Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor

Sidwell, Robert W.; Huffman, John H.; Barnard, Dale L.; Bailey, Kevin W.; Wong, Min-Hui; Morrison, A.; Syndergaard, Timothy; Kim, Choung U.

doi:10.1016/s0166-3542(97)00065-x

Cited by 164 publications

(124 citation statements)

References 21 publications

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“…In the case of zanamivir, it was reported that in mice, daily intranasal administration of 0.1 mg/kg body weight led to 90% survival, and 1 mg/kg body weight led to 100% survival, whereas oral treatment was only effective at higher doses (29). This efficacy is comparable with the ϳ95% inhibition of infection achieved with 0.13 mg/kg body weight of A22 as observed in this study.…”

Section: Discussionsupporting

confidence: 84%

A DNA Aptamer Prevents Influenza Infection by Blocking the Receptor Binding Region of the Viral Hemagglutinin

Jeon¹,

Kayhan²,

Ben-Yedidia³

et al. 2004

Journal of Biological Chemistry

157

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Influenza A virus infection is a major source of morbidity and mortality worldwide. Current means of control for influenza are based on prophylaxis by vaccines and on treatment by the available specific influenza neuraminidase inhibitor drugs. The approach taken in the present study is to prevent and/or ameliorate influenza infection by site-specific blocking of the viral binding to host cell receptors. We describe a novel oligonucleotide, known also as an aptamer, which has been designed to complement the receptor-binding region of the influenza hemagglutinin molecule. It was constructed by screening a DNA library and processing by the selective evolution of ligands by exponential enrichment (SELEX) procedure. We show that this DNA aptamer is indeed capable of inhibiting the hemagglutinin capacity of the virus, as well as in the prevention of viral infectivity in vitro, in tissue culture. Furthermore, it inhibits viral infection by different influenza strains in an animal model, as manifested by 90 -99% reduction of virus burden in the lungs of treated mice. The mode of action of this aptamer is by blocking the binding of influenza virus to target cell receptors and consequently prevention of the virus invasion into the host cells.

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Section: Discussionsupporting

confidence: 84%

A DNA Aptamer Prevents Influenza Infection by Blocking the Receptor Binding Region of the Viral Hemagglutinin

Jeon¹,

Kayhan²,

Ben-Yedidia³

et al. 2004

Journal of Biological Chemistry

157

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“…Effect of the synergistic combination of oseltamivir 0.05 mg/kg and rimantadine 5 mg/kg on lung parameters (Sidwell et al, 1998) AS Galabov et al 256 ©2006 International Medical Press (Leneva et al, 2000). An additive or synergistic effect of the combination as considered against H1N1 and H3N2 variants of influenza A virus was established in another previous study (Govorkova et al, 2004) (Bright et al, 2005), and to a lesser but gradually increasing degree towards NA inhibitors (de Jong et al, 2005).…”

Section: Estimation Of the Character Of The Combination Effectmentioning

confidence: 94%

“…The character of the combined antiviral effect of rimantadine hydrochloride and oseltamivir in influenza virus A (H3N2) infection in mice was determined according to the threedimensional model (Prichard and Shipman, 1990) for analysis of drug-drug interactions, modified for in vivo trials (Nikolaeva and Galabov, 2000 (Ilyenko et al, 1972;Galabov et al, 1991), and 1 mg/kg of oseltamivir as registered against A/Victoria/3/75(H3N2) and A/Shandong/09 /93(H3N2) (Sidwell et al, 1998). The results summarized in Table 1 Figure 2.…”

Section: Combination Activity Effectmentioning

confidence: 99%

Rimantadine and Oseltamivir Demonstrate Synergistic Combination Effect in an Experimental Infection with Type a (H3N2) Influenza Virus in Mice

Galabov

Simeonova

Gegova

2006

Antivir Chem Chemother

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We studied the combination effect of rimantadine hydrochloride and oseltamivir phosphate on mice infected with influenza A/Aichi/2/68 (H3N2) virus. Compounds were simultaneously administered in a 5-day-treatment course, starting 4 h before intranasal infection with 10 or 20 viral 50% mouse lethal doses. Initially, we tested combinations of oseltamivir (0.05, 0.1 and 0.2 mg/kg/day) and rimantadine (2.5, 5.0 and 7.5 mg/kg/day). Significant differences were recorded between combinationtreated groups, and groups with separately applied compounds and the placebo group, such as: protection index of oseltamivir with 5.0 or 7.5 mg/kg rimantadine varied between 34-41% and 43-87%, respectively, whereas the individual effects of oseltamivir, 5 mg/kg of rimantadine and 7.5 mg/kg of rimantadine were 0-10%, 0% and 18.7-29.6%, respectively; mean survival time in combination-treated groups was lengthened by 3.1-6.9 days, in oseltamivir groups by 0-1.9 days, and in rimantadine groups by 0.8-1.3 days at 5 mg/kg and 2.6-3.2 days at 7.5 mg/kg. The threedimensional method of Prichard and Shipman characterized the combination effect as synergistic. Further, we studied the activity of 0.05 mg/kg/day of oseltamivir combined with 5 mg/kg of rimantadine. Lung virus titre in Madin Darby canine kidney cells, lung index and consolidation score proved the high effectiveness of the combination. When compared with the placebo group, a 2.8 log 10 lower titre of 50% cell culture infectious dose (CCID 50 ) was recorded in the combinationtreated group at 48-60 h post-infection (the peak of lung virus growth). This is in contrast to the 0.1-1.0 log 10 and 1.1-1.4 log 10 reduction in CCID 50 titre observed in the oseltamivir and rimantadine groups, respectively. These data emphasize the high anti-influenza A potential of the combination.

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“…Because virus susceptibility in vitro does not always predict results in vivo (Sidwell et al, 1998(Sidwell et al, , 2001a, studies in an animal model are warranted. In the mouse animal model, we observed that the frequency and duration of peramivir administration are important factors in the adequate control of infection caused by the highly pathogenic H5N1 viruses.…”

Section: Discussionmentioning

confidence: 99%

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

Boltz¹,

Ilyushina²,

Arnold³

et al. 2008

Antiviral Research

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The replication efficiency and multi-organ dissemination of some influenza A (H5N1) viruses requires a rapid (re)evaluation of the available antiviral strategies. We assessed five regimens of the neuraminidase (NA) inhibitor peramivir in mice inoculated with H5N1 virus. The regimens differed by: (1) frequency of administration on first day (once vs twice); (2) duration of administration (1 day vs 8 days); (3) route of administration (intramuscular [IM] injection alone or followed by oral administration). In all regimens, BALB/c mice were administered 30 mg/kg peramivir IM one hour after lethal challenge with 5 MLD 50 of A/Vietnam/1203/04 (H5N1) influenza virus. When given only on the day of inoculation, a single IM injection produced a 33% survival rate, which increased to 55% with two injections. Eight-day regimens significantly increased survival; two IM injections followed by 7 daily IM injections was the most effective regimen (100% survival; inhibition of replication in lungs and brain). When this 8-day regimen began at 24 hours after inoculation, 78% of mice survived; 56% survived when treatment began at 48 after hours. Anti-HA antibody titer differed with the peramivir regimen and corresponded to the severity of disease. Overall, our results demonstrate that IM administration of peramivir is effective in promoting the survival of mice infected with systemically replicating H5N1 virus.

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Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor

Cited by 164 publications

References 21 publications

A DNA Aptamer Prevents Influenza Infection by Blocking the Receptor Binding Region of the Viral Hemagglutinin

A DNA Aptamer Prevents Influenza Infection by Blocking the Receptor Binding Region of the Viral Hemagglutinin

Rimantadine and Oseltamivir Demonstrate Synergistic Combination Effect in an Experimental Infection with Type a (H3N2) Influenza Virus in Mice

Intramuscularly administered neuraminidase inhibitor peramivir is effective against lethal H5N1 influenza virus in mice

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