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Antimicrobial Agents and Chemotherapy, February 2004, p. 404-412, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.404-412.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Oral Treatment of Cowpox and Vaccinia Virus Infections in Mice with Ether Lipid Esters of Cidofovir

Debra C. Quenelle,1 Deborah J. Collins,1 W. Brad Wan,2 James R. Beadle,2 Karl Y. Hostetler,2 and Earl R. Kern1*

The University of Alabama School of Medicine, Birmingham, Alabama,1 The San Diego Veterans Affairs Healthcare System and the University of California, San Diego, La Jolla, California2

Received 7 July 2003/ Returned for modification 23 September 2003/ Accepted 7 October 2003

Four newly synthesized ether lipid esters of cidofovir (CDV), hexadecyloxypropyl-CDV (HDP-CDV), octadecyloxyethyl-CDV (ODE-CDV), oleyloxypropyl-CDV (OLP-CDV), and oleyloxyethyl-CDV (OLE-CDV), were found to have enhanced activities against vaccinia virus (VV) and cowpox virus (CV) in vitro compared to those of CDV. The compounds were administered orally and were evaluated for their efficacies against lethal CV or VV infections in mice. HDP-CDV, ODE-CDV, and OLE-CDV were effective at preventing mortality from CV infection when treatments were initiated 24 h after viral inoculation, but only HDP-CDV and ODE-CDV maintained efficacy when treatments were initiated as late as 72 h postinfection. Oral pretreatment with HDP-CDV and ODE-CDV were also effective when they were given 5, 3, or 1 day prior to inoculation with CV, even when each compound was administered as a single dose. Both HDP-CDV and ODE-CDV were also effective against VV infections when they were administered orally 24 or 48 h after infection. In animals treated with HDP-CDV or ODE-CDV, the titers of both CV and VV in the liver, spleen, and kidney were reduced 3 to 7 log10. In contrast, virus replication in the lungs was not significantly reduced. These data indicate that HDP-CDV or ODE-CDV given orally is as effective as CDV given parenterally for the treatment of experimental CV and VV infections and suggest that these compounds may be useful for the treatment of orthopoxvirus infections in humans.

* Corresponding author. Mailing address: Department of Pediatrics, The University of Alabama at Birmingham, 128 Children's Harbor Building, 1600 6th Ave. South, Birmingham, AL 35233. Phone: (205) 934-1990. Fax (205) 975-1992. E-mail: Kern{at}uab.edu.

Antimicrobial Agents and Chemotherapy, February 2004, p. 404-412, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.404-412.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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