title: Efficacy of repeated intravenous administration of peramivir against highly pathogenic avian influenza A (H5N1) virus in cynomolgus macaques.
abstract: Highly pathogenic avian influenza A (H5N1) viruses cause severe and often fatal disease in humans. We evaluated the efficacy of repeated intravenous dosing of the neuraminidase inhibitor peramivir against highly pathogenic avian influenza virus A/Vietnam/UT3040/2004 (H5N1) infection in cynomolgus macaques. Repeated dosing of peramivir (30 mg/kg/day once a day for 5 days) starting immediately after infection significantly reduced viral titers in the upper respiratory tract, body weight loss, and cytokine production and resulted in a significant body temperature reduction in infected macaques compared with that of macaques administered a vehicle (P < 0.05). Repeated administration of peramivir starting at 24 h after infection also resulted in a reduction in viral titers and a reduction in the period of virus detection in the upper respiratory tract, although the body temperature change was not statistically significant. The macaque model used in the present study demonstrated that inhibition of viral replication at an early time point after infection by repeated intravenous treatment with peramivir is critical for reduction of the production of cytokines, i.e., interleukin-6 (IL-6), tumor necrosis factor α, gamma interferon, monocyte chemotactic protein 1, and IL-12p40, resulting in amelioration of symptoms caused by highly pathogenic avian influenza virus infection.
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Mitsutaka
authors.initials: M
authors.lastname: Kitano
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan yasushii@belle.shiga-med.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Ishigaki
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Nakayama
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Van Loi
authors.initials: VL
authors.lastname: Pham
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Arikata
authors.affiliation: Laboratory of Microbiology, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Shichinohe
authors.affiliation: Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tsuchiya
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kitagawa
authors.affiliation: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Yoshida
authors.affiliation: Infectious Diseases, Medicinal Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.affiliation: National Institute of Hygiene and Epidemiology, Hanoi, Vietnam.
authors.forename: Quynh Mai
authors.initials: QM
authors.lastname: Le
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan Department of Pathological Science, University of Wisconsin-Madison, Madison, Wisconsin, USA ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.affiliation: Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan Research Center for Animal Life Science, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogasawara
mesh_terms: D000146:Acids, Carbocyclic; D061605:Administration, Intravenous; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003517:Cyclopentanes / Q000494:pharmacology*; D004334:Drug Administration Schedule; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000472:pathogenicity* / Q000502:physiology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008252:Macaca fascicularis; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000503:physiopathology / Q000662:veterinary* / Q000821:virology; D013997:Time Factors; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014774:Virulence; D014779:Virus Replication / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D018932:Chemokine CCL2; D003517:Cyclopentanes; D006146:Guanidines; D007371:Interferon-gamma; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C414210:peramivir