Effect of delayed T-705 and ribavirin therapy on PICV infection outcome in hamsters.

<p>Drugs were given orally twice per day for 7 days. Treatments were initiated on day 4, 5 or 6. T-705 was administered as a daily dose of 100 mg/kg. Ribavirin was dosed at 40 mg/kg/day. Ten animals per group (20 for the placebo) were observed daily for 4 weeks for (A) survival and every third day for (B) mean group weight determination of survivors. ***P<0.001 compared to 0.4% CMC placebo-treated hamsters.</p

Reduced systemic absorption of orally administered T-705 in PICV-infected hamsters.

<p>Infected or sham-infected animals were treated with 50 mg/kg of T-705 on day 7 of infection and plasma samples were taken from animals sacrificed at 0.25, 0.5, 1, 2 or 4 h after treatment. Samples were processed and analyzed by HPLC for T-705 and its primary metabolite, T-705M1, as described in the <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003725#s2" target="_blank">methods</a> section. Data represent the mean and standard error of the mean from 3 hamsters (n = 3) per time point.</p

Reduction of viral load and liver disease in PICV-challenged hamsters following delayed treatment with T-705 and ribavirin.

<p>Five hamsters per group were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003725#pone-0003725-g003" target="_blank">Figure 3</a>, and sacrificed on day 7 of the infection to assess (A) systemic and (B) hepatic viral burden, and liver disease as determined by (C) ALT measurement. Data points represent values for individual animals and mean virus titers and ALT levels for each group are represented by horizontal lines. *P<0.05; **P<0.01 compared to 0.4% CMC placebo-treated hamsters. ^a P<0.05 compared to hamsters receiving ribavirin treatment starting on the same day.</p

Serum and tissue virus burden during the course of PICV infection in hamsters.

<p>All daily sacrifice groups had 4 hamsters/group except for the day-0 control group, which had 3 animals. Due to death prior to time of sacrifice, tissue and serum samples could only be obtained for 2 and 1 hamsters for the day 9 and 10 groups, respectively. The serum sample was unobtainable from 1 of the day-8 hamsters due to death just prior to sacrifice. (A) Serum, (B) liver, (C) spleen, (D) kidney, (E) lung, (F) intestinal, and (G) brain virus titers were determined by infectious virus cell culture assay. Data points represent viral loads for individual hamsters with the group mean represented by the respective horizontal bar.</p

Systemic ALT, AST and type I IFN levels during the course of PICV infection in hamsters.

<p>Serum samples assayed for viral burden, as described for <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003725#pone-0003725-g001" target="_blank">Figure 1</a>, were also assayed for (A) ALT, (B) AST, and (C) type I IFN. Data points represent levels for individual hamsters with the group mean represented by the respective horizontal bar.</p

Effect of delayed treatment with equitoxic doses of T-705 and ribavirin on PICV infection in hamsters.

<p>Drugs were given orally twice per day for 7 days starting on day 5, 6 or 7 for the drug-treated groups and day 7 for the placebo group. T-705 was dosed at 160 mg/kg/day on the first day and 80 mg/kg/day thereafter. Ribavirin was given at 22 mg/kg/day on the first day and 11 mg/kg/day thereafter. Hamsters were observed 28 days for (A) survival and weights and standard deviations of survivors are shown for treatments initiated on day (B) 5, (C) 6 or (D) 7. The 0.4% CMC-treated placebo and sham-infected, untreated groups are included in B–D for comparison. For the survival analysis, *P<0.05; ***P<0.001 compared to placebo-treated hamsters by log-rank test. ^a P<0.05 compared to hamsters receiving ribavirin treatment starting on the same day.</p

Effect of delayed high-dose T-705 therapy on viral burden and liver disease in PICV-challenged hamsters.

<p>Five hamsters per group for the treatment groups initiated on day 6 were treated as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0003725#pone-0003725-g007" target="_blank">Figure 7</a>, and sacrificed on day 7 of the infection to assess (A) systemic, (B) splenic, and (C) hepatic viral loads, and (D) ALT. Data points represent values for individual animals and mean virus titers and ALT levels for each group are represented by horizontal lines.</p

Survival outcome following i.p. treatment of JUNV-infected guinea pigs with favipiravir.

<p>Guinea pigs (n = 12/experimental group) were challenged i.p. with 750 PFU of JUNV and dosed i.p. with favipiravir (300 mg/kg/d), ribavirin (50 mg/kg/d), or 2.9% sodium bicarbonate vehicle (placebo) beginning 48 h post-infection (p.i.). Treatments (Tx) were administered twice daily for 14 days (capped hashed line). A) survival (n = 9/group), and B) mean body weight (relative to initial starting weight) and C) temperature were monitored in all surviving animals for 42 days. **<i>P</i><0.01, ***<i>P</i><0.001 compared to placebo-treated animals by the log-rank test.</p

PK analysis of favipiravir in male Hartley guinea pigs dosed by oral instillation or intraperitoneal (i.p.) injection.

<p>Favipiravir (100 mg/kg) was administered orally in carrot baby food vehicle or by i.p. injection in 2.9% sodium bicarbonate. Longitudinal plasma favipiravir levels are shown from 3 animals per treatment group at 15 and 30 minutes, and 1, 2, and 4 h after treatment. Data points represent the mean and standard error of the mean.</p

Effect of i.p. favipiravir treatment on day 14 viral loads in JUNV-challenged guinea pigs.

<p>Animals were infected and treated as described in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002614#pntd-0002614-g003" target="_blank">Figure 3</a>. Three pre-designated animals in each treatment group were sacrificed on day 14 post-infection for analysis of A) serum, B) brain, C) heart, D) kidney, E) liver, F) lung and G) spleen virus titers. Two serum samples and 1 liver sample collected from 2 moribund animals from the placebo group euthanized on days 12 and 14 were also included in the analysis. Unique symbols in each treatment group represent values for the same animal across all parameters and hashed lines indicate the assay limits of detection in tissue samples. **<i>P</i><0.01, ***<i>P</i><0.001 compared to placebo.</p