Prophylactic and therapeutic combination effects of rimantadine and oseltamivir against influenza virus A (H3N2) infection in mice

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• 作者：Lora Simeonova ; Galina Gegova ; Angel S. Galabov
• 关键词：Influenza ; Rimantadine ; Oseltamivir ; Combination therapy ; Mice
• 刊名：Antiviral Research
• 出版年：2012
• 出版时间：August, 2012
• 年：2012
• 卷：95
• 期：2
• 页码：172-181
• 全文大小：709 K

文摘

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).