Oral administration of cyclopentane neuraminidase inhibitors protects ferrets against influenza virus infection.
Several cyclopentane inhibitors of influenza virus neuraminidase that have inhibitory activities in tissue culture similar to those of zanamivir and oseltamivir have recently been described. These new inhibitors have been examined for efficacy against a virulent H3N2 influenza virus when administered orally to infected ferrets. Preliminary studies indicated that oral administration of BCX-1923, BCX-1827, or BCX-1812 (RWJ-270201) at a dose of 5 or 25 mg/kg of body weight was active in ferrets in reducing respiratory and constitutional signs and symptoms, but these antivirals affected virus titers in the upper and lower respiratory tracts only marginally. Of the three compounds, BCX-1812 seemed to be the most efficacious and was examined further at higher doses of 30 and 100 mg/kg. These doses significantly reduced peak virus titers in nasal washes and total virus shedding as measured by areas under the curve. Virus titers in lung homogenates were also reduced compared to those in controls, but the difference was not statistically significant. As was observed with BCX-1812 at lower doses, the nasal inflammatory cellular response, fever, and nasal signs were reduced while ferret activity was not, with activity remaining similar to uninfected animals.
Sweet
Clive
C
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom. C.Sweet@bham.ac.uk
Jakeman
Kenneth J
KJ
Bush
Karen
K
Wagaman
Pamela C
PC
McKown
Linda A
LA
Streeter
Anthony J
AJ
Desai-Krieger
Daksha
D
Chand
Pooran
P
Babu
Yarlagadda S
YS
D000081:Acetamides / Q000494:pharmacology; D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001831:Body Temperature; D002452:Cell Count; D003517:Cyclopentanes / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005289:Ferrets / Q000502:physiology*; D006146:Guanidines; D006207:Half-Life; D006385:Hemagglutination Inhibition Tests; D009980:Influenza A virus / Q000187:drug effects*; D008168:Lung / Q000382:microbiology; D008297:Male; D009296:Nasal Cavity / Q000166:cytology / Q000821:virology; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D053139:Oseltamivir
D000081:Acetamides; D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D006146:Guanidines; D053139:Oseltamivir; D009439:Neuraminidase; C414210:peramivir