We employed a murine model to test the concept of using an aerosolized, long-acting
antiviral drug to protect humans against
smallpox. We previously showed that a low dose of aerosolized
cidofovir (
HPMPC [
Vistide]) was highly protective against subsequent aerosolized cowpox virus challenge and was more effective than a much larger dose of
drug given by injection, suggesting that aerosolized
cidofovir is retained in the lung. Because the nephrotoxicity of
cidofovir is a major concern in
therapy, delivering the
drug directly to the respiratory tract might be an effective prophylactic strategy that maximizes the tissue concentration at the site of initial viral replication, while minimizing its accumulation in the kidneys. In the present study, we found that treating mice with aerosolized (14)C-labeled
cidofovir ((14)C-cidofovir) resulted in the prolonged retention of radiolabeled
drug in the lungs at levels greatly exceeding those in the kidneys. In contrast,
subcutaneous injection produced much higher concentrations of (14)C-cidofovir in the kidneys than in the lungs over the 96-h time course of the study. As further evidence of the protective efficacy of aerosolized
cidofovir, we found that
aerosol treatment before or after
infection was highly protective in mice challenged intranasally with cowpox virus. All or nearly all mice that were treated once by
aerosol, from 2 days before to 2 days after challenge, survived intranasal
infection, whereas all placebo-treated animals died.