Effects of therapy with mDEF201 and cidofovir on percent body weights of mice during a vaccinia virus (WR strain) respiratory infection.

<p>Intranasal treatments with mDEF201 (10⁸ PFU/mouse) were given one time. Cidofovir (100 mg/kg/day) was administered by intraperitoneal route once a day for two days. Test materials were given at the time indicated after intranasal virus exposure (1×10⁵ PFU). The data accompany those of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026330#pone-0026330-t003" target="_blank">Table 3</a> (body weight results of treatment with mDEF208 at 10⁷ PFU/mouse are not shown). Thus, the initial number of mice per group for each figure corresponds to the total number per group in the table.</p

Effects of prophylaxis with mDEF201 on percent body weights of mice during vaccinia virus (WR strain) respiratory infections.

<p>(A) Experiment 1, primary infection, (B) Experiment 1, reinfection, (C) Experiment 2, primary infection, (D) Experiment 2, reinfection. Intranasal treatments with mDEF201 (10⁷ PFU/mouse) were given one time only on the indicated day prior to virus exposure. In Experiment 1 the primary intranasal challenge was 1×10⁵ PFU of virus. Since this challenge dose failed to cause 100% mortality (as mice age their susceptibility to infection wanes), the primary virus challenge dose was increased to 2.5×10⁵ PFU of virus for Experiment 2. Reinfection of both sets of mice was performed intranasally with 5×10⁵ PFU of virus. The data accompany those of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0026330#pone-0026330-t002" target="_blank">Table 2</a>. Thus, the initial number of mice per group for each figure corresponds to the total number per group in the table.</p

Effects of treatment with mDEF201 on survival from a vaccinia virus systemic infection (initiated by a 100-µl i.p. virus inoculation) in mice.

<p>Intranasal 5- and 50-µl treatments with mDEF201 (PFU/mouse) were given one time only 24 hours prior to virus exposure. There were 10 treated animals per group and 20 placebos per group at the start of the experiment. ***P<0.001, compared to placebo.</p

Effects of therapy with mDEF201 and cidofovir on survival of mice from a vaccinia virus (WR strain) respiratory infection.

a<p>The doses of mDEF201 are in PFU/mouse units, whereas the dose of cidofovir is in mg/kg/day units. mDEF201 was given as a single intranasal treatment, as was the placebo Cidofovir was administered by intraperitoneal route once a day for two days. For consistency with the other groups, the cidofovir group also received intranasal saline at 24 h.</p>b<p>Mean day of death for mice that died on or before day 21 of the infection. The mice were inoculated intranasally with 1×10⁵ PFU of virus to initiate the infection.</p><p>**P<0.01.</p><p>***P<0.001, compared to placebo.</p

Effects of treatment with mDEF201 (5- and 50-µl) and cidofovir on survival (A) and body weight change (B) during a vaccinia virus lower respiratory infection (initiated by a 50-µl i.n. virus inoculation) in mice.

<p>Intranasal treatments with mDEF201 (PFU/mouse) were given one time only 24 hours prior to virus exposure. Cidofovir (mg/kg/day) was administered i.p. once a day for two days at 4 and 24 hours after infection. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068685#pone-0068685-g001" target="_blank">Figure 1B</a> shows mean values ± SEM. There were 10 treated animals per group and 20 placebos at the start of the experiment. *P<0.05, ***P<0.001, compared to placebo.</p

Effects of treatment with mDEF201 on survival from a cowpox virus upper respiratory infection (initiated by a 10-µl i.n. virus inoculation) in mice.

<p>Intranasal (5- and 50-µl) treatments with mDEF201 were given one time only 24 hours prior to virus exposure. There were 10 treated animals per group and 20 placebos per group at the start of the experiment. ***P<0.001, compared to placebo.</p

Effects of treatment with mDEF201 on survival (A) and body weight change (B) during a cowpox virus lower respiratory infection (initiated by a 50-µl i.n. virus inoculation) in mice.

<p>Intranasal (50-µl) treatments with mDEF201 (PFU/mouse) were given one time only 24 hours prior to virus exposure. Cidofovir (mg/kg/day) was administered once a day for 2 days starting 4 hours after virus challenge. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068685#pone-0068685-g003" target="_blank">Figure 3B</a> shows mean values ± SEM. There were 10 treated animals per group, 20 placebos, and 6 normal control mice (uninfected, untreated) at the start of the experiment. ***P<0.001, compared to placebo.</p

Effects of extended prophylaxis with different doses of mDEF201 on tissue parameters during a vaccinia virus lower respiratory infection (initiated by a 50-µl i.n. virus inoculation) in mice.

<p>Single 50-µl i.n. treatments (PFU/mouse) were given on the day indicated prior to virus challenge. Determinations were made five days after infection. A = lung weight, B = lung hemorrhage score, C = liver virus titer, D = lung virus titer, E = snout virus titer, F = spleen virus titer. Virus titers are expressed as log₁₀ PFU/g of tissue. The limits of detection for the assays approached 10² PFU/g (most liver and spleen samples from mDEF201-treated mice did not have detectable virus present). The horizontal bars on the figures represent means values (N = 5 per group). *P<0.05, **P<0.01, ***P<0.001, compared to placebo.</p

Effects of extended prophylaxis with different doses of mDEF201 on survival (A) and body weight change (B) during a vaccinia virus lower respiratory infection (initiated by a 50-µl i.n. virus inoculation) in mice.

<p>Single 50-µl i.n. treatments (PFU/mouse) were given on the day indicated prior to virus challenge. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0068685#pone-0068685-g005" target="_blank">Figure 5B</a> shows mean values ± SEM. There were 10 treated animals per group, 20 placebos, and 6 normal control mice (uninfected, untreated) at the start of the experiment. ***P<0.001, compared to placebo.</p

TCAD therapy is highly efficacious in mice.

<p>(A) The kinetics of A/H5N1 virus replication in mouse lungs. Mice were infected with an LD₁₀₀ dose of virus and the lungs were harvested at the indicated time points (N = 5), homogenized, and the virus titer was determined by endpoint titration in Madin-Darby canine kidney cells. Kaplan Meier survival curves for treatment of mice infected with lethal doses of (B) a drug susceptible A/H5N1 influenza virus (A/Duck/MN/1525/81) and (C) AMT-resistant 2009 A/H1N1 influenza virus (A/California/04/09). Maximum weight loss analysis for the treatment of mice infected with (D) drug susceptible A/H5N1 and (E) AMT-resistant 2009 A/H1N1. For this experiment, mice were treated with AMT (46 mg/kg/day), OSL (25 mg/kg/day), and RBV (27 mg/kg/day) as monotherapies and in double or triple combinations at the same doses. Treatments were given three times a day for 5 days starting 24 hours after virus challenge, and survival and body weight loss were monitored over 21 days.</p