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 direc tly to humans and killed six of the 18 people infected. In 1999, another av ian A/Hong/1074/99 (H9N2) virus caused influenza in two children. In such c ases in which vaccines are unavailable, antiviral drugs are crucial for pro phylaxis and therapy. Here we demonstrate the efficacy of the neuraminidase inhibitor GS4104 (oseltamivir phosphate) against these H5N1 and H9N2 virus es. GS4071 (the active metabolite of oseltamivir) inhibited viral replicati on in MDCK cells (EC50 values, 7.5-12 muM) and neuraminidase activity (IC50 values, 7.0-15 nM). When orally administered at doses of 1 and 10 mg/kg pe r day, GS4104 prevented death of mice infected with A/Hong Kong/156/97 (H5N 1), 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 wa s delayed until 36 h after exposure to the H5N1 virus, GS4104 was still eff ective 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 inf ected with 100 MLD50 of H9N2 virus and prevented the deaths of mice infecte d with 5 MLD50 of virus. Thus, GS4104 is efficacious in treating infections caused by H5N1 and H9N2 influenza viruses in mice. (C) 2000 Elsevier Scien ce B.V. All rights reserved.