title: Laninamivir octanoate and artificial surfactant combination therapy significantly increases survival of mice infected with lethal influenza H1N1 Virus.
abstract: BACKGROUND
  Patients with influenza virus infection can develop severe pneumonia and acute respiratory distress syndrome (ARDS) which have a high mortality. Influenza virus infection is treated worldwide mainly by neuraminidase inhibitors (NAIs). However, monotherapy with NAIs is insufficient for severe pneumonia secondary to influenza virus infection. We previously demonstrated that mice infected with a lethal dose of influenza virus develop diffuse alveolar damage (DAD) with alveolar collapse similar to that seen in ARDS in humans. Additionally, pulmonary surfactant proteins were gradually increased in mouse serum, suggesting a decrease in pulmonary surfactant in the lung. Therefore, the present study examined whether combination therapy of NAI with exogenous artificial surfactant affects mortality of influenza virus-infected mice.
  
  
  RESULTS
  BALB/c mice were inoculated with several viral doses of influenza A/Puerto Rico/8/34 (PR8) virus (H1N1). The mice were additionally administered exogenous artificial surfactant in the presence or absence of a new NAI, laninamivir octanoate. Mouse survival, body weight and general condition were observed for up to 20 days after inoculation. Viral titer and cytokine/chemokine levels in the lungs, lung weight, pathological analysis, and blood O(2) and CO(2) pressures were evaluated. Infected mice treated with combination therapy of laninamivir octanoate with artificial surfactant showed a significantly higher survival rate compared with those that received laninamivir octanoate monotherapy (p = 0.003). However, virus titer, lung weight and cytokine/chemokine responses were not different between the groups. Histopathological examination, a hydrostatic lung test and blood gas analysis showed positive results in the combination therapy group.
  
  
  CONCLUSIONS
  Combination therapy of laninamivir octanoate with artificial surfactant reduces lethality in mice infected with influenza virus, and eventually suppresses DAD formation and preserves lung function. This combination could be effective for prevention of severe pneumonia secondary to influenza virus infection in humans, which is not improved by NAI monotherapy.
authors.affiliation: Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Fukushi
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamashita
authors.forename: Tohru
authors.initials: T
authors.lastname: Miyoshi-Akiyama
authors.forename: Shuku
authors.initials: S
authors.lastname: Kubo
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kudo
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D018925:Chemokines / Q000378:metabolism; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D006146:Guanidines; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000502:physiology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009929:Organ Size / Q000187:drug effects; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D010100:Oxygen / Q000097:blood; D011312:Pressure; D037663:Pulmonary Surfactant-Associated Protein D / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000008:administration & dosage / Q000627:therapeutic use*; D011714:Pyrans; D012794:Sialic Acids; D016019:Survival Analysis; D019562:Viral Load / Q000187:drug effects; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018925:Chemokines; D006146:Guanidines; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants; D011714:Pyrans; D012794:Sialic Acids; D002245:Carbon Dioxide; C546918:laninamivir; D053243:Zanamivir; D010100:Oxygen