Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106Antimicrob Agents Chemother (2009)
AbstractTreatment with the nucleoside analog T-1106 was previously shown to be effective in a hamster model of yellow fever virus (YFV) disease, even though it had only slight activity in cell culture. In the study described in this report, the activity of T-705, a chemically related compound currently undergoing clinical trials for the treatment of inﬂuenza (FDANews 4:1, 2007), was tested against YFV in cell culture and in the hamster model. The antiviral efﬁcacy of T-705 in cell culture occurred at a concentration of 330 µM, which was more than threefold lower than the concentration at which T-1106 had antiviral efﬁcacy, as determined by a virus yield reduction assay and conﬁrmed by a luciferase-based ATP detection assay. Time-of-addition studies revealed that addition of T-705, T-1106, or ribavirin at 0, 4, 8, or 12 h after virus challenge was effective in inhibiting virus in Vero cells, suggesting that these three agents have similar mechanisms of action in cell culture. Because of its more potent activity in cell culture, it was anticipated that T-705 treatment of hamsters infected with YFV would result in protection from disease. Signiﬁcant improvements in survival and disease parameters were seen in infected animals when T-705 was administered orally at a dose of 200 or 400 mg/kg of body weight per day when it was given twice a day for 8 days. Signiﬁcant improvements were also observed with a dose of 400 mg/kg/day when treatment initiation was delayed as late as 3 days after virus inoculation. Although the dose of T-705 required for efﬁcacy in hamsters is higher than that of T-1106 required for efﬁcacy, T-705 treatment is effective in signiﬁcantly improving disease parameters in YFV-infected hamsters, which may indicate its potential utility in the treatment of YFV disease in humans.
- yellow fever,
- hamster model
Publication DateJanuary 1, 2009
Citation InformationJulander, J. G., K. Shafer, D. F. Smee, J. D. Morrey, and Y. Furuta. 2009. Activity of T- 705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106. Antimicrob Agents Chemother 53:202-209. PMID18955536 PMCPMC2612161