Table 1.
Effect of the double and triple drug combinations on influenza virus infections in vitro.
| Drug combinations | Influenza strain (subtype) | Method of analysis | Drug interactions | Ref. |
|---|---|---|---|---|
| Double combinations | ||||
| Rimantadine + Ribavirin | A/Chick/Germany/27 (FPV Weybridge) (H7N7) a |
Virus yield inhibition (PFU) | Additive-synergistic | [22] |
| A/USSR/77 (H1N1) A/Texas/77 (H3N2) |
Virus yield inhibition (PFU) | Additive-synergistic | [26] | |
| A/England/80 (H1N1) b A/Aichi/68 (H3N2) B/Lee/40 |
Virus yield inhibition (PFU) | Subadditive-additive-synergistic | [27] | |
| A/Virginia/87 (H1N1) A/Virginia/88 (H3N2) |
Virus yield inhibition (ELISA) | Additive | [34] | |
| Amantadine + Ribavirin | A/USSR/90/77 (H1N1) A/Texas/1/77 (H3N2) A/New Jersey/76 (H1N1) |
Virus yield inhibition (PFU) | Enhanced inhibitory effect | [26] |
| A/Duck/MN/1525/81 (H5N1) | Virus yield inhibition (TCID50) | Synergistic c | [38] | |
| A/Duck/MN/1525/81 (H5N1)d | Virus yield inhibition (TCID50) | No added benefit c | [38] | |
| A/California/04/09 (H1N1) e A/California/05/09 (H1N1) e A/California/10/09 (H1N1) e |
Virus yield inhibition (NR staining) | Additive c | [39] | |
| Zanamivir + Ribavirin | A/Virginia/87 (H1N1) A/Virginia/88 (H3N2) |
Virus replication inhibition (ELISA) | Additive | [34] |
| Zanamivir + Rimantadine | A/New Caledonia/20/99 (H1N1) A/Panama/2007/99 (H3N2) |
Virus (TCID50, MDCK) and cell-associated yield inhibition (ELISA) | Additive-synergistic c | [36] |
| Oseltamivir carboxylate + Amantadine | A/Nanchang/1/99 (H1N1) A/Panama/2007/99 (H3N2) A/Hong Kong/156/97 (H5N1) |
Virus yield inhibition (PFU) | Enhanced inhibitory effect | [37] |
| A/California/04/09 (H1N1) e A/California/05/09 (H1N1) e A/California/10/09 (H1N1) e |
Virus yield inhibition (NR staining) | Additive c | [39] | |
| A/Duck/MN/1525/81 (H5N1) | Virus yield inhibition (TCID50) | Synergistic c | [38] | |
| A/Duck/MN/1525/81 (H5N1)d | Virus yield inhibition (TCID50,) | No added benefit c | [38] | |
| Oseltamivir carboxylate + Ribavirin | A/California/04/09 (H1N1) e A/California/05/09 (H1N1) e A/California/10/09 (H1N1) e |
Virus yield inhibition (staining with NR) | Additive c | [39] |
| Oseltamivir carboxylate + Rimantadine | A/New Caledonia/20/99 (H1N1) A/Panama/2007/99 (H3N2) |
Virus (TCID50) and cell-associated yield inhibition (ELISA) | Additive-synergistic c | [36] |
| Peramivir + Rimantadine | A/New Caledonia/20/99 (H1N1) A/Panama/2007/99 (H3N2) |
Virus (TCID50) and cell-associated yield inhibition (ELISA) | Additive-synergistic c | [36] |
| Peramivir + Ribavirin | A/NWS/33 (H1N1) | Virus yield inhibition (TCID50) | Synergistic c | [35] |
| Triple combinations | ||||
| Oseltamivir carboxylate + Amantadine + Ribavirin | A/New Caledonia/20/99 (H1N1) A/Sydney/05/97 (H3N2) A/Duck/MN/1525/81 (H5N1) |
Virus yield inhibition (TCID50), NR staining, RNA copies | Highly synergistic c | [40] |
| A/California/04/09 (H1N1) e A/California/05/09 (H1N1) e A/California/10/09 (H1N1) e |
Virus yield inhibition (NR staining) | Synergistic c | [39] | |
|
A/New Caledonia/20/99(H1N1)d A/Wisconsin/67/05 (H3N2)d A/Duck/MN/1525/81 (H5N1)d |
Virus yield inhibition (NR staining) | Additive c | [39] | |
|
A/Mississippi/3/01 (H1N1)f A/Hawaii/21/07 (H1N1)f |
Virus yield nhibition (NR staining) | Synergistic c | [39] | |
Note: Drug interactions were evaluated based on inhibition of extracellular (in some experiments cell-associated) virus yield or virus replication in Madin Darby canine kidney (MDCK) cells (unless otherwise indicated). Unless indicated, the viruses were sensitive to all drugs used in the study. Abbreviations: Ref. = references; PFU = plaque forming units; TCID = tissue culture infectious dose; ELISA = enzyme linked immunosorbent assay; NR = neutral red.
Studies were done in chick embryo fibroblasts cells.
Studies were done in primary rhesus monkey kidney cells.
Drug-drug interactions were analyzed by the three-dimensional model of Prichard and Shipman [33] using the MacSynergy™ II software program.
Amantadine-resistant influenza virus variant (shown in italic).
Alternative subtype designation – (H1N1 pdm 2009).
Oseltamivir-resistant influenza virus variant (shown in italic).