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Antimicrobial Agents and Chemotherapy, April 2002, p. 996-1004, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.996-1004.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Oral Administration of Cyclopentane Neuraminidase Inhibitors Protects Ferrets against Influenza Virus Infection

Clive Sweet,1* Kenneth J. Jakeman,1 Karen Bush,2 Pamela C. Wagaman,3 Linda A. Mckown,4 Anthony J. Streeter,4 Daksha Desai-Krieger,4 Pooran Chand,5 and Yarlagadda S. Babu5

School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom,1 The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey,2 The R. W. Johnson Pharmaceutical Research Institute, La Jolla, California,3 The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania,4 BioCryst Pharmaceuticals, Inc., Birmingham, Alabama5

Received 7 August 2001/ Returned for modification 16 November 2001/ Accepted 4 January 2002

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.

* Corresponding author. Mailing address: School of Biosciences, University of Birmingham, Birmingham B15 2TT, United Kingdom. Phone: 121-414-6554. Fax: 121-414-5925. E-mail: C.Sweet{at}bham.ac.uk.

Antimicrobial Agents and Chemotherapy, April 2002, p. 996-1004, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.996-1004.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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