title: Treatment of mannan-enhanced influenza B virus infections in mice with oseltamivir, ribavirin and viramidine.
abstract: Mannan, a polysaccharide preparation from Saccharomyces cerevisiae, has previously been shown to enhance influenza virus replication in mice by inhibiting host defense collectins. The use of mannan in infections may serve to broaden the types of influenza viruses that can be studied in rodent infection models. When mannan was co-administered with influenza B/Sichuan/379/99 virus to mice, the animals died from the infection, whereas mice infected with only virus survived. Three types of influenza A (H1N1) and another influenza B (Hong Kong/330/01) virus infection were also enhanced by mannan, but not four types of influenza A (H3N2) viruses. Mannan was used at 0.16 or 0.5 mg/mouse for optimal disease-enhancing activity using influenza B/Sichuan/379/99 virus. Using this model, influenza B/Sichuan/379/99 infections were treated with oseltamivir, ribavirin or viramidine (the carboxamidine derivative of ribavirin). When oral gavage treatments started 4 h before virus and mannan challenge, oseltamivir was effective at 2.5, 5 and 10 mg/kg/day. Ribavirin was active at 20, 40 and 80 mg/kg/day. Viramidine was effective at 80 and 160 mg/kg/day but not at 40 mg/kg/day. Active drug doses improved lung consolidation scores and lung weights, with decreases in lung virus titres also noted. Arterial oxygen saturation values in treated groups were significantly better than those of the placebo group on days 7-11 of the infection. Oseltamivir (5 mg/kg/day) and ribavirin (40 mg/kg/day) were used alone and in combination to determine how late after infection they could be beneficially administered. Ribavirin alone was very effective (90-100% survival of mice) when treatments started as late as 3 days after infection. Forty percent survival was evident even when treatments started 4 days post-infection. Oseltamivir was active starting treatments 1 day after virus exposure, but lost considerable efficacy when treatments began after that time. The combination of ribavirin and oseltamivir appeared to be no better than ribavirin alone, due to the stronger beneficial effect of ribavirin in this model. The overall results demonstrate that mannan can be used to enhance certain non-lethal influenza virus infections sufficiently to allow antiviral studies.
authors.affiliation: Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA. dsmee@cc.usu.edu
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.forename: Miles K
authors.initials: MK
authors.lastname: Wandersee
authors.forename: Min-Hui
authors.initials: MH
authors.lastname: Wong
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Bailey
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sidwell
mesh_terms: D000081:Acetamides / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006723:Hong Kong; D009981:Influenza B virus / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000821:virology; D008351:Mannans / Q000494:pharmacology; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D053139:Oseltamivir; D012254:Ribavirin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D000081:Acetamides; D000998:Antiviral Agents; D008351:Mannans; D053139:Oseltamivir; D012254:Ribavirin; C026956:taribavirin