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Antimicrobial Agents and Chemotherapy, June 2007, p. 1962-1966, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01494-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Activity of T-1106 in a Hamster Model of Yellow Fever Virus Infection

Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, Utah 84322-5600,¹ Toyama Chemical Company, Ltd., 3-2-5 Nishishinjuku, Shinjuku-ku, Tokyo 187-0023, Japan²

Received 28 November 2006/ Returned for modification 22 January 2007/ Accepted 28 March 2007

Yellow fever virus (YFV) causes 30,000 deaths worldwide, despite the availability of a vaccine. There are no approved antiviral therapies for the treatment of YFV disease in humans, and, therefore, these studies were designed to investigate the anti-YFV properties of T-1106, a substituted pyrazine, in a hamster model of YFV disease. Intraperitoneal (i.p.) treatment with 100 mg/kg of body weight/day of T-1106 starting 4 h prior to virus inoculation and continuing twice daily through 7 days post-virus inoculation (dpi) resulted in significantly improved survival, alanine aminotransferase levels in the serum, weight gain, and mean day to death. Virus titer in the liver at 4 dpi was significantly reduced in treated animals, as determined by both quantitative real-time PCR and infectious cell culture assay. No toxicity (weight loss or mortality) was observed at a dose of 100 mg/kg/day in sham-infected control animals. The observed minimal effective dose of T-1106 was 32 mg/kg/day administered either by oral or i.p. treatment. Therapeutic treatment was effective in significantly improving survival when T-1106 was administered beginning as late as 4 days after virus challenge with twice-daily treatment for 8 days at a dose of 100 mg/kg/day. With favorable safety, bioavailability, and postviral challenge treatment efficacy, T-1106 was effective in the treatment of disease in hamsters infected with YFV and should be further studied for potential use as a therapy for human YFV disease.

Published ahead of print on 9 April 2007.