[Novel biocatalyst for productions of S-(-)-2-[6-benzyloxy -2,5,7,8-tetramethylchroman -2-yl] ethanol­precursor of natural α-tocols].

A novel promising strain of actinobacteria Rhodococcus sp. 77-32 was identified. Its acetonetreated biomass the could be used as a biocatalyst for production of S-(-)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (S-BCE), a precursor of natural α-tocols. It was established that a reaction of enantioselective hydrolysis of racemic (±)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman (BCEA) occurred in the phosphate buffer­acetone system, resulting in enrichment of the residual substrate by S-enantiomer (S-(+)-2-(2-acetoxyethyl)-6-benzyloxy-2,5,7,8-tetramethylchroman, S-BCEA). It was shown that the hydrolysis was accompanied by stereoinversion of the formed product, R-(+)-2-[6-benzyloxy-2,5,7,8-tetramethylchroman-2-yl] ethanol (R-BCE), into the S-BCE. The transformation conditions (acetone content, acidity, temperature, reaction duration) were optimized, providing simultaneous production of optically pure S-BCE and S-BCEA with an almost quantitative yield.

[Searching Radiation Countermeasures using the Model of Prolonged Irradiation of Mice with Low Dose Rate and Evaluation of Their Influence on Heat Shock Protein Genes Expression].

Different radiomodificators (cytokine betaleukine, antioxidant phenoxan, antigipoksant limontar and nucleoside riboxin) were investigated on mice for evaluating their radiation protective capacity against prolonged (21 h) exposure at a dose of 12.6 Gy at a low dose rate of 10 mGy/min. Bone marrow cellularity and endogenic CFUs were used as evaluation criteria 9 days after exposure. Simultaneously, expression of the heat shock proteins of 25, 70 and 90 kDa in unexposed mice bone marrow was studied 2, 24 and 48 h after injections. Betaleukine only had a positive significant effect in both tests in the variants of 50 mcg/kg and 3 mcg/kg when administered 2 h and 22 h before exposure, correspondingly. Effects of betaleukine HSPs on expression were both stimulating and inhibiting, that was in contradiction with a constant positive effect in 5 experiments on exposed mice for each betaleukine variant. It argues against the vital role of HSPs in the betaleukine antiradiation effect. In 2 experiments with high temperatures betaleukine administered at a dose of 50 mcg/kg evoked a very high HSP-70 gene expression after 24 h, and mice exposed to irradiation at that time in a parallel experiment showed an increased radiation effect. It corresponds to the idea that HSPs serve a stress indicator.

[Influence of indoinetophene on the antiradiation properties of indralin].

Radioprotective properties of indralin were studied at its combined administration with indometophene in the periods optimal for each preparation before acute radiation exposure. Animals were subjected to total radiation on the IGUR installation (137Cs): mice of the strain (CBA x C57B1) F1 at a dose of 9 Gy (LD100/30), purebred dogs--4 Gy (LD100/45). It was established in the experiments on mice that considerable radioprotective effect can be obtained by the use of indralin at a dose that is half the optimal radioprotective dose if it is applied against the background of indometophene administered at its optimal radioprotective dose four days before. The survival of mice increased on the average by 30-35% and provided the same effect of protection as a single indralin at the optimal radioprotective dose (100 mg/kg). The survivability of dogs after the combined application of the two radioprotectors makes up 43% against 14% after application of only indralin at a dose of 5 mg/kg (half the optimal radioprotective dose). Indometophene, along with strengthening the antiradiation activity of indralin at the ineffective (half the optimal) dose, allows the reduction of its undesirable postradiation effects in the hemopoietic tissue. The important role in the mechanism of the antiradiation activity of indometophene and indralin belongs to the increased ribonucleotide reductase activity and induction of the ribonucleotide synthesis that provides effective reparation of the damage to the DNA of the cells in radiosensitive tissues and organs as a result of administration of protective doses of radioprotectors at the optimal doses before radiation exposure.

[Evaluation of the treatment effectiveness of domestic G-SCF preparations in experiments on irradiated dogs].

We have evaluated the treatment effectiveness of Leucostim and Neupomax in dogs exposed to radiation at lethal doses of 3 and 3.5 Gy, correspondingly, by testing the dynamics of the blood cell number, first of all, leucocytes and neutrophiles, and the 45-day survival. Supportive therapy for all the dogs, including the control ones, consisted in antibiotic treatment during the acute period of 7-24 days. It was shown that both pre-parations administered consecutively for about 17-21 days after irradiation positively influenced the dynamics of all blood cells but predominantly impacted the neutrophile number dynamics. The latter ones manifested a higher nadir level and an earlier onset of restoration in the G-SCF treated dogs in comparison with the control ones. The tendency to a positive influence on the survival has been shown in Neupomax-treated dogs exposed to 3.5 Gy of radiation (plus about 40%). The results of the experiments were in good accordance with the data by foreign authors who used Neupogen. This allows a conclusion that home-produced G-SCF preparations can replace their foreign analogues.

[Recombinant thrombopoietin antiradiation therapeutic effectiveness evaluation on dogs according to hemopoiesis and survival criteria].

Recombinant human thrombopoietin (rh TPO) has been investigated as a means of acute radiation disease urgent treatment in the experiments on 24 mongrel dogs. The animals were exposed to total acute gamma-irradiation at the doses of 3.5 Gy (exceeding LD50/45 under our conditions) and 3 Gy. All the dogs including control ones received antibiotics Ampicillin and Gentamicin twice a day during the acute period from the 7th to the 21st day. TPO was injected one time s/c or i/v at the doses of5 or 10 mkg/kg 1.5-2 h after exposure. TPO at a dose of 5 mkg/kg was ineffective. TPO at a dose of 10 mkg/kg had a positive effect on the kinetics of blood forming units, especially platelets (nadir, restoration rate) in terms of the 45-day survival. As a result, in TPO groups, nadir averaged at both exposure doses on leucocytes (1.3-1.4) x 10(9)/l vs (0.70-0.75) x 10(9)/l in control groups and on thrombocytes (102-112) x 10(9)/l vs (44-33) x 10(9)/l in control ones. Despite the low number of animals in experimental groups, the results permit to regard rhTPO as a worth-while urgent therapeutic means for the acute radiation damage treatment and preventing thrombopenia.

[Comparative experimental study of antiemetic action of latranum in radiation-induced vomiting and vomiting caused by apomorphine]. / Sravnitel'noe éksperimental'noe izuchenie antiémeticheskogo deistviia latrana pri rvote radiatsionnogo i apomorfinovogo proiskhozhdeniia.

The experiments on dogs showed that Latranum, a selective blocker of serotonin 5-HT3-receptors, has a moderate capacity to modify emetic reaction caused by dophamin-stimulating action of Apomorphinum. These results, taking in account of our preliminary experimental data obtained by a model of early radiation-induced emetic reactions, show that the high antiemetic effect of Latranum may affect another mechanisms of the initiation of early radiation-inducing vomiting which do not connect immediately with the chemoreceptor trigger zone.

[Experimental study of the role of blocking 5-HT3-receptors of serotonin and D2-receptors of dopamine in the mechanism of early radiation vomiting in dogs]. / Eksperimental'noe izuchenie roli blokady 5-HT3-retseptorov serotonina i D2-retseptorov dofamina v mekhanizme vozniknoveniia rannei radiatsionnoi rvoty u sobak.

The experiments on dogs exposed to 137Cs gamma quanta at doses of 8 and 20 Gy showed that Latranum, a selective blocker of serotonin 5-HT3-receptors, is a more efficient antiemetic than Dimetpramidum, a D2-dophamin lytic. This is suggested by fewer animals with emetic reaction or by less severe vomiting in case they have any. The results, taking account of earlier data obtained in the experiments on M. fascicularis monkeys, show that the antiemetic effect of the blocker of serotonin 5-HT3-receptors Latranum is not species-specific and equally well manifests itself in animals with different constitutions of the chemoreceptor trigger zone.

[An experimental study of the role of prostaglandins in the mechanism of the occurrence of dyspeptic disorders during the primary reaction after body exposure to ionizing radiation at large doses]. / Eksperimental'noe izuchenie roli prostaglandinov v mekhanizme vozniknoveniia dispepticheskikh narushenii v period pervichnoi reaktsii posle vozdeistviia na organizm ioniziruiushchikh izluchenii v bol'shikh dozakh.

The experiments with dogs exposed to 100 Gy of accelerated electrons demonstrated a significant role of prostaglandins in the origin of early post-radiation dyspepsia. Their significance for genesis of post-radiation dyspeptic disturbance caused by exposure to superhigh doses becomes clear-cut when a combination of an antiemetic and inhibitors of prostaglandin biosynthesis is used. A study of the effect of dexamethasone, a blocker of arachidonic acid release, and of voltaren, an inhibitor of prostaglandin formation from cyclic endoperoxide, suggests that it would be appropriate to prevent radiation vomiting and diarrhea by inhibiting both of the above stages in prostaglandin biosynthesis.

[An experimental study of the role of a blockade of serotonin 5-HT3 receptors and dopamine D2 receptors in the mechanism of the occurrence of early radiation vomiting in monkeys]. / Eksperimental'noe izuchenie roli blokady 5-HT3-retseptorov serotonina i D2-retseptorov dofamina v mekhanizme vozniknoveniia rannei radiatsionnoi rvoty u obez'ian.

The experiments with M. fasciculata monkeys exposed to 137Cs gamma-radiation with a dose of 6.9 Gy showed that Latranum, a blocker of serotonin 5-HT3 receptors, is a more efficient antiemetic than Dimetphramidum, a D2 dophamin lytic. This is suggested by fewer animals with emetic reaction of by less severe vomiting in case they have any. The results agree well with a hypothesis that serotonin receptors are dominant in the chemoreceptor trigger zone of monkeys.

[Mechanism of the etiology of dyspeptic disorders during the period of primary reaction after exposure to high-dose ionizing radiation]. / O mekhanizme vozniknoveniia dispepsicheskikh narushenii v period pervichnoi reaktsii posle vozdeistviia na organizm ioniziruiushchikh izluchenii v bol'shikh dozakh.

The experiments with dogs exposed to accelerated electrons at a dose of 100 Gy have confirmed an important role of the central mechanism of early post-radiation dyspepsia which is realized through the excitation of receptors in the mechanism of postradiation gastrointestinal disturbance, alongside biogenic amines, prostaglandins also play a certain role. Studies on the effect of a prostaglandin biosynthesis blocker--dexamethasone, a corticosteroid--on post-radiation dyspepsia provide evidence that investigation of prostaglandin biosynthesis inhibitors with a mechanism different from that of dexamethasone is appropriate.

[The mechanism of the occurrence of vomiting during the primary reaction after exposure of the body to ionizing radiations at large doses]. / O mekhanizme vozniknoveniia rvoty v periode pervichnoi reaktsii posle vozdeistviia na organizm ioniziruiushchakh izluchenii v bol'shakh dozakh.

In the experiments of dogs exposed to ionizing radiations at doses of 50 and 70 Gy, an essential role of the central mechanism in the origin of early postradiation vomiting has been confirmed. Insufficient efficiency of dimethpramide, a dophamynolytics, in this case may be connected either with initiation of other (non-dophamynosensitive) structures of the chemoreceptor trigger zone of with a growing role of the reflex way of vomiting arising due to a considerable intestinal injury that causes diarrhea. The inhibition of intestinal M-cholinoreceptors by methacine prevented diarrhea but didn't change the intensity of the vomiting reaction which, however, does not eliminate the possibility of afferentation from receptors that respond to others biologically active substances.

[Comparative study of interferon inducers obtained from natural sources]. / Sravnitel'noe issledovanie induktorov interferona, poluchennykh iz prirodnykh istochnikov.

Interferon-inducing and antiviral effects of natural dsRNA preparations of phage phi 6 and yeast cells were studied in the culture of murine cells L-929 and on random bred albino mice. Both the preparations showed interferon inducing activity in the cell culture. However, for realization of their effect modification of the surface cell membrane by polycation exchange resin (DEAE-dextran) was required. The interferon-inducing activity of both of the natural dsRNA in the mice was high. The maximum interferon titers (1280-5120 units/ml) in blood serum were observed 4-6 hours after the inductor intraperitoneal administration. The interferon-inducing activity of the phage dsRNA was high in the cell culture and yeast dsRNA--in mice, respectively. Both the inductors had antiviral activity and protected 15 to 38.9 per cent of the experimental animals from the effect of 100 LD50 of the murine encephalomyocarditis virus and 10 LD50 of the influenza virus A/Aichi 2/68 (H3N2).