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

Abstract

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.

Triple Combination of Oseltamivir, Amantadine, and Ribavirin Displays Synergistic Activity against Multiple Influenza Virus Strains In Vitro

“…For instance, the combination of rimantadine (another M2 inhibitor) and oseltamivir was synergistic in vitro and in vivo against influenza H1N1 and H3N2 (13,14), but the combination of amantadine and oseltamivir was not synergistic in vivo against influenza H5N1 (25). In addition, the rimantadine/ribavirin combination was found to be synergistic against influenza H1N1 and H3N2 strains in one study (20) but was found to be additive against different H1N1 and H3N2 strains FIG.…”

“…The in vitro studies evaluating double combinations for influenza have included amantadine plus ribavirin (20,46); amantadine plus oseltamivir (23,46); rimantadine plus ribavirin (20,32); rimantadine plus zanamivir, oseltamivir, or peramivir (14); ribavirin plus peramivir (44); and ribavirin plus oseltamivir (46). The antiviral activity of double drug combinations also has been evaluated in animal studies for the combinations of oseltamivir plus rimantadine (13,31), oseltamivir plus amantadine (25,46), ribavirin plus peramivir (45), ribavirin plus oseltamivir (24,46,47), and ribavirin plus amantadine (46).…”

“…For example, it has been known since the mid-to late 1990s that the simultaneous use of three antiviral agents in combination for human immunodeficiency virus (HIV) will block viral replication and decrease the probability of the emergence of resistance, effectively establishing a chemicogenetic barrier to drug-resistant mutations (16,17). With regard to the use of combination therapy for influenza virus, clinical studies have tested the safety and drug interactions of double combinations of available anti-influenza drugs (36), and a number of studies have looked at the effect of double drug combinations for the treatment of influenza virus in vitro (14,19,20,23,32,44) and in animals (13,25,31,44,47). To date, there are no published studies of the effects of triple antiviral drug combinations for influenza virus.…”

Reduction of Neuraminidase Activity Exacerbates Disease in 2009 Pandemic Influenza Virus-Infected Mice

“…vir against new and emerging strains of influenza is frequently tested in mice and other animal species and is used as a predictor for efficacy in humans (12)(13)(14)(67)(68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78)(79)(80)), but we demonstrate here that evaluation of antiviral efficacy in in vitro assays as well as in vivo analyses in other animal species should be assessed collectively to ensure that an accurate understanding of antiviral efficacy for humans will be predicted.…”

Chemotherapy of Influenza: Current and Novel Approach

“…The synergistic effect of rimantadine and oseltamivir against H3N2 in mice was characterized by Galabov et al (22). Amantadine, when combined with oseltamivir in laboratory animals, demonstrated enhanced protection as compared to monotherapy against H1N1, H3N2, A/Duck/MN/1525/81 (H5N1) (40,52,80).…”