In vivo influenza virus-inhibitory effects of the cyclopentane neuraminidase inhibitor RWJ-270201

The cyclopentane influenza virus neuraminidase inhibitor RWJ-270201 was eva luated against influenza A/NWS/33 (H1N1), A/Shangdong/09/93 (H3N2), A/Victo ria/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 ribavir in was included in studies with the A/Shangdong and B/Hong Kong viruses. RW J-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, R ibavirin was also inhibitory but was less tolerated by the mire at the 75-m g/kg/day dose used. Disease-inhibitory effects included prevention of death , lessening of decline of arterial oxygen saturation, inhibition of lung co nsolidation, 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 e ffects on daily lung parameters in influenza A/Shangdong/09/93 virus-infect ed mice. Maximum virus titer inhibition was seen on day 1, with RWJ-270201 exhibiting the greater inhibitory effect, a titer reduction of > 10(4) cell culture 50% infective doses (CCID50)/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 10(1.2) CCID50/g, whereas tit ers from oseltamivir-treated animals were > 10(3) CCID50/g, Mean lung conso lidation was also higher in the oseltamivir-treated animals on day 8, Both neuraminidase inhibitors were well tolerated by the mice. RWJ-270201 was no ntoxic at doses as high as 1,000 mg/kg/day, These data indicate potential f or the oral use of RWJ-270201 in the treatment of influenza virus infection s in humans.