Antimicrob Agents Chemother. 2006 Dec 28; [Epub ahead of print]
Efficacy of Orally Administered T-705 on Lethal Avian Influenza A (H5N1) Virus Infections in Mice.
Sidwell RW, Barnard DL, Day CW, Smee DF, Bailey KW, Wong MH, Morrey JD, Furuta Y.
Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600 and Toyama Chemical Co., Ltd., 3-2-5 Nishishinjuku, Tokyo, Japan.
T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) was inhibitory to four strains of avian H5N1 influenza virus in MDCK cells, the EC90 values ranging from 1.3 to 7.7 microM using virus yield reduction assay. The efficacy was less than exerted by oseltamivir carboxylate or zanamivir, but greater than ribavirin. Experiments run in mice lethally infected with influenza A/Duck/MN/1525/81 (H5N1) virus showed that T-705 administered per os once, twice, or four times daily for 5 days beginning 1 h post-virus exposure was highly inhibitory to the infection. Dosages from 30 to 300 mg/kg/day were well tolerated; each prevented death, lessened decline of arterial oxygen saturation (SaO2), and inhibited lung consolidation and lung virus titers. Dosages from 30 to 300 mg/kg/day administered once or twice daily also significantly prevented deaths in the mice. Oseltamivir (20 mg/kg/day), administered p.o. twice daily for 5 days, was run in parallel in two experiments; it was only weakly effective against the infection. The four times daily T-705 treatments at 300 mg/kg/day could be delayed until 96 h after virus exposure and still significantly inhibit the infection. Single T-705 treatments administered up to 60 h after virus exposure also prevented deaths and SaO2 decline. Characterization of the pathogenesis of the duck influenza H5N1 virus used in these studies was undertaken; although the virus was highly pathogenic to mice, it was less neurotropic than has been described for clinical isolates of the H5N1 virus. These data indicate T-705 may be a useful means for the treatment of avian influenza virus infections. |
