Primary immune system effects of the orally administered cyclopentane neuraminidase inhibitor RWJ-270201 in influenza virus-infected mice

Abstract

The cyclopentane derivative [1 S,2 S,3 R,4 R]-3-[(1 S)-1-(acetylamino)-2-ethylbutyl]-4-[(aminoiminomethyl)amino]-2-hydroxy-cyclopentanecarboxylic acid (RWJ-270201) has been previously reported to be a potent and selective inhibitor of influenza virus neuraminidase, and to inhibit infections with this virus in vitro, in mice, and in clinical challenge studies. The effect of oral gavage therapy of 100 mg/kg/day of RWJ-270201 administered twice daily for 5 days beginning 16 h prior to virus exposure, on various immune factors of importance in response to primary influenza infection was determined in mice infected with influenza A/Shangdong/09/93 (H3N2) virus. Spleens taken from the mice 2 h after termination of treatment were processed for cytotoxic T lymphocytes (CTL) and natural killer (NK) cell activity and for enumeration of macrophages, T, T-helper, T-suppressor/cytotoxic, and B cells. Saline-treated mice and normal mice were run in parallel. Treatment had no significant effect on any immune parameter. In a second experiment, mice infected with influenza A/NWS/33 (H1N1) were treated similarly with RWJ-270201 beginning 4 h pre-virus exposure. Treatment prevented any deaths from occurring, and markedly lessened arterial oxygen decline, lung consolidation, and lung virus titers. The mice developed mean neutralizing antibody (NA) titers of 1:592, and six of seven rechallenged mice resisted rechallenge with the same virus, indicating the initial virus-inhibitory effect also did not prevent the animals from developing an adequate humoral immune response to the virus.