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Efficacy of delayed treatment with ST-246 given orally against systemic orthopoxvirus infections in mice.

Abstract
ST-246 was evaluated for activity against cowpox virus (CV), vaccinia virus (VV), and ectromelia virus (ECTV) and had an in vitro 50% effective concentration (EC50) of 0.48 microM against CV, 0.05 microM against VV, and 0.07 microM against ECTV. The selectivity indices were >208 and >2,000 for CV and VV, respectively. The in vitro antiviral activity of ST-246 was significantly greater than that of cidofovir, which had an EC50 of 41.1 microM against CV and 29.2 microM against VV, with selectivity indices of >7 and >10, respectively. ST-246 administered once daily by oral gavage to mice infected intranasally with CV beginning 4 h or delayed until 72 h postinoculation was highly effective when given for a 14-day duration using 100, 30, or 10 mg/kg of body weight. When 100 mg/kg of ST-246 was administered to VV-infected mice, a duration of 5 days was sufficient to significantly reduce mortality even when treatment was delayed 24 h postinoculation. Viral replication in liver, spleen, and kidney, but not lung, of CV- or VV-infected mice was reduced by ST-246 compared to levels for vehicle-treated mice. When 100 mg/kg of ST-246 was given once daily to mice infected by the intranasal route with ECTV, treatment for 10 days prevented mortality even when treatment was delayed up to 72 h after viral inoculation. Viral replication in target organs of ECTV-infected mice was also reduced.
AuthorsDebra C Quenelle, R M L Buller, Scott Parker, Kathy A Keith, Dennis E Hruby, Robert Jordan, Earl R Kern
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 51 Issue 2 Pg. 689-95 (Feb 2007) ISSN: 0066-4804 [Print] United States
PMID17116683 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Benzamides
  • Indoles
  • Isoindoles
  • ST-246
Topics
  • Administration, Oral
  • Animals
  • Benzamides (administration & dosage)
  • Disease Models, Animal
  • Female
  • Indoles (administration & dosage)
  • Isoindoles
  • Mice
  • Organ Specificity
  • Orthopoxvirus (drug effects, physiology)
  • Poxviridae Infections (drug therapy)
  • Time Factors
  • Treatment Outcome
  • Virus Replication (drug effects)

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