[New betulin derivatives in combination with rimantadine for inhibition of influenza virus reproduction].

The preliminary studies mainly revealed comparable inhibition activities of 3-oxime of betulonic acid, 3beta-O-acetyl-28-O-hemiphthalate of betulin and 3,28-dioxime of betulin against reproduction of influenza viruses A (H1N1), A (H7N1), A (H3N2) and B, as well as against the strains of influenza virus A (H1N1) with intrinsic resistance to rimantadine and A (H7N1) with acquired resistance to the drug. The level of the activity depended on the system used for the virus reproduction. The highest level was observed under conditions providing higher permissibivity, i.e. in the chick embryo fibroblast cell culture for A (H7N1) and in fragments of chick embryo chorioallantoic membranes (for all the viruses). In the experiments with virus A/FPV/Rostock/34 (H7N1) in the chick embryo fibroblast cell culture the average effective concentrations (EC50) of the triterpene compounds were 10.4-17.5 mcM in comparison to EC50 of rimantadine (0.014 mcM). The use of every of the compounds in combination with rimantadine resulted in a 2-16 times decrease of their EC50 and correction of the concentration-effect relation of rimantadine. However, when rimantadine was used alone within the higher range of the nontoxic concentrations (11.6-57.6 mcM). its antiviral properties were significantly less pronounced. As a result the virus titer difference in comparison to the control within the above range of the rimantadine concentrations increased from < 1 to > 2.35 Ig PPU/ml and the relations of the maximal tolerance concentrations of the compounds to their EC50 increased 1.7-15.9 times.