenic to lethal and the first to demonstrate a situation in which treatment with a NA activity inhibitor has an effect opposite to the intended therapeutic effect of ameliorating the infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Ranadheera

Hagan

Leung

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…These observations might be explained by possible antagonistic effects of combined NA inhibitor treatment, which have been suggested by in vitro experiments [19]. Other anti-influenza virus compounds, including AMT and RBV, have been studied in combination with OSL in animal models, with a synergistic effect noted in mice [29–31]. TCAD therapy consisting of OSL, AMT and RBV was subsequently shown to have greater antiviral activity compared with double combination therapy in vitro and in the mouse model [20–22].…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy with Amantadine, Oseltamivir and Ribavirin for Influenza a Infection: Safety and Pharmacokinetics

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The body weights were measured and the lungs were aseptically removed and weighed. The lung index used here was the lung weight as a percentage of the body weight as previously described [18] . Fifty mg of sterile lung tissue from each mouse was then minced to prepare the supernatant from lung homogenates.…”

Section: Methodsmentioning

confidence: 99%

Protocatechuic Acid, a Novel Active Substance against Avian Influenza Virus H9N2 Infection

Shi

Yang

et al. 2014

PLoS ONE

View full text Add to dashboard Cite

Influenza virus H9N2 subtype has triggered co-infection with other infectious agents, resulting in huge economical losses in the poultry industry. Our current study aims to evaluate the antiviral activity of protocatechuic acid (PCA) against a virulent H9N2 strain in a mouse model. 120 BALB/c mice were divided into one control group, one untreated group, one 50 mg/kg amantadine hydrochloride-treated group and three PCA groups treated 12 hours post-inoculation with 40, 20 or 10 mg/kg PCA for 7 days. All the infected animals were inoculated intranasally with 0.2 ml of a A/Chicken/Hebei/4/2008(H9N2) inoculum. A significant body weight loss was found in the 20 mg/kg and 40 mg/kg PCA-treated and amantadine groups as compared to the control group. The 14 day survivals were 94.4%, 100% and 95% in the PCA-treated groups and 94.4% in the amantadine hydrochloride group, compared to less than 60% in the untreated group. Virus loads were less in the PCA-treated groups compared to the amantadine-treated or the untreated groups. Neutrophil cells in BALF were significantly decreased while IFN-γ, IL-2, TNF-α and IL-6 decreased significantly at days 7 in the PCA-treated groups compared to the untreated group. Furthermore, a significantly decreased CD4+/CD8+ ratio and an increased proportion of CD19 cells were observed in the PCA-treated groups and amantadine-treated group compared to the untreated group. Mice administered with PCA exhibited a higher survival rate and greater viral clearance associated with an inhibition of inflammatory cytokines and activation of CD8+ T cell subsets. PCA is a promising novel agent against bird flu infection in the poultry industry.

show abstract

Prophylactic and therapeutic combination effects of rimantadine and oseltamivir against influenza virus A (H3N2) infection in mice

Cited by 10 publications

References 41 publications

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

Combination Therapy with Amantadine, Oseltamivir and Ribavirin for Influenza a Infection: Safety and Pharmacokinetics

Protocatechuic Acid, a Novel Active Substance against Avian Influenza Virus H9N2 Infection

Contact Info

Product

Resources

About