title: Evaluation of inhaled cidofovir as postexposure prophylactic in an aerosol rabbitpox model.
abstract: Smallpox is considered a biological threat based upon the possibility of deliberate reintroduction into the population, creating an urgent need for effective antivirals. The antiviral drug cidofovir (Cr) has shown to be effective against poxviruses, although route-specific nephrotoxicity has hampered its development for emergency post-exposure prophylaxis (PEP). In this study, we use a micronized dry powder formulation of pharmaceutical-grade Cr (NanoFOVIRTM; Nf) to treat rabbits exposed to aerosolized rabbitpox virus (RPXV) to further evaluate the effectiveness of direct drug delivery to the lung. Naïve rabbits were infected with RPXV by aerosol; three subsets received aerosolized Nf at 0.5, 1.0 or 1.75mg/kg daily for 3days post-exposure, positive and negative control groups received intravenous (IV) Cr treatments and no treatment, respectively. Nf groups showed an antiviral-dose associated survival of 50% (0.5mg/kg), 80% (1.0mg/kg) and 100% (1.75mg/kg). All animals (100%) from the IV-Cr treatment group and none (0%) from the untreated controls survived. Nf (1.75) protected rabbits from RPX at approximately 10% of the equivalent IV-Cr dose. A dose-related effect was observed in clinical development of RPX disease in Nf groups. Significant reduction of RPX-induced pathological changes was observed in Nf (1.75) and IV-Cr groups. Results suggest that Nf may be a viable antiviral for emergency post-exposure prophylaxis and should be evaluated in other models of poxviral disease.
authors.affiliation: Division of Microbiology, Tulane National Primate Research Center, Covington, LA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Verreault
authors.forename: Satheesh K
authors.initials: SK
authors.lastname: Sivasubramani
authors.forename: James D
authors.initials: JD
authors.lastname: Talton
authors.forename: Lara A
authors.initials: LA
authors.lastname: Doyle
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Reddy
authors.forename: Stephanie Z
authors.initials: SZ
authors.lastname: Killeen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Didier
authors.forename: Preston A
authors.initials: PA
authors.lastname: Marx
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Roy
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D002460:Cell Line; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004195:Disease Models, Animal; D005260:Female; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D063065:Organophosphonates / Q000008:administration & dosage*; D056990:Post-Exposure Prophylaxis; D011817:Rabbits; D014615:Vaccinia / Q000401:mortality / Q000517:prevention & control* / Q000821:virology; D014616:Vaccinia virus
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir