Treatment of Cowpox Virus Respiratory Infections in Mice with Ribavirin as a Single Agent or Followed Sequentially by Cidofovir

Abstract

To better understand the potential of ribavirin in the treatment of orthopoxvirus infections (such as those acquired through bioterrorist activities), the efficacy of the drug was studied in a cowpox respiratory infection model in mice under varying disease severity. Mice did not survive a high intranasal cowpox virus challenge [3 × 106 plaque forming units (pfu)/animal] treated with subcutaneous ribavirin (100 mg/kg/day for 5 days), but lived 3.9 days longer than placebos. In contrast, 100% of animals receiving the same dose of drug survived a 3 × 105 pfu challenge compared with 0% survival of those that received placebo. Survival rates of 50 and 30% occurred with ribavirin doses of 50 and 25 mg/kg/day, respectively. At the 100 mg/kg/day dose, ribavirin reduced lung virus titres 40-fold on day 6 of the infection relative to titres in the placebo group. Weight loss resulting from illness and mean lung weights of mice treated with ribavirin were also significantly reduced. Mice were infected intranasally with the high 3 × 106 pfu virus challenge dose and treated with 100 mg/kg/day ribavirin for 5 days, followed by single injections of 75 mg/kg cidofovir on day 6, 7, 8 or 9. Cidofovir alone (without ribavirin) administered on day 6 had no beneficial effect on disease outcome. Ribavirin alone increased the mean time to death by 3.7 days. Ribavirin treatment for 5 days followed by cidofovir treatment on days 6 and 7 significantly increased the mean time to death beyond that achieved with ribavirin alone by 8.2 and 4.4 days, respectively, with 30 and 40% of mice surviving the infection. These results suggest that many individuals infected with an orthopoxvirus by aerosol route would benefit by a course of ribavirin therapy. Later, the fewer number of very sick individuals could be treated with intravenous cidofovir.

Treatment of Lethal Vaccinia Virus Respiratory Infections in Mice with Cidofovir

“…infection model in mice, the efficacy of ribavirin was dependent upon virus challenge dose (Smee et al, 2000a). We hypothesized that the same virus challenge dose-dependent effect would be seen using cidofovir in the vaccinia virus model.…”

“…On day 5 of the infection, lungs from five mice/group were collected, given a severity score (from 0 to 4, correlating with degree of lung consolidation and haemorrhage of 0-100% lung involvement), weighed, and frozen for later virus titration. Poxvirus titres from homogenized lungs were later determined by plaque assay in Vero cells as described previously (Smee et al, 2000a). Virus titre determinations from tissues besides lungs were performed in the same manner as lungs, with the exception of blood.…”

“…The drug was also found to be active in treating molluscum contagiosum in immunocompromised humans (Meadows et al, 1997). An unrelated drug, ribavirin, showed a more moderate degree of efficacy compared to cidofovir against cowpox virus infection ( Smee et al, 2000a). When combined with immune globulin, ribavirin effectively treated a progressive vaccinia virus infection in a human cancer patient (Kesson et al, 1997).…”

Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro

“…Since MPA undergoes no metabolism in cells, it is most likely excreted rapidly from cells following removal of the drug from the extracellular medium. Treatment of animals or humans with either substance would logically require frequent administration (predicated upon biological half-life of the compounds in vivo), as was done using ribavirin to protect mice against lethal cowpox virus infections (Smee et al, 2000a).…”

“…HPMPC is effective in the treatment of molluscum contagiosum (poxvirus) infections in AIDS patients (Meadows et al, 1997;Davies et al, 1999;Toro et al, 2000). In addition, the drug is very effective in mouse models of cowpox (Bray et al, 2000;Smee et al, 2000a) and vaccinia (Smee et al, 2001a, b) virus infections. Ribavirin is reported to be active in a vaccinia tail lesion infection model (De Clercq et al, 1976) and against cowpox virus (Smee et al, 2000b) in mice.…”