Combined Interferon-α
            <sub>2</sub>
            , Rimantadine Hydrochloride, and Ribavirin Inhibition of Influenza Virus Replication In Vitro

Hayden, Frederick G.; Schlepushkin, Anatoli N.; Pushkarskaya, N. L.

doi:10.1128/aac.25.6.787-a

Cited by 13 publications

(16 citation statements)

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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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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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“…The three drugs are, individually, all active against infl uenza virus replication in vitro and act through different mechanisms, which implies that, when combined, they may achieve an additive or even synergistic action while reducing the risk of emergence of drug -resistant virus variants. As early as 1984, Hayden et al 125 pointed to the additive synergistic action between interferon -α 2, rimantadine, and ribavirin.…”

Section: Antiviral Drug Combinationsmentioning

confidence: 99%

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

Clercq

2007

Combating the Threat of Pandemic Influenza

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“…Although the combination of amantadine or rimantadine with ribavirin has been shown to have additive or synergistic activity in vitro (6,21) and when administered systemically in a murine model of acute influenzal pneumonia (11,33), only the combination of ribavirin and amantadine administered via SPA has been examined in an animal (murine) model and has been found to be more effective than singleagent therapy (33). Similar studies have not yet been done in humans.…”

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Safety and pharmacokinetics of rimantadine small-particle aerosol

Atmar

Greenberg

Quarles

et al. 1990

Antimicrob Agents Chemother

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The safety and pharmacokinetics of rimantadine administered by small-particle aerosol were assessed in healthy adults and adults with acute influenza virus infection. Aerosolized rimantadine delivered at a concentration of 40 ,Ig/liter of air was associated with nasal burning and irritation in normal volunteers. A concentration of 20 ,ug/liter of air was well tolerated for up to 12 h by normal volunteers and was not associated with any changes in pulmonary function, as measured by routine spirometry, plethysmography, or diffusion capacity of carbon monoxide. Mean peak levels of drug in serum were approximately 10-fold lower after 12 h of aerosol administration than they were after oral administration of 200 mg (29.7 versus 255 ng/ml, respectively), while mean nasal wash levels were approximately 100-fold higher (6,650 versus 66.6 ng/ml, respectively). Elimination half-lives were similar after both aerosol and oral administration (24.1 and 25.2 h, respectively), and rimantadine urinary excretion was <1% per 24 h in both groups. Twenty micrograms of aerosolized rimantadine per liter of air given 12 h daily for 3 days to nine adults with acute influenza virus infection was well tolerated. Levels in plasma after 12 h of aerosol inhalation were similar to those in normal volunteers, but were higher at the end of the third treatment than they were at the end of the first treatment (88.3 versus 47.9 ng/ml, respectively). Thus, rimantadine delivered via small-particle aerosol at a dose of 20 jig/liter of air was well tolerated in normal volunteers and in those with acute influenza and was associated with high local concentrations.Small-particle aerosol (SPA) delivery of antiviral agents was evaluated for the treatment of viral respiratory tract infections. This method of drug administration usually results in higher concentrations of drug at the site of infection than systemic administration does, may decrease or ameliorate systemic toxicities seen after systemic administration, and has been more effective than the systemic administration of antiviral agents in murine (31) and ferret (9) animal models of acute influenza virus infection. SPA delivery of antiviral agents has also been effective in the treatment of human respiratory viral diseases (13,14,17,22,24,28).Rimantadine has better antiviral activity against some influenza A virus strains than amantadine does (5), is better tolerated when taken orally (8), and is effective as a prophylactic (8, 35) and therapeutic (20,26,30,34,35) agent in influenza A virus infections. Hayden et al. (22) have previously reported the use of rimantadine delivered by ultrasonic nebulizer in subjects given an attenuated influenza A virus; except for minor complaints, the drug was well tolerated. No pharmacokinetic data were reported.Although the combination of amantadine or rimantadine with ribavirin has been shown to have additive or synergistic activity in vitro (6, 21) and when administered systemically in a murine model of acute influenzal pneumonia (11, 33), only the combination o...

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Combined Interferon-α ₂ , Rimantadine Hydrochloride, and Ribavirin Inhibition of Influenza Virus Replication In Vitro

Abstract: Volume 25, no. 1, p. 56, column 1, line 34: ... rimantadine had greater plaque inhibitory activity.. ." should read "... amantadine had greater plaque inhibitory activity.

Cited by 13 publications

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

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

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

Safety and pharmacokinetics of rimantadine small-particle aerosol

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Combined Interferon-α 2 , Rimantadine Hydrochloride, and Ribavirin Inhibition of Influenza Virus Replication In Vitro

Abstract: Volume 25, no. 1, p. 56, column 1, line 34: ... rimantadine had greater plaque inhibitory activity.. ." should read "... amantadine had greater plaque inhibitory activity.

Cited by 13 publications

References 0 publications

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

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

Existing Influenza Antivirals: Their Mechanisms of Action and Potential in the Face of Avian Influenza

Safety and pharmacokinetics of rimantadine small-particle aerosol

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Product

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Combined Interferon-α ₂ , Rimantadine Hydrochloride, and Ribavirin Inhibition of Influenza Virus Replication In Vitro