Giuseppe
Emeritus
Antimicrob Agents Chemother. 2008 Aug 25. [Epub ahead of print]
Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice.
Ilyushina NA, Hay A, Yilmaz N, Boon AC, Webster RG, Govorkova EA. - Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794; The D.I. Ivanovsky Institute of Virology, Moscow 123098, Russia; National Institute for Medical Research, Mill Hill, London NW7 1AA, UK; Virology and NIC of Turkey Refik Saydam Hygiene Institute, Ankara, Turkey; Department of Pathology, University of Tennessee, Memphis, Tennessee 38105.
We studied the effects of a neuraminidase (NA) inhibitor (oseltamivir) and an inhibitor of influenza virus polymerases (ribavirin) against two highly pathogenic H5N1 influenza viruses.
In vitro, A/Vietnam/1203/04 virus (clade 1) was highly susceptible to oseltamivir carboxylate (IC50=0.3 nM), whereas A/Turkey/15/06 virus (clade 2.2) had reduced susceptibility (IC50=5.5 nM).
In vivo, BALB/c mice were treated with oseltamivir (1, 10, 50, or 100 mg/kg/day), ribavirin (37.5, 55, or 75 mg/kg/day), or their combinations for 8 days, starting 4 hours before virus inoculation.
Monotherapy produced a dose-dependent antiviral effect against the two H5N1 viruses in vivo.
Three-dimensional analysis of the drug-drug interactions revealed that oseltamivir and ribavirin interacted principally in an additive manner, with several exceptions of marginal synergy or marginal antagonism at some concentrations.
The combinations of ribavirin at 37.5 mg/kg/day and 1 or 10 mg/kg/day of oseltamivir were synergistic against A/Vietnam/1203/04 and A/Turkey/15/06 viruses, respectively.
These optimal oseltamivir-ribavirin combinations significantly inhibited virus replication in mouse organs, prevented the spread of H5N1 viruses beyond the respiratory tract, and abrogated the cytokine response (P < 0.01).
Importantly, we observed clear differences between the efficacy of drug combinations against two H5N1 viruses: higher doses were required for the protection of mice against A/Turkey/15/06 virus than for A/Vietnam/1203/04 virus.
Our preliminary results suggest that the oseltamivir-ribavirin combinations can have a greater or lesser antiviral effect than monotherapy dependent on the H5N1 virus and concentrations used.
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PMID: 18725448 [PubMed - as supplied by publisher
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Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice.
Ilyushina NA, Hay A, Yilmaz N, Boon AC, Webster RG, Govorkova EA. - Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794; The D.I. Ivanovsky Institute of Virology, Moscow 123098, Russia; National Institute for Medical Research, Mill Hill, London NW7 1AA, UK; Virology and NIC of Turkey Refik Saydam Hygiene Institute, Ankara, Turkey; Department of Pathology, University of Tennessee, Memphis, Tennessee 38105.
We studied the effects of a neuraminidase (NA) inhibitor (oseltamivir) and an inhibitor of influenza virus polymerases (ribavirin) against two highly pathogenic H5N1 influenza viruses.
In vitro, A/Vietnam/1203/04 virus (clade 1) was highly susceptible to oseltamivir carboxylate (IC50=0.3 nM), whereas A/Turkey/15/06 virus (clade 2.2) had reduced susceptibility (IC50=5.5 nM).
In vivo, BALB/c mice were treated with oseltamivir (1, 10, 50, or 100 mg/kg/day), ribavirin (37.5, 55, or 75 mg/kg/day), or their combinations for 8 days, starting 4 hours before virus inoculation.
Monotherapy produced a dose-dependent antiviral effect against the two H5N1 viruses in vivo.
Three-dimensional analysis of the drug-drug interactions revealed that oseltamivir and ribavirin interacted principally in an additive manner, with several exceptions of marginal synergy or marginal antagonism at some concentrations.
The combinations of ribavirin at 37.5 mg/kg/day and 1 or 10 mg/kg/day of oseltamivir were synergistic against A/Vietnam/1203/04 and A/Turkey/15/06 viruses, respectively.
These optimal oseltamivir-ribavirin combinations significantly inhibited virus replication in mouse organs, prevented the spread of H5N1 viruses beyond the respiratory tract, and abrogated the cytokine response (P < 0.01).
Importantly, we observed clear differences between the efficacy of drug combinations against two H5N1 viruses: higher doses were required for the protection of mice against A/Turkey/15/06 virus than for A/Vietnam/1203/04 virus.
Our preliminary results suggest that the oseltamivir-ribavirin combinations can have a greater or lesser antiviral effect than monotherapy dependent on the H5N1 virus and concentrations used.
-
PMID: 18725448 [PubMed - as supplied by publisher
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