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Antimicrobial Agents and Chemotherapy, March 2001, p. 749-757, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.749-757.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

In Vivo Influenza Virus-Inhibitory Effects of the Cyclopentane Neuraminidase Inhibitor RWJ-270201

Robert W. Sidwell,1,* Donald F. Smee,1 John H. Huffman,1 Dale L. Barnard,1 Kevin W. Bailey,1 John D. Morrey,1 and Y. S. Babu2

Institute for Antiviral Research, Utah State University, Logan, Utah 84322-5600,1 and BioCryst Pharmaceuticals, Inc., Birmingham, Alabama 352442

Received 12 July 2000/Returned for modification 11 October 2000/Accepted 30 November 2000

The cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 was evaluated against influenza A/NWS/33 (H1N1), A/Shangdong/09/93 (H3N2), A/Victoria/3/75 (H3N2), and B/Hong Kong/05/72 virus infections in mice. Treatment was by oral gavage twice daily for 5 days beginning 4 h pre-virus exposure. The influenza virus inhibitor oseltamivir was run in parallel, and ribavirin was included in studies with the A/Shangdong and B/Hong Kong viruses. RWJ-270201 was inhibitory to all infections using doses as low as 1 mg/kg/day. Oseltamivir was generally up to 10-fold less effective than RWJ-270201. Ribavirin was also inhibitory but was less tolerated by the mice at the 75-mg/kg/day dose used. Disease-inhibitory effects included prevention of death, lessening of decline of arterial oxygen saturation, inhibition of lung consolidation, and reduction in lung virus titers. RWJ-270201 and oseltamivir, at doses of 10 and 1 mg/kg/day each, were compared with regard to their effects on daily lung parameters in influenza A/Shangdong/09/93 virus-infected mice. Maximum virus titer inhibition was seen on day 1, with RWJ-270201 exhibiting the greater inhibitory effect, a titer reduction of >104 cell culture 50% infective doses (CCID50)/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 101.2 CCID50/g, whereas titers from oseltamivir-treated animals were >103 CCID50/g. Mean lung consolidation was also higher in the oseltamivir-treated animals on day 8. Both neuraminidase inhibitors were well tolerated by the mice. RWJ-270201 was nontoxic at doses as high as 1,000 mg/kg/day. These data indicate potential for the oral use of RWJ-270201 in the treatment of influenza virus infections in humans.

* Corresponding author. Mailing address: Institute for Antiviral Research, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600. Phone: (435) 797-1902. Fax: (435) 797-3959. E-mail: Rsidwell{at}cc.usu.edu

Antimicrobial Agents and Chemotherapy, March 2001, p. 749-757, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.749-757.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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