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

The cyclopentane derivative [1S,2S,3R,4R]-3-[(1S)-1 -(acetylamino)-2-ethylb utyl]-4-[(aminomethyl)amino]-2-hydroxy-cyclopentanecarboxylic acid (RWJ-270 201) has been previously reported to be a potent and selective inhibitor of influenza virus neuraminidase, and to inhibit infections with this virus i n vitro, in mice, and in clinical challenge studies. The effect of oral gav age therapy of 100 mg/kg/day of RWJ-2710201 administered twice daily for 5 days beginning 16 h prior to virus exposure, on various immune factors of i mportance 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 enumeratio n of macrophages, T, T-helper, T-suppressor/cytotoxic, and B cells. Saline- treated mice and normal mice were run in parallel. Treatment had no signifi cant effect on any immune parameter. In a second experiment, mice infected with influenza A/NWS/33 (H1N1) were treated similarly with RWJ-270201 begin ning 4 h pre-virus exposure. Treatment prevented any deaths from occurring, and markedly lessened arterial oxygen decline, lung consolidation, and lun g virus titers. The mice developed mean neutralizing antibody (NA) titers o f 1:592, and six of seven rechallenged mice resisted rechallenge with the s ame virus, indicating the initial virus-inhibitory effect also did not prev ent the animals from developing an adequate humoral immune response to the virus. (C) 2001 Elsevier Science :B.V. All rights reserved.