Because of the conflicting data concerning the SARS-CoV inhibitory efficacy of
ribavirin, an
inosine monophosphate (
IMP) dehydrogenase inhibitor, studies were done to evaluate the efficacy of
ribavirin and other
IMP dehydrogenase inhibitors (5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), mizoribine, and mycophenolic acid) in preventing viral replication in the lungs of BALB/c mice, a replication model for
severe acute respiratory syndrome (SARS)
infections (Subbarao, K., McAuliffe, J., Vogel, L., Fahle, G., Fischer, S., Tatti, K., Packard, M., Shieh, W.J., Zaki, S., Murphy, B., 2004. Prior
infection and passive transfer of
neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in the respiratory tract of mice. J. Virol. 78, 3572-3577).
Ribavirin given at 75 mg/kg 4 h prior to virus exposure and then given twice daily for 3 days beginning at day 0 was found to increase virus lung titers and extend the length of time that virus could be detected in the lungs of mice. Other
IMP dehydrogenase inhibitors administered near maximum tolerated doses using the same dosing regimen as for
ribavirin were found to slightly enhance virus replication in the lungs. In addition,
ribavirin treatment seemed also to promote the production of pro-inflammatory
cytokines 4 days after
cessation of treatment, although after 3 days of treatment
ribavirin inhibited pro-inflammatory
cytokine production in infected mice, significantly reducing the levels of the
cytokines IL-1alpha,
interleukin-5 (IL-5),
monocyte chemotactic protein-1 (MCP-1), and
granulocyte-macrophage colony stimulating factor (
GM-CSF). These findings suggest that
ribavirin may actually contribute to the pathogenesis of SARS-CoV by prolonging and/or enhancing viral replication in the lungs. By not inhibiting viral replication in the lungs of infected mice,
ribavirin treatment may have provided a continual source of stimulation for the inflammatory response thought to contribute to the pathogenesis of the
infection. Our data do not support the use of
ribavirin or other
IMP dehydrogenase inhibitors for treating SARS
infections in humans.