Combined Protective Effects of Oseltamivir and Biological Response Modulators against Influenza Virus Type A/H3N2 in Vivo

Abstract from Fourth National Congress of Virology with International Participation /Days of Virology in Bulgaria Sofia, May 18th - 20th, 2016

Lora Simeonova, Galina Gegova, Kirilka Todorova, Elitsa Pavlova

The Stephan Angeloff Institute of Microbiology

Bulgarian Academy of Sciences, Sofia, Bulgaria

University of Sofia “St. Kliment Ohridski”, Sofia, Bulgaria

Influenza continues to cause a number of morbidity cases, not rarely complicated with even a lethal outcome. Multi-target inhibition of pathology could serve as strategy to reduce the severity of the disease. Combined activity of low dosage of oseltamivir – a licensed anti-influenza inhibitor with proved efficacy and some potent biological response modifiers enhancing the host responses against the toxic effects of viral replication in the organism was evaluated.

White male mice 18-20 g were inoculated intranasally (i.n.) with influenza A/Panama/2007/99 (H3N2) virus. Oseltamivir phosphate (OS) was administered per os in five-day-treatment course beginning 4-hours before virus inoculation with 10MLD50. Ellagic acid (EA) - antioxidant was applied orally once daily for five days starting 2 hours prior viral inoculation. Isoprinosine (ISO) as an immune modulator was administered for 10 days in two intakes the daily dosage beginning from the day of infection. Mortality rates, protection index (PI) and mean survival time (MST), as well as body weight changes were determined through 14 days post infection. Viral titers, lung index and consolidation score were evaluated, too.

We observed beneficial effects of double combinations of oseltamivir of 1.25, 2.5 and 5 mg/kg with ellagic acid (500 mg/kg) and Isoprinosine (500 mg/kg) by reduction of mortality rates comparing to placebo and individually treated groups up to 69.1% PI. Mice treated with the triple combination were protected with 70.1%. MST was prolonged up to 12.7 days as well as body weight loss was reduced. No significant effect was recorded for monotherapy groups with ellagic acid and isoprinosine. Comparison of lung parameters between treated groups also revealed the enhanced combined protection with a decrease of more than 1.66 lg CCID50 titres and 1.4 lung pathology score of selected groups.

These data suggest that oseltamivir at daily doses lower than optimal effective one in vivo in combination with antioxidants and immune modulators has an enhanced protective effect against experimental infection with influenza virus A (H3N2) in mice.

Aknowledgement: This work is financially supported by Project№ DFNI B01/19/, 2012, National Science Fund, Republic of Bulgaria.