title: 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 combination-treated 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 three-dimensional 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 log10 lower titre of 50% cell culture infectious dose (CCID50) was recorded in the combination-treated group at 48-60 h post-infection (the peak of lung virus growth). This is in contrast to the 0.1-1.0 log10 and 1.1-1.4 log10 reduction in CCID50 titre observed in the oseltamivir and rimantadine groups, respectively. These data emphasize the high anti-influenza A potential of the combination.
authors.affiliation: The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria. galabov@microbio.bas.bg
authors.forename: Angel S
authors.initials: AS
authors.lastname: Galabov
authors.forename: Lora
authors.initials: L
authors.lastname: Simeonova
authors.forename: Galina
authors.initials: G
authors.lastname: Gegova
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D008168:Lung / Q000187:drug effects / Q000821:virology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009976:Orthomyxoviridae Infections / Q000188:drug therapy*; D053139:Oseltamivir / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D012299:Rimantadine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D015996:Survival Rate
chemical_list: D000998:Antiviral Agents; D012299:Rimantadine; D053139:Oseltamivir