[Pharmacokinetic features of sildenafil spray in healthy men depending on food intake].

AIM: In order to evaluate the bioequivalence and benefits of a new dosage form of the type 5 phosphodiesterase inhibitor, sildenafil, two open-label studies in healthy male volunteers were carried out. MATERIALS AND METHODS: An open, randomized, crossover study to compare the pharmacokinetics after a single dose of sildenafil at a dosage of 50 mg on an empty stomach in a new spray form (test drug) and in a traditional tablet form (comparison drug) on 44 volunteers (18 to 43 years old) was done. To assess the effect of food intake on pharmacokinetics, an open, non-randomized study was conducted on 6 healthy male volunteers (from 23 to 35 years old) who received sildenafil (50 mg) after a meal in timely fashion: 1) spray, under the tongue, without drinking, 2) spray , in the mouth, drinking water and 3) the tablet form, drinking water. For pharmacokinetic analysis, blood was analyzed for 24 hours. Plasma concentration of sildenafil was determined by high performance liquid chromatography with tandem mass spectrometric detection (HPLC/TM/SD). The main parameters were the rate (maximum concentration; Cmax) and the degree of absorption (area under the pharmacokinetic curve "concentration-time" during the observation period; AUC0-t) after a single dose of drugs. In addition, the pharmacokinetic profiles of the bioavailability of sildenafil and its active metabolite, N-desmethyl sildenafil, as well as the safety of the different dosage forms, were evaluated. RESULTS: When comparing taking drugs on an empty stomach, the 90% confidence intervals (CI) of the ratios of the mean Cmax and AUC0-t values of sildenafil were 82-106% and 82-101%, respectively. An earlier achievement of the maximum concentration of sildenafil was detected when taking the test drug compared with the standard form (51 and 62 minutes, respectively, Z-value=-2.25, p-value=0.0244). In addition, it was shown that when taking Viagra after a meal, the determination of sildenafil in plasma was delayed (after 30 minutes) compared to the tested drugs (after 10 minutes), however, significant differences in Tmax between the dosage forms were not seen. In two studies, most adverse events were mild to moderate and resolved uneventfully. DISCUSSION: The bioavailability of the new dosage form, the sildenafil spray, is equivalent to the traditional form, however, it has an advantage in terms of onset of action. For example, when taking a spray, an earlier achievement of the maximum concentration of sildenafil and an earlier detection of sildenafil in plasma are shown compared to the traditional tablet form. CONCLUSIONS: Our results suggest that the new dosage form of sildenafil is a reliable alternative therapeutic option for the treatment of erectile dysfunction.

Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in children and adults.

Acute and chronic steroid-refractory graft-versus-host disease (srGVHD) is a life-threatening complication of allogeneic stem cell transplantation. There are a number of reports on case series describing efficacy of ruxolitinib in both acute and chronic srGVHD. We conducted a prospective study (NCT02997280) in 75 patients with srGVHD (32 acute, 43 chronic, 41 adults, and 34 children). Patients with chronic GVHD had severe disease in 83% of cases, and acute GVHD patients had grade III-IV disease in 66% of cases. The overall response rate (ORR) was 75% (95% CI 57-89%) in acute GVHD and 81% (95% CI 67-92%) in chronic. Overall survival was 59% (95% CI 49-74%) in acute group and 85% (95% CI 70-93%). The major risk factors for lower survival were grade III-IV gastrointestinal involvement (29% vs 93%, p = 0.0001) in acute form and high disease risk score in chronic (65% vs 90%, p = 0.038). Toxicity was predominantly hematologic with 79% and 44% of grade III-IV neutropenia in acute and chronic groups, respectively. There was no difference between adults and children in terms of ORR (p = 0.31, p = 0.35), survival (p = 0.44, p = 0.12) and toxicity (p > 0.93). The study demonstrated that ruxolitinib is an effective option in acute and chronic srGVHD and can be used both in adults and children.

[The Association of Brain-Derived Neurotrophic Factor and Serotonin Transporter Genes with the Parameters of Early Event-Related Potentials During the Passive Perception of Words].

We explored the association of brain-derived neurotrophic factor (BDNF) and serotonin transporter genes with neurophysiological characteristics of the early stages of verbal information processing in the brain in the groups of patients with schizophrenia and schizophrenia spectrum disorders and healthy people. It has been shown that Val66Met and 5-HTTLPR polymorphisms are associated with P100 and N170 during the passive reading of single words written in Russian presented with different occurrence frequency. The healthy carriers of the ValVal genotype (BDN F Val66Met) allele or the SS (5-HTTLPR) genotype performed the task better compared to those with an Met or an L allele. The differences were significant in healthy people and observed as a trend in thepatients.

[THE CHROMATOGRAPHY-MASS SPECTROMETRY ANALYSIS OF MICROBIAL FATTY ACIDS IN HUMAN BIOLOGICAL FLUIDS AND THEIR CLINICAL SIGNIFICANCE].

The technique of mass-spectrometric microbial markers is known for almost 20 years. The technique is described in a number of research publications, dissertations and methodological literature. It passed the registration in Roszdravnadzor and is permitted for implementation as a new medical technology in medical institutions on the territory of the Russian Federation ("The evaluation of microecological human status using technique of mass-spectrometry" license FS No 2010/038 of 24.02.2010). The technique of mass-spectrometric microbial markers began to be developed as instrument of clinical routine analysis and monitoring of microecological status, infection and disbiosises in clinical and out-patient practice. The description of technology of mass- spectrometric microbial markers in this aspect requires different than before approach to introduction of clinical laboratory assistants and physicians into technique application. The substantiation given concerning species specificity of composition of fatty acids and (fatty) aldehydes of cellular wall of microorganisms as a basis of their species differentiation in pure culture. The choice is explained concerning molecular markers for their detection in blood and other clinical material with the purpose of further reconstruction of composition of human microbial cenosis (microecology) on blood or calculation of composition of mixed infection in organs om samples of inflammation focus--urine, liquor, phlegm, exudate, drainage, and similar samples containing chemical information about microbes.

[Mechanisms of damage of internal ear capsules labyrinths at head injury, caused by non-lethal kinetic weapon].

Structural, physical, chemical and micromechanical properties capsules labyrinths of an internal ear are studied at influence of the shock wave caused by wound of a head by not lethal kinetic weapon. It is established, that under the influence of a shock wave in bone plates capsules labyrinths processes remodeling, and accompanied osteolysis amplify. Hydroxyapatites capsules labyrinths tests polymorphic phase transitions and depending on an initial condition is exposed amorphizationor increases the crystallinity. As a result of change of micromechanical properties in capsules labyrinths there are cracks, ruptures matrix and bone cavities.

Involvement of dopaminergic processes in the striatum during the effects of corticoliberin on the behavior of active and passive rats.

The effects of intranasal corticoliberin on behavior in the open field test were studied in rats with active and passive behavioral strategies (lines KHA and KLA); levels of dopamine and noradrenaline and their metabolites were measured in the striatum and hypothalamus. In KLA rats, administration of the neurohormone led to increases in motor and investigative activity, while decreases were seen in KHA rats. There were no interline differences in catecholamine levels in the hypothalamus, while dopamine levels in the KLA striatum nearly doubled and metabolite levels (DOPAC, HVA) were significantly lower than in KHA rats. Corticoliberin increased dopamine and noradrenaline levels in the hypothalamus of both rat lines, with significant decreases in the striatum. This decrease was more marked in KLA rats, probably due to the faster metabolism of transmitters in the presence of neurohormones, as indicated by the increase in metabolite levels in this structure.

[Dopaminergic processes in the striatum mediating corticoliberin effect on behavior of active and passive rats]. / Uchastie dofaminergicheskikh protsessov v striatume v deistvii kortikoliberina na povedenie aktivnykh i passivnykh krys.

The action of intranasal corticotropin-releasing hormone (CRH) administration on open field behavior and striatal and hypothalamic levels of dopamine, noradrenaline and their metabolites has been studied in rats with different behavior strategies (KHA and KLA strains). In KLA rats, CRH administration resulted in increased locomotor and exploratory activity, while KHA rats demonstrated decreased that. The analysis of catecholamine levels did not detect any strain differences in hypothalamus, but in striatum the dopamine levels have been twice higher, while the metabolite levels (DOPAC and HVA) were significantly lower in KLA rats as compared to KHA rats. The CRH administration led to increased dopamine and noradrenaline levels in hypothalamus and decreased those in striatum in rats of both strains, but in KLA the decrease was more evident. It is probably a result of intensified mediator turnover induced by the neurohormone in KLA rats, as supported by a fact of increased dopamine metabolite levels in this structure.

Treatment with BAT monoclonal antibody decreases tumor burden in a murine model of leukemia/lymphoma.

BAT is a monoclonal antibody produced against membranes of Daudi cells that induces anti-tumor activity in mice against a variety of solid murine and human tumors, mediated by its immune stimulatory properties on murine and human lymphocytes. The present study analyzes the effect of BAT on leukemia/lymphoma using the BCL1 model of leukemia/lymphoma in BALB/C mice. BAT antibody binds to BCL1 leukemia cells and recognizes a 48 kDa protein similar to the antigen on Daudi cells. Mice inoculated with leukemia cells were treated either by direct BAT injections or by adoptive transfer of lymphocytes from BAT-injected mice. Administration of BAT monoclonal antibody was either once, on day 14, or daily on days 10-13 post tumor inoculation. A single injection of BAT resulted in reduction of peripheral blood tumor cells, however additional injections further decreased the tumor cell number reaching a 95-fold reduction on day 20 post tumor inoculation. Anti-tumor effect was also obtained when animals were injected with splenocytes from BAT-treated donor mice. A significant prolongation of survival of BAT-treated mice was observed although with no cure. The results of this study indicate that BAT might be used for reducing the tumor burden in leukemia for immunotherapy and in combination with other treatment modalities.

[The study of some mechanisms of injurious effects of low-frequency noises]. / Issledovanie nekotorykh mekhanizmov povrezhdaiushchikh éffektov nizkochastotnykh shumov.

Low-frequency noise has been shown to cause certain functional changes in the organism of laboratory animals that manifest in changes of the state of the regulatory systems and metabolic disturbances at cellular and subcellular levels. The obtained data support the hypothesis of the mechanism of injurious effect of this physical factor including two basically correlated ways, i.e. the central mechanism associated with overexcitation of the hypotalamohypophysis-adrenal system and mediating the homeostatic parameters of the body, and the local one which is determined by a direct effect of low-frequency noise on highly organized structure of membraneous and genetic apparatus of cells.

CD4+ T lymphocytes as a primary cellular target for BAT mAb stimulation.

BAT is a monoclonal antibody (mAb) produced against membranes of a human Burkitt lymphoma cell line (Daudi) that was selected for its ability to stimulate lymphocyte proliferation. BAT manifests anti-tumor properties in mice bearing a variety of murine tumors. BAT also induced regression of human tumors inoculated into SCID mice that had been engrafted with human lymphocytes. The anti-tumor activity of BAT was related to its immune stimulatory properties. Previous data indicated that T lymphocytes and NK cells mediate in vivo the anti-tumor activity. In order to define the primary target cell for BAT stimulatory activity, the in vitro stimulatory effect of BAT on purified lymphocyte subpopulations was investigated. Human CD4(+), CD8(+) T cells and CD56(+) NK cells were purified and their in vitro response to BAT was investigated. Results indicate that BAT selectively stimulated CD4(+) cells as assessed by proliferation and secretion of IFN-gamma. FACS analysis has also revealed a selective increase in BAT antigen on CD4(+) T cells that were cultured with BAT antibody. The effector cells that mediate BAT-induced tumor eradication may, however, be distinct from those that serve as the primary cellular target of the antibody. Cytokines such as IFN-gamma that are produced by CD4(+) cells may be involved in activation of additional cell types that may be involved in tumor destruction.

[Clinical and laboratory grounds for using solcoseryl in high-risk patients]. / Kliniko-laboratornoe obosnovanie ispol'zovaniia solkoserila u bol'nykh vysokogo riska.

In 56 patients aged from 58 to 82 years with the III and IV degrees of risk operated upon for malignant tumors of organs of the thoracic and abdominal organs Solcoseryl was included in the complex of anesthesia measures. It was given intravenously or as inhalation in dosage of 1000 mg. It was found that using Solcoseryl considerably reduced the amount of postoperative complications in high risk patients. It led to lower level of lipid peroxidation and activation of the antioxidant system and thus may be considered as an important component of therapy at the intra- and postoperative periods.

[Biochemical and morphological changes in white rat lung and liver tissues in experimental paraquat poisoning]. / Biokhminicheskie i morfologicheskie izmeneniia v tkaniakh legkikh i pecheni belykh krys pri éksperimental'noi intoksikatsii parakvatom.

Superoxide dismutase (SOD) activity, the number of free radicals and pathomorphological changes were studied in lung and liver tissues of white rats with experimental paraquat poisoning. It was shown that SOD activity in the lungs and liver decreased and the number of free radicals rose. The inhibition of SOD activity after repeated administration of paraquat (1/10 of LD50) was more pronounced than in acute poisoning. Dystrophic and proliferative histomorphological changes characteristic for acute and chronic experiments and disturbed vascular permeability were revealed. It is suggested that the toxic action of paraquat on the animals is particularly consequent on the lack of SOD activity and enhancement of free radical processes.

[Blastomogenic activity of substance complexes that leached out of rubbers into food media]. / Blastomogennaia aktivnost' kompleksov veshchestv, vymyvaemykh v pishchevye sredy iz rezin.

The complex of agents migrating from low-dispersed soot resins PM-15 and PGM-33, injected in the stomach or applied onto the skin of mice C57Bl, showed an insignificant blastomogenic activity. Most sensitive to their effect were the tissues of organs at the site of injection (proventricular papillomas in 8.3% of cases, skin papillomas in 12.5%), in the lung (adenomas in 12.5%) and in the pancreas (fibroadenoma in 4.2%). In the negative control groups of animals no tumors of such localization were noted. The whole complex of substances migrating from resins renders the blastomogenic effect, i. e. there is a combined action with an enhancement of blastomogenic effect.