In Vivo Synergistic Combination Effect of Rimantadine and Oseltamivir Against Influenza A(H3N2) is Manifested in Several Dose Ratios

Pharmacokinetics and Safety of Coadministered Oseltamivir and Rimantadine in Healthy Volunteers: An Open‐Label, Multiple‐Dose, Randomized, Crossover Study

“…12 In vivo combination work in mice with oseltamivir and rimantadine has also shown synergistic effects, with increased indices of protection and survival times relative to monotherapy with either drug. 11,18 Although the clinical or virologic benefits of coadministration of oseltamivir and rimantadine in humans have yet to be investigated, these preliminary indications together with the present findings are encouraging.…”

“…Inoculation of MDCK cells infected with influenza A (H1N1 or H3N2) with oseltamivir and rimantadine resulted in a synergistic cytotoxic effect that led to reduced viral yields under exposure to both drugs 12 . In vivo combination work in mice with oseltamivir and rimantadine has also shown synergistic effects, with increased indices of protection and survival times relative to monotherapy with either drug 11 , 18 . Although the clinical or virologic benefits of coadministration of oseltamivir and rimantadine in humans have yet to be investigated, these preliminary indications together with the present findings are encouraging.…”

“…10 In vitro and in vivo preclinical studies involving influenza A (H1, H3, and H5) viruses have shown that combination therapy with oseltamivir and amantadine or rimantadine is more effective and is associated with less resistance than either agent alone. [11][12][13][14][15][16][17][18][19] Coadministration of oseltamivir and amantadine was shown to be safe and to lack pharmacokinetic consequences in a small crossover study in 17 healthy volunteers. 20 Rimantadine is potentially a more suitable combination partner for oseltamivir, however, because central nervous system events are less frequently reported with this agent.…”

Pharmacological Characterization of the Spectrum of Antiviral Activity and Genetic Barrier to Drug Resistance of M2-S31N Channel Blockers

“…The need for combination therapy is further justified because monotherapy with oseltamivir was suboptimal in the treatment of H5N1-infected patients, with a mortality rate as high as 60% (Abdel-Ghafar et al, 2008;Kandun et al, 2008). It has been shown in a number of studies that a combination of M2 inhibitors (amantadine or rimantadine) with neuraminidase inhibitors (oseltamivir carboxylate or peramivir), ribavirin, or a combination of all three was in general synergistic in in vitro cell culture assays and in vivo mouse studies (Govorkova et al, 2004;Ilyushina et al, 2006Ilyushina et al, , 2007Simeonova et al, 2007Simeonova et al, , 2008Simeonova et al, , 2009Smee et al, 2009;Bantia et al, 2010). Gratifyingly, our rationally designed M2-S31N inhibitor WJ379 displayed strong synergy with oseltamivir carboxylate, with a synergy volume of 166, suggesting that combination therapy of WJ379 with oseltamivir carboxylate might be an option for controlling influenza viruses in the future.…”