The neuraminidase inhibitor GS4104 (oseltamivir phosphate) is efficacious against A/Hong Kong/156/97 (H5N1) and A/Hong Kong/1074/99 (H9N2) influenza viruses.
In 1997, an H5N1 avian influenza A/Hong Kong/156/97 virus transmitted directly to humans and killed six of the 18 people infected. In 1999, another avian A/Hong/1074/99 (H9N2) virus caused influenza in two children. In such cases in which vaccines are unavailable, antiviral drugs are crucial for prophylaxis and therapy. Here we demonstrate the efficacy of the neuraminidase inhibitor GS4104 (oseltamivir phosphate) against these H5N1 and H9N2 viruses. GS4071 (the active metabolite of oseltamivir) inhibited viral replication in MDCK cells (EC(50) values, 7.5-12 microM) and neuraminidase activity (IC(50) values, 7.0-15 nM). When orally administered at doses of 1 and 10 mg/kg per day, GS4104 prevented death of mice infected with A/Hong Kong/156/97 (H5N1), mouse-adapted A/Quail/Hong Kong/G1/97 (H9N2), or human A/Hong Kong/1074/99 (H9N2) viruses and reduced virus titers in the lungs and prevented the spread of virus to the brain of mice infected with A/Hong Kong/156/97 (H5N1) and mouse-adapted A/Quail/Hong Kong/G1/97 (H9N2) viruses. When therapy was delayed until 36 h after exposure to the H5N1 virus, GS4104 was still effective and significantly increased the number of survivors as compared with control. Oral administration of GS4104 (0.1 mg/kg per day) in combination with rimantadine (1 mg/kg per day) reduced the number of deaths of mice infected with 100 MLD(50) of H9N2 virus and prevented the deaths of mice infected with 5 MLD(50) of virus. Thus, GS4104 is efficacious in treating infections caused by H5N1 and H9N2 influenza viruses in mice.
Leneva
I A
IA
Department of Virology and Molecular Biology, St. Jude Children's Research Hospital, PO Box 318, 332 N. Lauderdale, Memphis, TN 38105-2794, USA.
Roberts
N
N
Govorkova
E A
EA
Goloubeva
O G
OG
Webster
R G
RG
D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000821:virology; D002460:Cell Line; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype; D053127:Influenza A Virus, H9N2 Subtype; D009980:Influenza A virus / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology; D007668:Kidney; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053139:Oseltamivir; D012299:Rimantadine / Q000627:therapeutic use; D014779:Virus Replication / Q000187:drug effects
D000081:Acetamides; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012299:Rimantadine; D053139:Oseltamivir; D009439:Neuraminidase