Efficacy of orally administered T-705 on lethal avian influenza A (H5N1) virus infections in mice

Abstract

T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) was inhibitory to four strains of avian H5N1 influenza virus in MDCK cells, with the 90% effective concentrations ranging from 1.3 to 7.7 microM, as determined by a virus yield reduction assay. The efficacy was less than that exerted by oseltamivir carboxylate or zanamivir but was greater than that exerted by ribavirin. Experiments with 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 after virus exposure was highly inhibitory to the infection. Dosages from 30 to 300 mg/kg of body weight/day were well tolerated; each prevented death, lessened the decline of arterial oxygen saturation (SaO(2)), and inhibited lung consolidation and lung virus titers. Dosages from 30 to 300 mg/kg/day administered once or twice daily also significantly prevented the death of the mice. Oseltamivir (20 mg/kg/day), administered per os twice daily for 5 days, was tested 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 death and the decline of SaO(2). 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 that T-705 may be useful for the treatment of avian influenza virus infections.

FIG. 1.

Effect of four-times-daily treatment with T-705 or twice-daily treatment with oseltamivir beginning 1 h after virus exposure on arterial oxygen saturation decline in BALB/c mice infected with influenza A/Duck/MN/1525/81 (H5N1) virus. Data are expressed as the mean values for 10 mice per time point. *, P < 0.05 compared to the results for the CMC-treated controls; **, P < 0.01 compared to the results for the CMC-treated controls; ***, P < 0.001 compared to the results for the CMC-treated controls.

FIG. 2.

Effect of single T-705 treatment at various times after virus exposure on prevention of death in mice infected with influenza A A/Duck/MN/1525/81 (H5N1) virus. *, P < 0.05 compared to the results for the carboxymethyl cellulose-treated controls (CMC); **, P < 0.01 compared to the results for the carboxymethyl cellulose-treated controls (CMC); ***, P < 0.001 compared to the results for the CMC-treated controls.