Enhancement of activity against influenza viruses by combinations of antiviral agents

Hayden, Frederick G.; Douglas, R. Gordon; Simons, Ruth L.

doi:10.1128/aac.18.4.536

Cited by 50 publications

(38 citation statements)

References 24 publications

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“…In contrast to this study, we used highly purified HuIFN-a2 and clinical isolates of contemporary influenza A viruses. Our results also confirm earlier in vitro studies in MDCK (9) and chicken embryo fibroblast (5) cell cultures, which showed that rimantadine and ribavirin combinations have enhanced antiviral activity against influenza A viruses. More importantly, we found that under certain in vitro conditions the combination of all three antiviral agents could be shown to have greater inhibitory activity than the combination of any two agents.…”

Section: Discussionsupporting

confidence: 81%

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Combined interferon-alpha 2, rimantadine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro

Hayden

Schlepushkin

Pushkarskaya

1984

Antimicrob Agents Chemother

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Recombinant DNA-produced human interferon-alpha 2 inhibited the replication of influenza A and B viruses in primary rhesus monkey kidney cells (RMK). Human interferon-alpha 2 interacted additively or synergistically with rimantadine hydrochloride or ribavirin in reducing the yield of clinical isolates of either H3N2 or H1N1 subtype influenza A viruses. The combination of human interferon-alpha 2 and ribavirin also inhibited the replication of an influenza B virus to a greater extent than either single agent. In addition to drug concentration, the virus inoculum and duration of culture were important variables in determining the degree of inhibition. Single drugs or combinations did not significantly inhibit the growth of uninfected RMK cells, which indicated that the observed interactions with respect to antiviral activity were not due to cell cytotoxicity.

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Section: Discussionsupporting

confidence: 81%

“…Before each experiment, thawed samples were further diluted in Eagle minimal essential medium containing 1% glutamine, 100 U of penicillin per ml and 50 ,ug of gentamicin per ml. (5,9,15).…”

Section: Methodsmentioning

confidence: 99%

Combined interferon-alpha 2, rimantadine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro

Hayden

Schlepushkin

Pushkarskaya

1984

Antimicrob Agents Chemother

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“…Ribavirin, a broad-spectrum antiviral compound, which displays an anti-flu effect, is an example in this respect (Sidwell et al, 1985). (Galegov et al, 1977;Wilson et al, 1980;Hayden et al, 1980Hayden et al, , 1984Hayden, 1986), and with some biological response modifiers: human interferon-α (Hayden et al, 1984), protease inhibitor aprotonin (Zhirnov, 1987) and the antioxidant ionol (4-methyl-2,6-ditretbutylphenol) (Galabov et al, 1994b).…”

Section: Some Authors Noticed a More Rapid Development Of Resistancmentioning

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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“…The activity of ribavirin alone or in combination with other antiviral agents against highly pathogenic H5N1 viruses has not been studied, but the activity of ribavirin against influenza viruses of the H1N1 and H3N2 subtypes has been investigated in vitro and in vivo (14,18,23,39,40,45). Ribavirin combined with rimantadine or zanamivir exerted an additive antiviral effect and, at specific concentrations, a synergistic antiviral effect to reduce the yield of influenza viruses in Madin-Darby canine kidney (MDCK) cells (14,23). In a mouse model, the use of ribavirin with the M2 ion-channel blocker amantadine enhanced the survival of the mice, and the combination was significantly more effective than either drug alone (45).…”

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confidence: 99%

Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice

Ilyushina

Hay²,

Yılmaz³

et al. 2008

Antimicrob Agents Chemother

120

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We studied the effects of a neuraminidase inhibitor (oseltamivir) and an inhibitor of influenza virus polymerases (ribavirin) against two highly pathogenic H5N1 influenza viruses. In vitro, A/Vietnam/1203/04 virus (clade 1) was highly susceptible to oseltamivir carboxylate (50% inhibitory concentration [IC 50 ] ‫؍‬ 0.3 nM), whereas A/Turkey/15/06 virus (clade 2.2) had reduced susceptibility (IC 50 ‫؍‬ 5.5 nM). In vivo, BALB/c mice were treated with oseltamivir (1, 10, 50, or 100 mg/kg of body weight/day), ribavirin (37.5, 55, or 75 mg/kg/day), or the combination of both drugs for 8 days, starting 4 h before virus inoculation. Monotherapy produced a dose-dependent antiviral effect against the two H5N1 viruses in vivo. Three-dimensional analysis of the drug-drug interactions revealed that oseltamivir and ribavirin interacted principally in an additive manner, with several exceptions of marginal synergy or marginal antagonism at some concentrations. The combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 1 mg/kg/day and the combination of ribavirin at 37.5 mg/kg/day and oseltamivir at 10 mg/kg/day were synergistic against A/Vietnam/1203/04 and A/Turkey/ 15/06 viruses, respectively. These optimal oseltamivir-ribavirin combinations significantly inhibited virus replication in mouse organs, prevented the spread of H5N1 viruses beyond the respiratory tract, and abrogated the cytokine response (P < 0.01). Importantly, we observed clear differences between the efficacies of the drug combinations against two H5N1 viruses: higher doses were required for the protection of mice against A/Turkey/15/06 virus than for the protection of mice against A/Vietnam/1203/04 virus. Our preliminary results suggest that oseltamivir-ribavirin combinations can have a greater or lesser antiviral effect than monotherapy, depending on the H5N1 virus and the concentrations used.

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Enhancement of activity against influenza viruses by combinations of antiviral agents

Cited by 50 publications

References 24 publications

Combined interferon-alpha 2, rimantadine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro

Combined interferon-alpha 2, rimantadine hydrochloride, and ribavirin inhibition of influenza virus replication in vitro

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

Oseltamivir-Ribavirin Combination Therapy for Highly Pathogenic H5N1 Influenza Virus Infection in Mice

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