Activity of T-1106 in a hamster model of yellow Fever virus infection.
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.
Julander
Justin G
JG
Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, USA. jgjulander@cc.usu.edu
Furuta
Yousuke
Y
Shafer
Kristiina
K
Sidwell
Robert W
RW
D000577:Amides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008647:Mesocricetus; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014709:Vero Cells; D015004:Yellow Fever / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D015005:Yellow fever virus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology
D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; C462182:favipiravir