title: Neuraminidase inhibitor-rimantadine combinations exert additive and synergistic anti-influenza virus effects in MDCK cells.
abstract: There is insufficient information about combination therapy with approved anti-influenza agents. We tested combinations that paired a neuraminidase (NA) inhibitor (zanamivir, oseltamivir carboxylate, or peramivir) with rimantadine against infection of MDCK cells with H1N1 and H3N2 subtypes of influenza A virus and characterized their mode of interaction. When reduction of extracellular virus was analyzed by individual regression models and three-dimensional representations of the data, all three combinations showed additive and synergistic effects with no cytotoxicity. Maximum synergy against A/New Caledonia/20/99 (H1N1) virus infection was observed with <2.5 microM rimantadine paired with low concentrations of NA inhibitors. All combinations reduced the extracellular yield of A/Panama/2007/99 (H3N2) influenza virus synergistically. However, our findings were different for the cell-associated virus yield. At some drug concentrations, the yield of cell-associated virus was inhibited antagonistically. Therefore, the method of analysis can be a crucial factor in evaluating the interactions of drugs with different mechanisms. We hypothesize that assays based on cell-associated virus yield may underestimate the efficacies of drug combinations that include an NA inhibitor. Taken together, our results suggest that regimens that combine NA inhibitors and rimantadine exert synergistic anti-influenza effects in vitro. These findings provide baseline information for therapeutic testing of the drug combinations in vivo.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Govorkova
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Fang
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.forename: Robert G
authors.initials: RG
authors.lastname: Webster
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006146:Guanidines; D009980:Influenza A virus / Q000187:drug effects*; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir; D011714:Pyrans; D012299:Rimantadine / Q000494:pharmacology* / Q000633:toxicity; D012794:Sialic Acids / Q000494:pharmacology / Q000633:toxicity; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects; D053243:Zanamivir
chemical_list: D000081:Acetamides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D012299:Rimantadine; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir