Delayed antiviral plus immunomodulator treatment still reduces mortality in mice infected by high inoculum of influenza A/H5N1 virus
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- 10 June 2008
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 105 (23) , 8091-8096
- https://doi.org/10.1073/pnas.0711942105
Abstract
The mortality of human infection by influenza A/H5N1 virus can exceed 80%. The high mortality and its poor response to the neuraminidase inhibitor oseltamivir have been attributed to uncontrolled virus-induced cytokine storm. We challenged BALB/c mice with 1,000 LD50of influenza A/Vietnam/1194/04. Survival, body weight, histopathology, inflammatory markers, viral loads, T lymphocyte counts, and neutralizing antibody response were documented in infected mice treated individually or in combination with zanamvir, celecoxib, gemfibrozil, and mesalazine. To imitate the real-life scenario, treatment was initiated at 48 h after viral challenge. There were significant improvements in survival rate (P= 0.02), survival time (P< 0.02), and inflammatory markers (P< 0.01) in the group treated with a triple combination of zanamivir, celecoxib, and mesalazine when compared with zanamivir alone. Zanamivir with or without immunomodulators reduced viral load to a similar extent. Insignificant prolongation of survival was observed when individual agents were used alone. Significantly higher levels of CD4+and CD8+T lymphocytes and less pulmonary inflammation were also found in the group receiving triple therapy. Zanamivir alone reduced viral load but not inflammation and mortality. The survival benefits of adding celecoxib and mesalazine to zanamivir could be caused by their synergistic effects in reducing cytokine dysfunction and preventing apoptosis. Combinations of a neuraminidase inhibitor with these immunomodulators should be considered in randomized controlled treatment trials of patients suffering from H5N1 infection.Keywords
This publication has 27 references indexed in Scilit:
- Intranasal Vaccination of Recombinant Adeno-Associated Virus Encoding Receptor-Binding Domain of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Spike Protein Induces Strong Mucosal Immune Responses and Provides Long-Term Protection against SARS-CoV InfectionThe Journal of Immunology, 2008
- Re-emergence of fatal human influenza A subtype H5N1 diseaseThe Lancet, 2004
- Preclinical evaluation of the nonsteroidal anti‐inflammatory agent celecoxib on malignant mesothelioma chemopreventionInternational Journal of Cancer, 2004
- Effect of 5-aminosalicylic acid on radiation-induced micronuclei in mouse bone marrowMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 2003
- Comparison of Efficacies of RWJ-270201, Zanamivir, and Oseltamivir against H5N1, H9N2, and Other Avian Influenza VirusesAntimicrobial Agents and Chemotherapy, 2001
- 5-Aminosalicylate stimulates phospholipase D activity in macrophagesBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2001
- Peroxisome proliferator-activated receptors (PPARs): Nuclear receptors at the crossroads between lipid metabolism and inflammationInflammation Research, 2000
- Dihydropyrancarboxamides Related to Zanamivir: A New Series of Inhibitors of Influenza Virus Sialidases. 1. Discovery, Synthesis, Biological Activity, and Structure−Activity Relationships of 4-Guanidino- and 4-Amino-4H-pyran-6-carboxamidesJournal of Medicinal Chemistry, 1998
- Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virusThe Lancet, 1998
- Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral neuraminidase (sialidase)Antimicrobial Agents and Chemotherapy, 1994