Lack of efficacy of aurintricarboxylic acid and ethacrynic acid against vaccinia virus respiratory infections in mice.
BACKGROUND
Aurintricarboxylic acid (ATA) and ethacrynic acid (ECA) have been reported to exhibit antiviral activity against vaccinia virus infections in cell culture by inhibiting early and late gene transcription, respectively. The purpose of this work was to determine if these inhibitors would effectively treat vaccinia virus infections in mice, which has not previously been studied.


METHODS
ECA was investigated by cell culture plaque reduction assay for the inhibition of cowpox and vaccinia virus infections to clarify issues regarding its potency and selectivity. Mice infected intranasally with vaccinia virus were treated by intraperitoneal route twice daily for 5 days with ATA (10 and 30 mg/kg/day) and ECA (15 and 30 mg/kg/day) or once daily for 2 days with cidofovir (100 mg/kg/day).


RESULTS
ECA caused 50% inhibition of virus plaque formation at 20-79 muM in four cultured cell lines, with 50% cytotoxicity at 84-173 muM, giving low (1.3-4.2) selectivity index values. Preliminary toxicity tests in uninfected mice indicated that ATA and ECA were both overtly toxic at 100 mg/kg/day. No protection from mortality was afforded by treatment of vaccinia virus infections with ATA or ECA, but 100% survival was achieved in the cidofovir group. ATA- and ECA-treated mice died significantly sooner than placebo-treated animals, indicating that these compounds exacerbated the infection.


CONCLUSIONS
Both ATA and ECA lack antiviral potency and selectivity in cell culture. The compounds were ineffective in treating mice at intraperitoneal doses of <or=30 mg/kg/day. These compounds do not appear to have potential for the treatment of poxvirus infections in vivo.
Smee
Donald F
DF
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA. don.smee@usu.edu
Hurst
Brett L
BL
Wong
Min-Hui
MH
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001312:Aurintricarboxylic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D063065:Organophosphonates / Q000494:pharmacology; D012141:Respiratory Tract Infections / Q000188:drug therapy* / Q000821:virology; D013997:Time Factors; D014615:Vaccinia / Q000188:drug therapy*; D014616:Vaccinia virus / Q000187:drug effects*
D000998:Antiviral Agents; D063065:Organophosphonates; D001312:Aurintricarboxylic Acid; D003596:Cytosine; D000077404:Cidofovir; D004976:Ethacrynic Acid