Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses - PubMed (original) (raw)

Comparative Study

Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses

E A Govorkova et al. Antimicrob Agents Chemother. 2001 Oct.

Abstract

The orally administered neuraminidase (NA) inhibitor RWJ-270201 was tested in parallel with zanamivir and oseltamivir against a panel of avian influenza viruses for inhibition of NA activity and replication in tissue culture. The agents were then tested for protection of mice against lethal H5N1 and H9N2 virus infection. In vitro, RWJ-270201 was highly effective against all nine NA subtypes. NA inhibition by RWJ-270201 (50% inhibitory concentration, 0.9 to 4.3 nM) was superior to that by zanamivir and oseltamivir carboxylate. RWJ-270201 inhibited the replication of avian influenza viruses of both Eurasian and American lineages in MDCK cells (50% effective concentration, 0.5 to 11.8 microM). Mice given 10 mg of RWJ-270201 per kg of body weight per day were completely protected against lethal challenge with influenza A/Hong Kong/156/97 (H5N1) and A/quail/Hong Kong/G1/97 (H9N2) viruses. Both RWJ-270201 and oseltamivir significantly reduced virus titers in mouse lungs at daily dosages of 1.0 and 10 mg/kg and prevented the spread of virus to the brain. When treatment began 48 h after exposure to H5N1 virus, 10 mg of RWJ-270201/kg/day protected 50% of mice from death. These results suggest that RWJ-270201 is at least as effective as either zanamivir or oseltamivir against avian influenza viruses and may be of potential clinical use for treatment of emerging influenza viruses that may be transmitted from birds to humans.

PubMed Disclaimer

Figures

FIG. 1

FIG. 1

Effect of oral treatment with RWJ-270201 and oseltamivir on virus titers in the lungs of mice infected with influenza H5N1 and H9N2. RWJ-270201 and oseltamivir at dosages of 0.01 (○), 0.1 (▴), 1.0 (⧫), and 10 (□) mg/kg/day were administered to BALB/c mice by twice-daily oral gavage for 5 days beginning 4 h before viral infection. Mice were infected with 5 MLD50s of A/HK/156/97 (H5N1) (A and B) or mouse-adapted A/quail/HK/G1/97 (H9N2) (C and D) influenza viruses. Values shown are mean virus titers determined from three animals (log10 EID50/0.1 ml). Control untreated animals (▪) received sterile PBS on the same schedule.

FIG. 2

FIG. 2

Effect of treatment with RWJ-270201 and oseltamivir on mean loss or gain of weight in mice infected with H5N1 and H9N2 influenza viruses. RWJ-270201 and oseltamivir at dosages of 0.01 (○), 0.1 (▴), 1.0 (⧫), and 10 (□) mg/kg/day were administered to BALB/c mice by twice-daily oral gavage for 5 days beginning 4 h before viral infection. Mice were infected with 5 MLD50s of A/HK/156/97 (H5N1) (A and B) or mouse-adapted A/quail/HK/G1/97 (H9N2) (C and D) influenza viruses. Control untreated animals (▪) received PBS. The mice were weighed on day 0 (before inoculation) and days 4, 7, 9, 11, 14, and 16 after inoculation. Loss or gain of weight was calculated for each mouse as a percentage of its weight on day 0. Values are the averages for each group.

FIG. 3

FIG. 3

Effect of delayed treatment with RWJ-270201 or oseltamivir on survival rates of mice infected with A/HK/156/97 (H5N1) influenza virus. BALB/c mice (n = 9 to 10 per group) were infected intranasally with 10 MLD50s of influenza A/HK/156/97 (H5N1) virus and treated with RWJ-270201 or oseltamivir at 10 mg/kg/day by twice-daily oral gavage for 5 days. Treatment began 24 (▪), 36 (○), 48 (▴), or 60 (⧫) hours after virus inoculation. Control untreated animals (□) received PBS.

Similar articles

Cited by

References

    1. Babu Y S, Chand P, Bantia S, Kotian P, Dehghani A, El-Kattan Y, Lin T H, Hutchison T L, Elliott A J, Parker C D, Ananth S L, Horn L L, Laver G W, Montgomery J A. BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J Med Chem. 2000;43:3482–3486. - PubMed
    1. Barnett J M, Cadman A, Gor D, Dempsey M, Walters M, Candlin A, Tisdale M, Morley P J, Owens I J, Fenton R J, Lewis A P, Claas E C, Rimmelzwaan G F, De Groot R, Osterhaus A D. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies. Antimicrob Agents Chemother. 2000;44:78–87. - PMC - PubMed
    1. Belshe R B, Smith H M, Hall C B, Betts R, Hay A J. Genetic basis of resistance to rimantadine emerging during treatment of influenza virus infection. J Virol. 1988;62:1508–1512. - PMC - PubMed
    1. Bossart-Whitaker P, Carson M, Babu Y S, Smith C D, Laver W G, Air G M. Three-dimensional structure of influenza A N9 neuraminidase and its complex with inhibitor 2-deoxy-2,3-dehydro-N-acetyl-neuraminic acid. J Mol Biol. 1993;232:1069–1083. - PubMed
    1. Castrucci M R, Kawaoka Y. Biologic importance of neuraminidase stalk length in influenza A virus. J Virol. 1993;67:759–764. - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources