Biomedical subjects
Publications and source records attributed to N N Nosik.
The antiviral drug arbidole reduces influenza and acute respiratory diseases (ARD) in children by 1.5-2 times when given in a dose of 0.1-0.2 g 2-3 or 5 times a week, by making influenza and ARD milder and decreasing their duration by 1.4-2.8 days. Unified regimens for prophylactic use of arbidole in influenza and ARD in children and adults are proposed.
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It was shown that human recombinant gamma IFN given to volunteers intramuscularly (90 x 10(3) IU) and by inhalation (120 x 10(3) IU) induced 5-10-fold increase circulating IFN (up to 40-60 IU/ml); the activities of 2,5-oligoadenylate synthetase increased 1.5-2 fold and protein kinase of lymphocytes--3-5-fold. The repeated doses of gamma IFN at 12-15-hour intervals maintained a relatively stable IFN status, the inhalatory route of application being more effective. Convalescents after influenza different from healthy donors by a higher level of serum interferon and activity of 2.5-oligoadenylate synthetase but the activity of protein kinase was lowered in lymphocytes and plasma. The side effects induced by IFN administration were more marked only after intramuscular injections of 90 10 IU and were absent after inhalation of IFN (120,000 IU).
Interferon inductor larifan used parenterally was combined with herpetic vaccine to treat severe recurrent herpes in 32 patients. This combination therapy started at initiation of herpetic infection activation and resulted in amelioration of the clinical symptoms of the recurrence, a more favourable course of the disease due to stimulation of the interferon system and natural killer activity. In combination the above modalities proved more effective than in monotherapy.
Double-stranded RNAs (dsRNA) - larifan and ridostin, and recombinant interferons-alpha-2 and beta-1, manufactured in the USSR, inhibited the reproduction of CMV in cell culture. Antiviral effect depended on concentration of preparations, time of administration and m. o. i. DEAE-dextran enhances antiviral effect dsRNA. DsRNA and interferons added to cells infected with CMV at high m. o. i. enhance the viral reproduction. Among studied preparations highest antiviral effect was shown by natural leucocyte interferon (Egis). It was 10 times more active, than recombinant IFNs and in concentration of 1000 U/ml was comparable to activity of larifan (200 mg/ml).
The enzymes activities of interferon system at viral infections of different etiology/influenza, parainfluenza, hepatitis B with delta infection and urticaria chronica with respiratory and herpes infection/has been studied and evaluation of the noted changes in the enzymes activity is discussed. It is shown that the same pathological changes in enzymes activities of interferon system were observed at different viral infections.
The number of aberrant metaphases was used to assess the influence of a highly active interferon inducer--ridostin, a two-spiral RNA, on spontaneous mutagenesis and that induced by an antitumor drug photrin. A new property of ridostin, viz. the antimutagenic effect, was established. The effect may be important for protection of cells from potent mutagens such as cytotoxic drugs used for cancer treatment.
The activity of the interferon-dependent enzymes: 2',5'-oligoadenylate synthetase and protein kinase was determined in blood specimens of volunteers in the clinical trials on reaferon (recombinant alpha 2-interferon) and larifan (replicate RNA of phage f2). It was shown that the preparations increased the activity of 2',5'-oligoadenylate synthetase in the lymphocytes and protein kinase in the plasma of 60 to 70 per cent of the volunteers. The increase in the 2',5'-oligoadenylate synthetase activity did not always correlate with the increase in the interferon content in the serum and was sometimes observed in the absence of the interferon. Marked individual variations in the activity of the enzymes were detected in the volunteers before and after administration of the preparations. The plasma kinase activated by reaferon and larifan phosphorylated proteins with molecular weights of 72 and 30 kD and histones. The effect of reaferon and larifan on the lymphocyte protein kinase activity was determined for the first time. There was a decrease in the enzyme activity under the effect of reaferon which increased after its repeated injections. Unlike the effect of larifan, the inhibitory effect of reaferon was transient. Afterwards, it appeared to be accompanied by a significant increase in the activity of protein kinase in 70 per cent of the volunteers. The dynamics of the changes in the activity of the plasma and lymphocyte protein kinases did not coincide.
Double stranded RNA was isolated from bacteriophage phi 6 parasitizing on phytobacteria. Its interferon-inducing and antiviral activities were shown in vitro and in vivo. In the culture of L-929 cells, interferon resistant to heat and acids was synthesized. The interferon could be practically completely neutralized by specific anti-interferon serum. The phage phi 6 preparation dsRNA in the lyophilized form was studied. The preparation retained its biological activity. It was shown that a preparation containing 30 per cent of dsRNA was less toxic than a preparation containing 100 per cent of dsRNA, the difference in the interferon-inducing activity being insignificant.
Methods for isolation and purification of yeast double spiral RNA (dsRNA) are described. The most simple method includes reprecipitation of dsRNA in solutions of lithium chloride and its interphase distribution in the system of chloroform: isoamilic alcohol: water. Preparations with the content (w/w) of dsRNA from 30 to 90 per cent were obtained. They possess a high interferon-inducing activity and an antiviral effect on the experimental infection caused by the virus of mouse encephalomyocarditis.
The suppressed cytotoxic natural killer activity was observed in the mouse spleen during 2 days after 6 h of immobilization stress. Both serum interferon level and interferon production by spleen cells under PHA, ConA and enterotoxin stimulation were also significantly decreased. The period of suppression was followed by the recovery of the activity of the two systems by day 7-9. The experimental data form the basis for the suggestion that endogenous interferon has major significance for the mechanism of disturbed natural killer activity after stress influences.
Interferon inducers, dsRNA and poly (G) X poly (C) ( polyguacyl ), injected into mice intraperitoneally induced interferon formation, the maximal activity being equal to 640-1280 U/ml. Antiviral effect of the inducers was studied upon intraperitoneal and intracerebral injections. Both polyguacyl and dsRNA exerted a marked antiviral action against infection induced by murine encephalomyocarditis virus. The most powerful effect was attained when the inducers were injected 24 or 4 h before challenge. The protective action was produced by polyguacyl and dsRNA even after intracerebral infection. There is a good agreement between the interferon-inducing and antiviral activity of interferon inducers. The data obtained demonstrate the fitness of experimental encephalomyocarditis of mice for testing interferon inducers.
The rates and time course of interferon production in mice administered nine inductors of different nature were studied and compared. Use was made of the most prospective synthetic and natural polymers as well as of low-molecular preparations. It was established that polymers bring about early interferon production with a peak being reached in 4-6 hours, followed by rapid disappearance. Low-molecular inductors are marked by late interferon production, with the maximal titers attained in 24-48 hours, followed by prolonged circulation (4 days of observation).
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Biological activities of the RNA replicative form of phage f2, a natural interferon inductor and poly-I -- poly-C, a synthetic polyribonucleotide complex were studied comparatively. Differences in the comparative interferonogenic and antiviral activity of the inductors were as dependent on the type of the cell system. It was shown that DEAE-dextran increased the interferon-inducing activity of RFf2 in the cell culture by 4 to 8 times. The dynamics of the interferonogenic and antiviral activity of RFf2 in the L-929 cell culture was studied. Interferon appeared in the culture fluid in 6--8 hours and reached its maximum titers (128 IU50/ml) by the 24th hour, the maximum protection of the cells being also developed by the 12th--24th hour, reaching on an average 51 g PFU/ml. It was shown in the experiments with green marmosets that administration of RFf2 in the form of aerosol in a dose of 2.3 mg/kg induced interferon production in the blood serum the titers of which amounted to 80--160 IU50/ml 24 hours after the administration.
The effect of the interferon inductor of the natural origin (RFf2) on formation of vaccinal immunity to vernal encephalitis was studied. A single intraperitoneal administration of the preparation in a dose of 10 gamma per a mouse 2 hours after the first injection of the vaccine resulted in increased resistance of the mice to the lethal dose of the infecting virus which was introduced 14 days after the vaccination completion. The production dynamics of interferon induced by RFf2 and its level in the serum of the immunized mice were the same as those in the non-vaccinated animals. An increased number of the vaccine injections, up to 3 did not result in a significant increase in the immunity with respect to either the level of the antiviral resistance or the level of the virus-neutralizing antibody accumulation.
A comparative study of the reproduction of an alphavirus. Venezuelan equine encephalomyelitis virus (VEE), in chick embryo fibroblasts (CEF) and oncornavirus type D (OV-D) produced spontaneously by human continuous cells (HEp-2) was carried out. The differential index of reproduction of both viruses was the yield of RNA-containing virus structures released from the cells. For VEE this index increased in the course of infection 100-150-fold. For OV-D the index changed little during long-term cultivation of the cells and was only 0.2%--1%. The effect of inhibitors, ethidium bromide and cycloheximide, on the RNA synthesis and production of virus structures was studied. Ethidium bromide was shown to inhibit reproduction of both the viruses considerably, whereas the effect of cyclohemimide on them was dissimilar: its effect on VEE virus depended on the time of its addition, while OV-D virus production did not depend on the time of its addition and was even stimulated in the presence of cycloheximide.
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