Fig. 4.12.

Synergistic therapeutic effect in mice infected with FluV-A (H1N1/PR8) using PM-523 and ribavirin. All of the control mice (inbred 8-week-old female Balb/c) were infected with ten lethal doses of FluV-A, which corresponds to 1.6 × 10⁴ median tissue culture infection dose (TCID₅₀) titers in MDCK cell line. From 8 h after infection, the mice (ten mice/group) were treated with aerosols of PM-523 and ribavirin either singly or in combination every 12 h for 4 days. Compound solutions were prepared in phosphate-buffered saline (PBS) solutions (at pH 7.2), and the infected mice were exposed to the compounds by using a continuous aerosol generator for 2 h at a rate of distribution of 120 μl of solution/h to each chamber. Each infected 20-g mouse was placed in a chamber separately; no compound (filled circle)-treated, 40 mM ribavirin (filled triangle)-treated, 80 mM ribavirin (filled square)-treated, 2.4 mM PM-523 (open triangle)-treated, 4.8 mM PM-523 (open square)-treated, and 40 mM ribavirin/2.4 mM PM-523 combination (open circle)-treated mice. Levels of significance of p < 0.001 for 2.4-mMPM-523/40-mM ribavirin combination, p < 0.01 for 4.8-mM PM-523, and p < 0.05 for 80-mM ribavirin-treated mice on day 14 after infection