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Currently, virtually all circulating strains of influenza A virus in the United States are resistant to either of the two major classes of anti-influenza drugs (adamantanes and neuraminidase inhibitors). Thus, new therapeutic approaches that can be rapidly deployed and that will address the issue of recurring resistance should be developed. We have tested double and triple combinations of the approved anti-influenza drugs oseltamivir and amantadine together with ribavirin against three influenza virus strains using cytopathic effect inhibition assays in MDCK cells. We selected A\/New Caledonia\/20\/99 (H1N1) and A\/Sydney\/05\/97 (H3N2) as representatives of the wild-type versions of the predominant circulating seasonal influenza virus strains and A\/Duck\/MN\/1525\/81 (H5N1) as a representative of avian influenza virus strains. Dose-response curves were generated for all drug combinations, and the degree of drug interaction was quantified using a model that calculates the synergy (or antagonism) between the drugs in double and triple combinations. This report demonstrates that a triple combination of antivirals was highly synergistic against influenza A virus. Importantly, the synergy of the triple combination was 2- to 13-fold greater than the synergy of any double combination depending on the influenza virus subtype. These data support the investigation of a novel combination of oseltamivir, amantadine, and ribavirin as an effective treatment for both seasonal and pandemic influenza virus, allowing the efficient use of the existing drug supplies.<\/jats:p>","DOI":"10.1128\/aac.00476-09","type":"journal-article","created":{"date-parts":[[2009,7,21]],"date-time":"2009-07-21T00:58:33Z","timestamp":1248137913000},"page":"4115-4126","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":100,"title":["Triple Combination of Oseltamivir, Amantadine, and Ribavirin Displays Synergistic Activity against Multiple Influenza Virus Strains In Vitro"],"prefix":"10.1128","volume":"53","author":[{"given":"Jack T.","family":"Nguyen","sequence":"first","affiliation":[{"name":"Adamas Pharmaceuticals, Inc., Emeryville, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin D.","family":"Hoopes","sequence":"additional","affiliation":[{"name":"Institute for Antiviral Research, Utah State University, Logan, Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald F.","family":"Smee","sequence":"additional","affiliation":[{"name":"Institute for Antiviral Research, Utah State University, Logan, Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark N.","family":"Prichard","sequence":"additional","affiliation":[{"name":"University of Alabama School of Medicine, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Driebe","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Flagstaff, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Engelthaler","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Flagstaff, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh H.","family":"Le","sequence":"additional","affiliation":[{"name":"Adamas Pharmaceuticals, Inc., Emeryville, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Keim","sequence":"additional","affiliation":[{"name":"Translational Genomics Research Institute, Flagstaff, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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