GOVORKOVA EA, LENEVA IA, BUSH K, WEBSTER RG; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 271.

St. Jude Childrens Res. Hosp., Memphis, TN

BACKGROUND: The direct transmission of avian H5N1 and H9N2 influenza A viruses to humans in Hong Kong with high mortality after infection with H5N1 and mild clinical influenza after infection with H9N2 alerts us to the possibility of interspecies transmission of all influenza viruses. In such cases in which vaccines are unavailable, antiviral drugs are crucial for prophylaxis and therapy. Here we evaluated in vitro and in vivo efficacy of the anti-neuraminidase (NA) inhibitor RWJ-270201 against influenza viruses from the nine NA subtypes in comparison with zanamivir and oseltamivir.METHODS: NA activity was measured in the fluorescence-based assay with 2-(4-methylumbelliferyl)alpha-D-N-acetylneuraminic acid as a substrate. EC[50] values were determined in a cell ELISA method in MDCK cells. Treatment of Balb/c mice (10-12 per group) was by oral lavage twice daily for 5 days. The beginning of virus challenge (5 MLD[50]) varied according to the experiment.RESULTS: RWJ-270201 inhibited viral replication in MDCK cells (EC[50] values, 3.0 to 13.5 micro-M) and NA activity (IC[50] values, 5.0 to 10.0 nM) of avian influenza viruses representing both Eurasian and American lineages. In vivo studies in mice receiving between 1.0 and 10.0 mg/kg/day showed that RWJ-270201 completely protected animals against lethal challenge with A/Hong Kong/156/97 (H5N1) and A/quail/Hong Kong/G1/97 (H9N2) viruses. Both, RWJ-270201 and oseltamivir at doses of 1.0 and 10.0 mg/kg/day significantly reduced viral titers in mouse lungs, and prevented the spread of virus to the brain. Delay of initiation of treatment of mice infected with lethal doses of H5N1 with RWJ-270201 is under investigation and combination therapies are being examined to further reduce the amount of drug required to protect mice from death. Conclusion: All NA subtypes (N1[TM] N9) of avian influenza viruses are sensitive to the RWJ-270201 and it is efficacious in treating H5N1 and H9N2 avian influenza viruses that have been transmitted to humans.KEYWORDS: Influenza; Inhibitors; Neuraminidase

Publication Types:

• Meeting Abstracts

Keywords:

• Acetamides
• Animals
• Antiviral Agents
• Cell Line
• Cyclopentanes
• Hong Kong
• Humans
• In Vitro
• Influenza A virus
• Influenza Vaccines
• Influenza, Human
• Mice
• Mice, Inbred BALB C
• Neuraminidase
• Orthomyxoviridae
• Orthomyxoviridae Infections
• Oseltamivir
• Sialic Acids
• Zanamivir
• peramivir

Other ID:

• GWAIDS0011335

UI: 102248833

From Meeting Abstracts