Intranasal treatment of cowpox virus respiratory infections in mice with cidofovir.
Orthopoxvirus infections in mice have been effectively treated with cidofovir, a clinically approved drug given by intravenous infusion to treat cytomegalovirus infections. In a bioterrorist scenario it would be technically difficult to give this drug to a large number of exposed individuals. New treatment approaches are being sought, which include giving cidofovir by alternative routes or designing oral prodrugs of cidofovir. In this report, intranasal cidofovir was investigated as a treatment of pulmonary cowpox virus infections in BALB/c mice. Ninety to 100% of animals given a single intranasal drug treatment (10, 20 or 40 mg/kg) 24 h after virus challenge survived the infection, whereas all placebo-treated mice died. Doses of 2.5 and 5 mg/kg resulted in 60 and 80% survival, respectively. Single treatments of 20 and 40 mg/kg could be given up to 3 days after virus inoculation and still be 80-90% protective. A single 40 mg/kg treatment of infected mice given 1 or 2 days after infection also resulted in statistically significant decreases in virus titer in lungs and nose/sinus compared to the placebo group. Drug efficacy was found to be contingent upon treatment volume. A 10 mg/kg intranasal dose given 24 h after virus challenge was 100 and 50% effective in volumes of 40 and 20 microl, respectively. The same dose in 5 and 10 microl volumes caused no decrease in mortality. The results of these studies establish the utility of cidofovir treatment of poxvirus infections in mice by intranasal route. The data suggest the possibility that aerosol delivery of cidofovir to human lungs may be a viable alternative to intravenous dosing.
Smee
D F
DF
Department of Animal, Dairy and Veterinary Sciences, Institute for Antiviral Research, Utah State University, Logan, UT 84322-5600, USA. dsmee@cc.usu.edu
Bailey
K W
KW
Wong
M
M
Sidwell
R W
RW
D000281:Administration, Intranasal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002522:Chlorocebus aethiops; D000077404:Cidofovir; D015605:Cowpox / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D015608:Cowpox virus / Q000187:drug effects* / Q000254:growth & development; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012137:Respiratory System / Q000187:drug effects / Q000821:virology; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D014709:Vero Cells; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D003596:Cytosine; D000077404:Cidofovir