In vivo influenza virus-inhibitory effects of the cyclopentane neuraminidase inhibitor RJW-270201.
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 >10(4) cell culture 50% infective doses (CCID(50))/g. By day 8, the lung virus titers in mice treated with RWJ-270201 had declined to 10(1.2) CCID(50)/g, whereas titers from oseltamivir-treated animals were >10(3) CCID(50)/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.
Sidwell
R W
RW
Institute for Antiviral Research, Utah State University, Logan, Utah 84322-5600, USA. Rsidwell@cc.usu.edu
Smee
D F
DF
Huffman
J H
JH
Barnard
D L
DL
Bailey
K W
KW
Morrey
J D
JD
Babu
Y S
YS
D000081:Acetamides / Q000627:therapeutic use; D000146:Acids, Carbocyclic; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006146:Guanidines; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology; D009981:Influenza B virus / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D053139:Oseltamivir; D012129:Respiratory Function Tests; D012254:Ribavirin / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects
D000081:Acetamides; D000146:Acids, Carbocyclic; D000998:Antiviral Agents; D003517:Cyclopentanes; D006146:Guanidines; D053139:Oseltamivir; D012254:Ribavirin; D009439:Neuraminidase; C414210:peramivir