title: Prophylactic and therapeutic combination effects of rimantadine and oseltamivir against influenza virus A (H3N2) infection in mice.
abstract: The combined effect of rimantadine and oseltamivir in a prophylactic context (therapy beginning 4 h pre-virus infection) and therapeutic context (therapy started at 24 h post-viral inoculation) course on influenza H3N2 virus infection in mice was studied. In the prophylactic course 5 and 10 mg/kg/day rimantadine with 0.2 and 0.4 mg/kg/day (25:1 dose ratio) oseltamivir showed a protection index (PI) of 79.6% and 75%, respectively and a mean survival time (MST) of 13.1 and 12.9 days. The individual effects of the same doses ranged from 0% to 33.3% PI and 8.2 to 10.3 days MST, respectively. Lung virus titers were decreased 630-fold in the combination-treated groups as compared to monotherapy and placebo groups. The reduction of surface lung pathology in combination-treated groups demonstrated a protective effect for the combination of both antivirals. In the therapeutic course 5 and 10 mg/kg rimantadine combined with 0.2 and 0.4 mg/kg oseltamivir showed no beneficial effect. At higher dosage (0.8, 1.6, 3.2 mg/kg oseltamivir and 20, 40, 80 mg/kg rimantadine) preserving the 25:1 ratio, the resultant PI ranged from 57.6% to 80.5% and the MST was 12.8-13.4 days. Used alone at the same doses the compounds' protection varied between 10.7% and 71.8% PI, MST 9.8-12.8 days (8.7 days in PBS control). Compared to vehicle and individual treatment, a decrease in infectious viral titers of up to 1000-fold and other viral pneumonia parameters were also recorded. The therapeutic effect of the drugs' optimal effective doses combinations was characterized as synergistic. Survival of animals was 81.2-100% and MST was extended by 5-7 days compared to placebos. Monotherapy protection was from 9.1% to a maximum of 56.5%, MST being prolonged only by 1.3-4.2 days compared to 7.5 days in the PBS control group. Lung viral titers were decreased 1445-fold for the most efficacious combination groups and a significant reduction in lung parameters was observed. These data emphasize that prophylactic and therapeutic courses using a combination of oseltamivir and rimantadine have a significant protective effect in mice experimentally infected with drug-sensitive influenza virus A (H3N2).
authors.affiliation: The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
authors.forename: Lora
authors.initials: L
authors.lastname: Simeonova
authors.forename: Galina
authors.initials: G
authors.lastname: Gegova
authors.forename: Angel S
authors.initials: AS
authors.lastname: Galabov
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000494:pharmacology; D018890:Chemoprevention / Q000379:methods; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects*; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000517:prevention & control*; D053139:Oseltamivir / Q000008:administration & dosage* / Q000494:pharmacology; D011024:Pneumonia, Viral / Q000473:pathology / Q000821:virology; D012299:Rimantadine / Q000008:administration & dosage* / Q000494:pharmacology; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D012299:Rimantadine; D053139:Oseltamivir