Combined effect of selected antiviral substances of natural and synthetic origin. II. Anti-influenza activity of a combination of a polyphenolic complex isolated from Geranium sanguineum L. and rimantadine in vivo.

The synergistic effect shown by the combination of a natural product, polyphenolic complex (PC) isolated from Geranium sanguineum L., and rimantadine (R) in vitro and in ovo [7], encouraged us to continue these studies by in vivo testing. A marked protective effect in experimental influenza virus A (H3N2) infection in mice was found when PC was applied nasally (i.n.) (1.0 mg/kg) only once 6 h before infection in combination with R applied orally in concentration 10.5 and 2.5 mg/kg 2h before and 2.24 and 48 h after viral inoculation (PI = 72.55%, 55% and 57.8% respectively).

[The antiviral action of a modified bacterial ribonuclease]. / Izuchenie antivirusnogo deistviia modifitsirovannoi bakterial'noi ribonukleazy.

The antiviral activity of a bacterial ribonuclease conjugate with chitosane of Kamchatka crab (in a form of water soluble chito-oligosaccharides) has been studied. The conjugate inhibitory activity for A and B viruses as well as to Sindbis arbovirus in tissue cultures is shown. The preparation efficiency at intramuscular and intranasal administration was observed at experimental influenza infection of white mice.

Virion transcriptase activity of rimantadine-sensitive and rimantadine-resistant variants of human influenza virus.

All rimantadine-resistant variants of influenza virus prepared by consecutive passages in the presence of rimantadine had increased virion transcriptase activity as compared to the original strains. The increased virion transcriptase activity of rimantadine-resistant strains was unrelated to the possible role of M1 protein, since RNPs isolated from the virions of these variants also revealed higher transcriptase activity as compared to RNPs isolated from rimantadine-sensitive virus. The study of rimantadine-resistant recombinant X-4 which inherited from the resistant fowl plague virus (FPV) only the gene 7 coding for M proteins provided additional evidence for the suggestion that the increased virion transcriptase activity of rimantadine-resistant influenza virus variants is coincidental rather than directly associated with such resistance.

Deproteinization of influenza virus in the presence of rimantadine.

Virion deproteinization and viral RNA transport to the isolated cell nuclei have been studied in the presence of rimantadine with rimantadine-sensitive influenza viruses fowl plague (H7N7), A/Krasnodar/101/59 (H2N2) and rimantadine-resistant influenza strains (WSN/H1N1 and A/Krasnodar/101/59-R). Rimantadine failed to affect deproteinization during incubation with the isolated cellular plasma membranes as well as the transport to isolated cell nuclei of the viral RNA of either sensitive or resistant strains of influenza virus. Using photosensitive viruses (labelled with neutral red) rimantadine exerted dissimilar effects on deproteinization of the sensitive and resistant influenza virus strains. The possible effects of rimantadine on influenza virus deproteinization is discussed.

Effects of streptovirudin on influenza viruses type A and B: inhibition of the lipid-linked oligosaccharide synthesis of fowl plague virus.

Antibiotics of the streptovirudin complex (SV) inhibited the growth of influenza A and B viruses such as influenza A/fowl plague virus (FPV), strain Weybridge (Hav1 Neq1), influenza A/England 42/72 (H3N2), influenza A/Port Chalmers 1/73 (H3N2), influenza B/Leningrad 235/74, influenza B/Tokyo 7/66, and influenza B/Jamagata in chick embryo cell (CEC) cultures, in permanent canine kidney cells (MDCK), and in suspended fragments of chick embryo chorioallantoic membranes (CAM). As revealed by spectrophotometric turbidity measurements, SV completely inhibited the FPV-induced cytopathic effect (CPE). A 99.99% reduction of infectious virus yield was obtained in one-step growth cycle experiments and in the plaque reduction test. The haemagglutination inhibition titres of influenza viruses in suspended CAM fragment cultures in the presence of SV drugs were also substantially reduced. The incorporation assays indicated that SV exhibited no effect on virus-induced RNA synthesis, but influenced virus maturation by inhibition of lipid-linked oligosaccharide synthesis. A partial protection from infection was found in influenza virus A/England infected mice.

Antiviral action of dipyridamole and its derivatives against influenza virus A.

Dipyridamole proved to be active against influenza viruses A/England 42/72, A/Bangkok 1/79 and A/fowl plague (FPV). The antiviral activities assayed by various methods varied from 90-99 per cent. No inhibition was found against influenza virus B/Leningrad 235/74 in vitro. Three dipyridamole derivatives were significantly active in tissue cultures against influenza virus A/England 42/72 and A/FPV. In white mice infected with influenza virus A/England 42/72 dipyridamole administered orally showed a protection rate of 62.5 per cent.

Antiviral activity of hetarylhydrazones.

Some hetarylhydrazones showed antiviral activity against Mengo virus in vitro. The replication of influenza A and B viruses was affected neither in vitro (chick chorioallantoic membranes) nor in vivo (mice). Based on dose response curves of the active hetarylhydrazones the compound Z 98/69 appeared most effective in vitro. This compound neither inactivated the extracellular virus nor inhibited its adsorption and penetration; it reduced virus replication when added 1-3 hr after Mengo virus inoculation. As shown by plaque reduction test vaccinia virus was also inhibited. A partial inhibition of rhinovirus 1B multiplication was observed whereas other picornaviruses were not affected.

Occurrence of amantadine- and rimantadine-resistant influenza A virus strains during the 1980 epidemic.

The sensitivities to amantadine and rimantadine of influenza A virus epidemic strains were assayed by the haem-adsorption reduction test in mouse Ehrlich ascites cells in comparison with prototype strains and a rimantadine-resistant mutant. Besides a majority of sensitive strains, two relatively resistant epidemic strains were identified. The possible origin of resistant strains and their importance for medical practice are discussed.

Antiviral effect of 3-[bis-(2-hydroxyethyl)-amino]-acetophenone-[4,5-diphenyl-oxyazolyl-(2)]hydrazone (IMET 98/69) in mice.

The potential in vivo antiviral activity of 3-[bis-(2-hydroxyethyl)-amino]-acetophenone-[4,5-diphenyl-oxazolyl-(2)]-hydrazone (IMET 98/69) was evaluated on model infections in mice. Animals treated subcutaneously (s.c.) with 1 mmole of the drug per kg body weight once daily for five days were significantly protected against a lethal infection with cardioviruses, Semliki forest virus and vaccinia virus. In influenza A and B virus models no antiviral activity was observed either after s.c. or oral treatment.

Effect of adamantane derivatives on the activity of orthomyxovirus RNA-dependent RNA polymerase.

The effect of several adamantane derivatives on the activity of virion-associated RNA-dependent RNA polymerase of fowl plague virus (FPV) and influenza B virus was studied in vitro. Some of the derivatives inhibited the activity of the polymerase by 60 per cent. A correlation was established between the previously demonstrated capacity of these inhibitors to suppress orthomyxovirus reproduction in vivo and their ability to reduce the activity of virion-associated RNA-dependent RNA polymerase in vitro.