title: Efficacy of combined therapy with amantadine, oseltamivir, and ribavirin in vivo against susceptible and amantadine-resistant influenza A viruses.
abstract: The limited efficacy of existing antiviral therapies for influenza--coupled with widespread baseline antiviral resistance--highlights the urgent need for more effective therapy. We describe a triple combination antiviral drug (TCAD) regimen composed of amantadine, oseltamivir, and ribavirin that is highly efficacious at reducing mortality and weight loss in mouse models of influenza infection. TCAD therapy was superior to dual and single drug regimens in mice infected with drug-susceptible, low pathogenic A/H5N1 (A/Duck/MN/1525/81) and amantadine-resistant 2009 A/H1N1 influenza (A/California/04/09). Treatment with TCAD afforded >90% survival in mice infected with both viruses, whereas treatment with dual and single drug regimens resulted in 0% to 60% survival. Importantly, amantadine had no activity as monotherapy against the amantadine-resistant virus, but demonstrated dose-dependent protection in combination with oseltamivir and ribavirin, indicative that amantadine's activity had been restored in the context of TCAD therapy. Furthermore, TCAD therapy provided survival benefit when treatment was delayed until 72 hours post-infection, whereas oseltamivir monotherapy was not protective after 24 hours post-infection. These findings demonstrate in vivo efficacy of TCAD therapy and confirm previous reports of the synergy and broad spectrum activity of TCAD therapy against susceptible and resistant influenza strains in vitro.
authors.affiliation: Adamas Pharmaceuticals, Inc., Emeryville, California, United States of America. jnguyen@adamaspharma.com
authors.forename: Jack T
authors.initials: JT
authors.lastname: Nguyen
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: Dale L
authors.initials: DL
authors.lastname: Barnard
authors.forename: Justin G
authors.initials: JG
authors.lastname: Julander
authors.forename: Matthew
authors.initials: M
authors.lastname: Gross
authors.forename: Menno D
authors.initials: MD
authors.lastname: de Jong
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Went
mesh_terms: D000547:Amantadine / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D004338:Drug Combinations; D024882:Drug Resistance, Viral / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000473:pathology; D053139:Oseltamivir / Q000008:administration & dosage*; D010919:Placebos; D012254:Ribavirin / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D004338:Drug Combinations; D010919:Placebos; D053139:Oseltamivir; D012254:Ribavirin; D000547:Amantadine