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Biomedical subjects

A S Galabov

Publications and source records attributed to A S Galabov.

At least 19 recordsLinked to original sources

Virucidal activity of a new hand disinfectant with reduced ethanol content: comparison with other alcohol-based formulations.

A new formula with reduced ethanol content (55%) in combination with 10% propan-1-ol, 5.9% propan-1.2-diol, 5.7% butan-1.3-diol and 0.7% phosphoric acid exhibited a broad spectrum of virucidal activity. In quantitative suspension tests, with and without protein load, this formulation reduced the infectivity titre of seven enveloped (influenza A and B, herpes simplex 1 and 2, bovine corona, respiratory syncytial, vaccinia, hepatitis B, bovine viral diarrhoea) and four non-enveloped (hepatitis A, polio, rota, feline calici) viruses >10(3)-fold within 30s. In comparative testing, only 95% ethanol showed similar levels of activity. In fingerpad tests, the formulation produced a log10 reduction factor of the titre of poliovirus type 1 (Sabin) of 3.04 in 30s compared with 1.32 by 60% propan-2-ol. Testing against feline calicivirus produced a log10 reduction factor of 2.38 by the test formulation; in contrast, the log10 reduction factors with 70% ethanol and 70% propan-1-ol were 0.68 and 0.70, respectively.

1-Propanol↗

Effect of vitamin E and vitamin C combination on experimental influenza virus infection.

Successful antioxidant treatment of the so-called "free radical diseases" has been reported in the literature. In this study we examined the preventive effect of vitamin E and vitamin C, alone and in combination, on the damage caused by influenza virus infection (IVI). Male mice (ICR), infected with influenza virus A/2/68/(H3N2) (1.5 of LD(50)), were administered single once-daily doses of vitamin E (60 mg/kg b.w.) and vitamin C (80 mg/kg b.w.) intraperitoneally (3 days before virus inoculation). On the 5th and 7th day, respectively, after virus inoculation, animals were decapitated. Monooxygenase enzyme activity (ethylmorphine N-demethylase, amidopyrin N-demethylase, analgin N-demethylase, aniline hydroxylase, cytochrome P-450 content and NADPH-cytochrome C reductase [CCR]) was determined in liver 9000 x g supernatant. Primary and secondary products of lipid peroxidation (LPO; conjugated dienes [CD] and TBA-reactive substances) were measured in blood plasma, lung and liver 9000 x g supernatant. Vitamin E effectively restored LPO-levels increased by IVI. The effect of vitamin C was similar, but slighter. The combination (vitamin E + C) had greater effect on LPO levels than their separate administration. P-450-dependent monooxygenase activity was significantly restored and more pronounced cytochrome P-450 content and NADPH-CCR activity was noted. The preventive effect of vitamin E was stronger than the effect of vitamin C, but the combination (vitamin E + C) had the strongest effect. The superior protective effect of the combination is probably due to vitamin C's repairing effect on vitamin E's tocopheroxyl radical.

Animals↗

Gastric mucosal lesions in influenza virus infected mice: role of gastric lipid peroxidation.

The present study provides direct experimental proof that the combination of influenza virus infection A/Aichi/2/68 (H3N3) with different models of oxidative stress, such as immobilization, cold and cold-restraint, is associated with graduated oxidative disturbances in the stomach of mice, despite the absence of virus replication and inflammation in this tissue. It was found that experimental influenza virus infection is accompanied with significant changes in gastric mucosal integrity, as well as an increase in the products of lipid peroxidation in the stomachs of mice. Preliminary exposure of mice to immobilization stress and subsequent inoculation of influenza virus did not significantly influence gastric ulceration or lipid peroxidation compared with infected mice. Cold stress resulted in a significant decrease in the index of stomach ulceration and did not influence the fluorescent products of lipid peroxidation and MDA compared with infected animals. The simultaneous application of cold-restraint stress and influenza virus infection provoked synergism in the activity of all factors on the parameters under investigation. Ulceration increased approximately two-fold, as did the amount of fluorescent products of lipid peroxidation and MDA, compared with influenza virus-infected and non-stressed animals.

Animals↗

Antiviral effect of the combination of enviroxime and disoxaril on coxsackievirus B1 infection.

Effects of enviroxime and disoxaril, inhibitors of replication of some picornaviruses with known mechanisms of action, alone or in combination, on replication of coxsackievirus B1 (CVB1) in FL cells and on experimental CVB1 infection in newborn mice were tested. The combination of enviroxime and disoxaril resulted in vitro in a synergistic interaction. Both compounds were administered in vivo, alone or in combination, daily by subcutaneous (s.c.) route since the day of virus inoculation till the 5th day post inoculation (p.i.). Our findings about the in vivo antiviral effects of the individual compounds correlated with those of other authors, i.e. disoxaril significantly reduced the virus-induced death (the minimum 50% effective dose (ED50) was 12.5 mg/kg; P = 0.0037), while enviroxime was not effective even when applied at a dose as high as 100 mg/kg (P = 0.264). However, when both the substances were combined, the same protective effect was achieved with concentrations of disoxaril two to four times lower than those of the drug administered alone. In this way a higher selectivity ratio was achieved. Namely, the combination of 50 mg/kg enviroxime and 3.125-6.25 mg/kg disoxaril was synergistic. Along with reduction in mortality a marked delay in the course of the disease was observed.

Animals↗

Cytotoxicity of the synergistic antienteroviral combination of enviroxime and disoxaril.

When combined, enviroxime and disoxaril, two selective picornavirus inhibitors, exert a marked synergistic inhibitory effect on poliovirus type 1 replication in FL cells. The cytotoxicity of the compounds applied individually and in combination to the same cells was examined. The quantitative assay of the cytotoxic effect was made by determination of the growth curve of uninfected FL cells in the presence of increasing concentrations of the compounds applied alone and in combination. The obtained results indicate lack of a synergic cytotoxic effect of the combination of enviroxime and disoxaril. The previously established synergistic antiviral effect, and the lack of cross-resistance and synergic cytotoxic effect classify the combination of enviroxime and disoxaril as a very promising chemotherapeutic.

Antiviral Agents↗

In vitro inhibitory effects of dual combinations of picornavirus replication inhibitors.

To assess the possible interactions among picornavirus replication inhibitors, inhibitory effects of dual combinations of enviroxime, disoxaril, arildone, S-7, guanidine, PTU-23, and HBB on poliovirus type 1 (Mahoney) replication in FL cells were tested. Beforehand, the 50% inhibitory concentration (IC50) in the plaque inhibition test was been determined for each individual compound, i.e. enviroxime-0.2 micromol/l, disoxaril-0.3 micromol/l, arildone-2.7 micromol/l, (S-7)-100 micromol/l, guanidine-200 micromol/l, (PTU-23)-200 micromol/l, and HBB-300 micromol/l. Each of the dual combinations, in which enviroxime or HBB was one of the partners, showed synergistic or additive effects. Combining disoxaril with enviroxime, HBB or PTU-23 resulted in synergism, while combining it with guanidine, S-7 or arildone led to antagonism. Arildone showed additive or synergistic effects when combined with enviroxime, HBB and PTU-23, and antagonistic ones when combined with disoxaril, S-7 or guanidine. All dual combinations of PTU-23 were synergistic with the exception of the pair of PTU-23 + guanidine that was antagonistic. Guanidine had additive to synergistic interactions with HBB or enviroxime but antagonistic ones with disoxaril, arildone and PTU-23. Guanidine or PTU-23 when combined with S-7 showed an unusual effect - synergistic one with an antagonistic zone. The combinations of S-7 with enviroxime or HBB were synergistic but those with disoxaril or arildone were antagonistic. Research on interactions of picornavirus replication inhibitors could possibly contribute to the development of efficient chemotherapy of infectious diseases caused by picornaviruses as well as to the better understanding of the mode of action of those inhibitors.

Antiviral Agents↗

Characterization of the virions of mopyridone-sensitive wild strain and mopyridone-resistant mutant of influenza virus A(H3N2)

Some differences were established between mopyridone-sensitive (MCU-s) wild strain and mopyridone-resistant (MCU-r) mutant progenies of influenza virus A/Hong Kong/1/68 (H3N2). The virions of MCU-r mutant had a lower buoyant density in linear sucrose gradient as compared to those of MCU-s strain, and an increased ability of aggregation as well. HA content (HAU/micrograms protein) in the purified virions of MCU-r mutant was twice lower as compared to MCU-s strain. The surface glycoproteins of MCU-r mutant were solubilized by octylglucoside faster than those of MCU-s strain. No differences were found between MCU-r strain and MCU-s mutant-induced red blood cell lysis at acid pH, and mopyridone did not influence this phenomenon. MCU-r mutant showed a lower thermostability as compared with MCU-s strain, but similar UV-inactivation curves for both viruses were observed. The quantity of the purified HA-NA complex and M1 protein incorporated into multilamellar liposomes was greater in the case of MCU-s mutant. Electron microscopy examination of liposomes which contained M1 protein from MCU-r mutant manifested pleomorphism with unusual gigantic forms tending to aggregate, whereas MCU-s M1 protein-containing liposomes were uniform and did not form aggregates. No morphological differences were found between the two viruses in HA-NA complex containing liposomes. These data indicate changes in the protein-lipid interactions in MCU-r mutant virions. Amino acid analysis of M1 protein revealed significantly lower content of asparagine, glutamine and serine, and a higher one oof hisitidine in MCU-r mutant as compared to MCU-s wild strain.

Amino Acids↗

Synergistic inhibitory effect of enviroxime and disoxaril on poliovirus type 1 replication.

The effects of enviroxime, disoxaril and ribavirin in pair combinations on poliovirus type 1 (Mahoney) replication in FL cells were tested. Beforehand, the fifty percent inhibitory concentration (IC50) was determined for each compound alone: enviroxime - 0.2 mumol/1, disoxaril - 0.3 mumol/1, ribavirin - 3 mumol/1. Combining enviroxime with disoxaril resulted in synergistic interaction, while combinations with ribavirin were markedly antagonistic. Enviroxime-and disoxaril-resistant poliovirus mutants appeared following 10 and 2 consecutive passages in FL cells, respectively. No cross-resistance was observed between these mutants towards disoxaril and enviroxime, respectively.

Antiviral Agents↗

Alteration in the antigenic structure of M1 protein of influenza A virus mutant resistant to a new antiviral compound mopyridone.

Using 14 monoclonal antibodies (MoAbs) in solid-phase ELISA it was found that influenza virus A/Hong Kong/1/68 (H3N2) mutants resistant to the antiviral compound mopyridone as compared to the mopyridone-sensitive mutant manifested significant changes in the antigenic structure (sites 1A, 2 and 3) of M1 protein. No differences in M1 were found between rimantadine-resistant and rimantadine-sensitive mutants of influenza virus A(H3N2).

Animals↗

Acute toxicity and effects on hepatic oxidative drug metabolism of mopyridone.

Mopyridone (CAS 82822-14-8) is a new chemotherapeutic with a strong antiviral effect (vs. influenza- and toga viruses) and certain advantages over the chemotherapeutics known so far. Toxicological studies reveal its low oral and intraperitoneal toxicity in mice and rats. The 5- and 14-day administration of mopyridone (37.5 mg/kg b.w., orally) to male rats established a growing tendency to the shortening of hexobarbital sleeping time, associated with moderate changes in the hepatic oxidase activity on the 15th day, most pronounced for amidopyrine N-demethylase (by 37%) and less for benzphetamine N-demethylase (by 17%). Aniline hydroxylase activity was slightly diminished (by 18% and 16%, resp.). No significant changes in the components of the electron-transport chain of cytochrome P-450 were established--the content of cytochrome P-450, cytochrome b-5 and cytochrome C reductase, both after 5- and 14-day mopyridone administration.

Animals↗

The effects of the anti-enteroviral agent PTU-23 on immune response in normal mice.

The anti-enteroviral agent PTU-23 (N-phenyl-N'-3-hydroxyphenyl carbamide) was tested for an effect on humoral and cellular immune response in normal BD2F1 hybrid mice. Humoral immune response was assessed by hemolytic plaque technique and cellular immunity--by the delayed type hypersensitivity reaction and by the rate of activated lymphocytes in the mesenteric lymph nodes. PTU-23 was administered subcutaneously in doses of 200, 400 and 800 mg/kg body weight during 6 consecutive days. The immune response was recorded on day 1, 7 and 14 after the treatment. The changes observed in humoral and cellular immunity were found to be dependent on the time interval between the administration of the drug and of the antigen (sheep red blood cells), as well as dose-dependent. On day 1 a considerable suppression of humoral and cellular immune response was recorded at the three dose levels used. On day 7 the inhibition of humoral and cellular immunity was less. On day 14 the immune response in the animals treated with 400 and 800 mg/kg of the tested substance approached the control values, whereas it was observed that the dose of 200 mg/kg results in a certain stimulation of humoral and cellular immune response.

Animals↗

Antiviral effect of 1-morpholinomethyl-tetrahydro-2(1H)-pyrimidinone (DD-13) in experimental alphaviral infections in white mice.

1-Morpholinomethyl-tetrahydro-2(1H)-pyrimidinone (DD-13), a selective inhibitor of the alphaviral reproduction in vitro, manifests a pronounced antiviral activity in experimental infections with Semliki forest virus (SFV) and Sindbis virus in white mice (intraperitoneally inoculated with 10-10 000 LD50). Introduced subcutaneously in mice infected with SFV the compound was effective within the dose range of 4.7-300 mg/kg. The effective dose (ED)50 value of DD-13 is about 18.7 mg/kg and the maximum effect is reached with a 150-300 mg/kg dose. The protection index reached 80% and the mean survival time from approximately 7 days in the placebo group was lengthened to 26 days. This high antiviral effect is distinguished by its high selectivity, the selectivity ratio (LD50/ED50) being 385 (LD50 = 7200 mg/kg) and is manifested in infections with massive viral inocula (100-1000 LD50). The effective treatment schedule was determined: two divided daily doses of 37.5-150 mg/kg, beginning on the 3rd day after infection to the 8th day. After intravenous administration of DD-13 in mice infected with SFV a high protective effect was also observed, which was equal to that of the subcutaneous application, but with doses several times lower: in the 3-40 mg/kg. ED50 is about 3.5 mg/kg and the optimal effective dose is 10-20 mg/kg, i.e. 1/12-1/6 of LD50 (116 mg/kg). The selectivity ratio is about 33. The most effective treatment course is accomplished by a 10-20 mg/kg daily dose (in two applications) starting on the 2nd day after the virus inoculation up to the 8th day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Dipyridamole-induced interferon production in mouse peritoneal leukocytes.

The in vitro explanted mouse peritoneal leukocytes were used for the optimization of the dipyridamole-induced interferon production. After 90-120 min incubation of cells with 30-100 microM dipyridamole, the production of interferon reached 6.4 X 10(4) IU/ml. It was demonstrated that the interferon production phase is preceded by the dipyridamole-dependent increase in cAMP concentration. The possibility of cAMP involvement in the mechanism of interferon production is being discussed.

3',5'-Cyclic-AMP Phosphodiesterases↗

[Epidemiological trial of the prophylactic effectiveness of the interferon inducer dipyridamole with respect to influenza and acute respiratory diseases].

The epidemiological effectiveness of dipyridamol, an interferon-inducing agent used for the prevention of influenza and viral acute respiratory diseases, was tested in 4 epidemiological trials, 3 of them carried out as double blind trials. Observations were made in groups of adults (a research institute, a factory) and children (a kindergarten, a school), comprising 1040 subjects in the test groups and 771 subjects in the control groups. The drug was used during the whole epidemic period (January--March 1983) according to the following schedule: 1 oral administration in 8 days, in doses of 8 mg for adults, 50 mg for schoolchildren and 24 mg for children in the kindergarten. The epidemiological effectiveness of the drug was evaluated by comparing the total morbidity rates in influenza and acute respiratory diseases in the test and control groups. The results of 4 trials showed a pronounced epidemiological effectiveness of dipyridamol. The values of the epidemiological effectiveness index of the drug were 2.38 in the kindergarten, 1.55 at the school, 7.42 at the factory and 2.16 at the research institute. The results of the study of dipyridamol suggest that further investigations should be made with a view to use it for the mass prevention of influenza and acute respiratory diseases.

Acute Disease↗

Antiviral activity of tetrahydro-2(1H)-pyrimidinones and related compounds.

24 derivatives of tetrahydro-2(1H)-pyrimidinone and related compounds were tested in vitro for antiviral activity against representatives of six viral taxonomic groups. The screening was carried out by a two-stage procedure including the agar-diffusion plaque-inhibition test and the one-step growth cycle setup. A distinct activity of three mono- and bis-morpholinomethyl derivatives of tetrahydro-2(1H)-pyrimidinone (THP), 1,3-bis(piperidinomethyl)-THP, the 1-morpholinomethyl derivative of tetrahydro-2(1H)-pyrimidinethione (THPT) and the related N,N'-bis(morpholinomethyl)-urea against the fowl plague virus was established. In the one-step growth cycle setup these compounds inhibited 87.5-99.6% of the infectious virus yield. Two of the compounds, namely 1-morpholinomethyl derivatives of THP and THPT manifested a strong inhibitory effect on the reproduction of Semliki Forest virus as well, exceeding 99.9% in the one-step growth cycle test. A borderline effect was observed in some derivatives against vaccinia virus and Newcastle disease virus. The structure-activity relationship of this group of compounds is discussed.

Alphavirus↗

Dipyridamole induces interferon in man.

Thirty-six out of 40 healthy volunteers responded with a markedly elevated blood interferon (IFN) content to a single oral administration of dipyridamole (a 100 mg dose): 958.0 +/- 23.5 IU/ml serum at the 24th-48th hour. A hyporeactivity state to the repeated inducer application was found within the time interval of 4th-6th day. It was established that 7/8 of the dipyridamole-induced IFN represented IFN-alpha.

Adult↗