BACKGROUND: The clinical management of H5N1 influenza virus infection in humans remains unclear. Combination chemotherapy with drugs that target different viral proteins might be more effective than monotherapy. METHODS: BALB/c mice were treated by oral gavage for 5 days with amantadine (1.5, 15 or 30 mg/kg/day) and oseltamivir (1 or 10 mg/kg/day) separately or in combination. Mice were challenged 24 h after initiation of treatment with 10 mouse 50% lethal doses of either amantadine-sensitive (having S31 in the M2 protein) or amantadine-resistant (having N31 in the M2 protein) recombinant A/Vietnam/1203/04 (H5N1) virus. RESULTS: Combination treatment with amantadine (15 or 30 mg/kg/day) and oseltamivir (10 mg/kg/day) provided greater protection (60% and 90%, respectively) against lethal infection with amantadine-sensitive H5N1 virus than did monotherapy. Moreover, spread of the virus to the brain was prevented by both combination regimens. The efficacy of the drug combinations against amantadine-resistant H5N1 virus was comparable to that of oseltamivir alone. Oseltamivir produced a dose-dependent effect against both recombinant H5N1 viruses (P < 0.05) but did not provide complete protection against lethal infection. Importantly, no mutations in the HA, NA and M2 proteins were detected when the two drugs were used in combination. CONCLUSIONS: Combination chemotherapy provided a survival advantage over single-agent treatment of mice inoculated with neurotropic H5N1 influenza virus. This strategy might be an option for the control of pandemic influenza viruses that are sensitive to amantadine. Combinations that include other drugs should be explored.
BACKGROUND: The clinical management of H5N1 influenza virus infection in humans remains unclear. Combination chemotherapy with drugs that target different viral proteins might be more effective than monotherapy. METHODS: BALB/c mice were treated by oral gavage for 5 days with amantadine (1.5, 15 or 30 mg/kg/day) and oseltamivir (1 or 10 mg/kg/day) separately or in combination. Mice were challenged 24 h after initiation of treatment with 10 mouse 50% lethal doses of either amantadine-sensitive (having S31 in the M2 protein) or amantadine-resistant (having N31 in the M2 protein) recombinant A/Vietnam/1203/04 (H5N1) virus. RESULTS: Combination treatment with amantadine (15 or 30 mg/kg/day) and oseltamivir (10 mg/kg/day) provided greater protection (60% and 90%, respectively) against lethal infection with amantadine-sensitive H5N1 virus than did monotherapy. Moreover, spread of the virus to the brain was prevented by both combination regimens. The efficacy of the drug combinations against amantadine-resistant H5N1 virus was comparable to that of oseltamivir alone. Oseltamivir produced a dose-dependent effect against both recombinant H5N1 viruses (P < 0.05) but did not provide complete protection against lethal infection. Importantly, no mutations in the HA, NA and M2 proteins were detected when the two drugs were used in combination. CONCLUSIONS: Combination chemotherapy provided a survival advantage over single-agent treatment of mice inoculated with neurotropic H5N1influenza virus. This strategy might be an option for the control of pandemic influenza viruses that are sensitive to amantadine. Combinations that include other drugs should be explored.
Authors: Frédéric Kendirgi; Nadezda E Yun; Nathaniel S Linde; Michele A Zacks; Jeanon N Smith; Jennifer K Smith; Harilyn McMicken; Yin Chen; Slobodan Paessler Journal: Hum Vaccin Date: 2008-11-21
Authors: Neal Van Hoeven; Jessica A Belser; Kristy J Szretter; Hui Zeng; Peter Staeheli; David E Swayne; Jacqueline M Katz; Terrence M Tumpey Journal: J Virol Date: 2009-01-14 Impact factor: 5.103
Authors: Elena A Govorkova; Tatiana Baranovich; Patrick Seiler; Jianling Armstrong; Andrew Burnham; Yi Guan; Malik Peiris; Richard J Webby; Robert G Webster Journal: Antiviral Res Date: 2013-02-28 Impact factor: 5.970
Authors: Donald F Smee; Brett L Hurst; Min-Hui Wong; Kevin W Bailey; E Bart Tarbet; John D Morrey; Yousuke Furuta Journal: Antimicrob Agents Chemother Date: 2009-11-09 Impact factor: 5.191
Authors: Anwar M Hashem; Anathea S Flaman; Aaron Farnsworth; Earl G Brown; Gary Van Domselaar; Runtao He; Xuguang Li Journal: PLoS One Date: 2009-12-17 Impact factor: 3.240