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We studied the action of a new indolinone derivative GRS, acetylsalicylic acid (ASA), and their combination on platelet aggregation, vasodilatory endothelial function, neurological status, and cerebral infarction area in experimental focal cerebral ischemia/reperfusion in rats. GRS compound (10 mg/kg), ASA (10 mg/kg), and their combination in the same doses were administered orally once a day as a suspension in 1% starch solution over 5 days after pathology modeling. Sham-operated and control animals were administered 1% starch solution. On day 5 after pathology modeling, platelet aggregation and brain damage area were studied in a half of rats in each group, and the vasodilatory function of the endothelium was studied in the other half. Neurological deficit was assessed 4 h and 1, 3, and 5 days after pathology modeling. GRS compound and ASA equally effectively prevent platelet aggregation and the development of neurological deficit in rats. GRS compound restores the vasodilatory effects of the endothelium, but only ASA contributes to reduction of the cerebral infarction area. In case of combined administration, GRS and ASA do not exhibit synergy in their antiaggregant effect. [ABSTRACT FROM AUTHOR]

We studied the effect of a new indolinone derivative GRS on animal survival and on functioning and histological structure of the lungs in rats with experimental pneumonitis. The rats of experimental groups were intratracheally administered 0.5% aqueous solution of carrageenan under intramuscular anesthesia. Compound GRS (10 mg/kg; a suspension in 0.5% aqueous solution of carboxymethyl cellulose) was orally administered for 4 days starting from the day of carrageenan administration; another rat group received the aqueous solution of carboxymethyl cellulose alone. Control rats received intratracheally isotonic solution of sodium chloride. Animal mortality was registered over 5 days; on day 5, the respiratory parameters were measured, the lungs were weighed, pulmonary edema was evaluated, and histological structure of the lungs was studied. GRS compound improved survival of animals with modeled pneumonitis, restored the respiratory parameters to the level of control animals, and reduced pulmonary edema by 35% and the severity of histological damage score in the lungs by 17% (p<0.05). [ABSTRACT FROM AUTHOR]

We studied the effect of an indolinone derivative GRS on the development of experimental atherosclerosis in C57BL/6 mice. Atherosclerosis was modeled by intraperitoneal administration of endothelial lipoprotein lipase inhibitor Kolliphor P 407 micro Geismar over 5 months. GRS was administered orally in a dose of 10 mg/kg once a day throughout the experiment. In 5 months, the levels of total cholesterol, LDL, and triglycerides in blood serum, as well as histological composition of the ascending aorta were studied. In mice with experimental atherosclerosis, we observed pronounced dyslipidemia with an increase in serum cholesterol, LDL, and triglycerides and accumulation of xanthoma cells in the aorta wall. Repeat administration of GRS did not eliminate dyslipidemia, but prevented an increase in the number of xanthoma cells in the aorta wall (p<0.05). The stimulator of soluble guanylate cyclase GRS did not exhibit hypolipidemic activity, but restored impaired endothelial function in the atherosclerosis model and prevented atherosclerotic damage to blood vessels and vascular wall remodeling. [ABSTRACT FROM AUTHOR]

We studied antihypertensive activity of an indolinone derivative (compound GRS), a soluble guanylate cyclase stimulator and a drug with previously proven antiaggregant effects. Contraction activity of isolated aorta segments of Wistar-Kyoto (WKY) rats was assessed in vitro using a mechanographic method. Addition of GRS (0.1-100 μМ) resulted in dose-dependent relaxation of endothelium-denuded aorta segments. Pretreatment of aorta smooth muscle segments with a specific inhibitor of soluble guanylate cyclase (ODQ, 1 μM) weakened the vasodilatory effect of GRS. Antihypertensive activity of the indolinone derivative GRS was studied in spontaneously hypertensive SHR rats. Single oral administration of 5 and 10 mg/kg GRS was followed by a significant dose-dependent reduction of systolic and diastolic BP in SHR rats. Antihypertensive effect of GRS in a dose of 5 mg/kg was more potent than that of the reference drug isosorbide dinitrate. GRS in a dose of 10 mg/kg did not affect systolic and diastolic BP in normotensive WKY rats. [ABSTRACT FROM AUTHOR]

New antithrombotic drug GRS, a soluble guanylate cyclase stimulator, after repeated administration in a dose of 10 mg/kg alleviates the symptoms of endothelial dysfunction in rats with myocardial infarction; it restores antiplatelet activity of the blood vessel wall and vasodilatory function of the endothelium without producing significant effect on endothelium-independent vasodilation. GRS also has direct antiaggregant and antihypertensive effects in therapeutic doses. The obtained data suggest that GRS can be therapeutically useful in patients with cardiovascular diseases accompanied by endothelial dysfunction. [ABSTRACT FROM AUTHOR]

The anti-inflammatory effect of the ester derivative of indomethacin (IML) in doses of 6.25, 12.5, and 25 mg/kg was studied in rats with modeled rheumatoid arthritis (adjuvant arthritis) and compared to the effects of the reference drug indomethacin in a dose of 1 mg/kg. IML in doses of 12.5 and 25 mg/kg reduced joint inflammation and promoted recovery of the microstructure of the synovial membrane and articular cartilage better than indomethacin. IML produced no ulcerogenic effect, while indomethacin concentration in the stomach wall after administration of IML was 1.8-3.4 times lower than after administration of the reference drug (p<0.05). [ABSTRACT FROM AUTHOR]

Cytochrome p450-mediated metabolism of GRS (indolinone antiaggregant) and its effects on activities of cytochrome p450 isoenzymes were studied. Inhibition of 6 isomers of cytochrome p450 in human liver microsomes was studied with the use of specific substrates. It was found that human liver cytochrome p450 enzymes could not induce degradation of GRS and that GRS was not an inductor or inhibitor of cytochrome p450 family members 1A2, 2C9, 2C19, 2D6, 2C8, and 3A4. Hence, clinical use of the prospective antiaggregant would not involve the risk of uncontrolled fluctuations in GRS concentrations in the organism because of interactions between the drugs. [ABSTRACT FROM AUTHOR]

We give a complete description of Lebesgue sets of lower Izobov -exponents and lower Izobov exponential exponents for families of linear differential systems continuously depending on a parameter belonging to a metric space. The exact Baire class is established for the upper Izobov exponential exponents viewed as functions on the space of systems with the compact-open topology. [ABSTRACT FROM AUTHOR]

We give a complete description of the Lebesgue sets of upper Izobov -exponents of linear differential systems continuously depending on a parameter varying in a metric space. We prove the simultaneous attainability of the upper Izobov -exponents by the Lyapunov exponents and their upper semicontinuity as functions of the perturbation exponent . [ABSTRACT FROM AUTHOR]

We consider families of n-dimensional (n ≥ 2) linear differential systems on the time half-line with parameter belonging to a metric space. We obtain a complete description of the Lyapunov irregularity coefficient as a function of the parameter for families whose dependence on the parameter is continuous in the sense of uniform convergence on the time half-line. As a corollary, we completely describe the parametric dependence of the Lyapunov irregularity coefficient of a regular linear system with a linear parametric perturbation decaying at infinity uniformly with respect to the parameter. [ABSTRACT FROM AUTHOR]

For parametric families of n-dimensional linear differential systems on the time semiaxis with parameter varying in a metric space, we consider two functions of the parameter defined as the dimension of the subspace of solutions that have the characteristic exponent that, respectively, is less than or does not exceed a given real number. A complete description is derived both for the functions themselves and for the vector function composed of them, for the families of systems continuous in one of the two topologies: uniform or compact-open. In addition, the Lebesgue sets and the sets of points of upper and lower semicontinuity are described for the indicated functions. [ABSTRACT FROM AUTHOR]

We consider families of n-dimensional (n ≥ 2) linear differential systems on the time semiaxis with parameter varying in a metric space. For such families continuously depending on the parameter in the sense of uniform convergence on the time semiaxis, we completely describe the spectra of their Lyapunov exponents as vector functions of the parameter. [ABSTRACT FROM AUTHOR]

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice. [ABSTRACT FROM AUTHOR]

Objective. Specific activity of an antiplatelet drug of indolinone series (codenamed DI) was studied in vitro in a model of ADP-induced platelet aggregation in vitro and in vivo in a model of streptozotocininduced diabetes mellitus in rats. Material and Methods. Acetylsalicylic acid and dipyridamole were used as reference drugs. In vitro tests have demonstrated that DI exhibits antiplatelet activity in a wide range of concentrations (0,75×10-6 - 1.5×10-5 M, P<0,05), being comparable to acetylsalicylic acid and dipyridamole. In vivo tests have demonstrated dose-dependent antiplatelet activity of DI in doses of 2,5 - 20 mg/kg (21-14 %). Results and Discussion.Increasing the dose of DI above 10 mg/kg doesn't increase its antiplatelet activity. After multiple oral administration to rats with streptozotocin-induced diabetes mellitus in 10 mg/kg dose, DI has exhibited antiplatelet activity, reducing the platelet aggregation rate to that of the control group (P<0,05).Conclusion. Thus, DI isapromisingcompound for furtherdevelopmentof an antiplatelet drug with new mechanism of action [ABSTRACT FROM AUTHOR]

Synthesis of an innovative drug 9-(2,5-dihydroxyphenyl)-2-(4-ethoxyphenyl)-2,3,7,8-tetrahydro-1H-pyrido[1,2-a]pyrazine-1,4(6H)-dione (PPI) for the treatment of peptic ulcer with a new mechanism of action has necessitated the pharmacokinetics study of the substance in the blood plasma and investigation of its absorption and elimination processes. This paper describes the development and validation of a technique for the quantitative determination of new compound PPI in rat blood plasma by HPLC/MS. The method of solid-phase extraction is applied to extract PPI from blood plasma in the process of biological sample preparation. The lower limit of quantification is 0.1 ng/mL with a linearity range from 0.1 to 1000 ng/mL. By the developed technique, the sample analysis of rat blood plasma was carried out after the introduction of PPI pharmaceutical substance in a dose of 20 mg/kg, a pharmacokinetic profile of the substance was established, and pharmacokinetic parameters were calculated in order to judge the degrees and rates of absorption and excretion of the new antiulcer drug in the blood of laboratory rats. [ABSTRACT FROM AUTHOR]

Numerical simulation of supersonic combustion with transverse hydrogen injection is performed by solving the three-dimensional Favre-averaged Navier-Stokes equations coupled by the k -ω turbulence model. These equations are solved using an algorithm that is based on the third-order essentially nonoscillatory scheme. Several cases of the jet compositions (pure hydrogen and hydrogen diluted by nitrogen in 50:50 mol%) are considered to study the influence of the composition onto the structure and reactivity of the supersonic combustion systems. Seven step modified version of Spark model developed by Jachimowski is implemented to model chemical reaction of hydrogen combustion, which performs quite well in the considered relatively high temperatures. The simulation revealed that the jet penetration heights are equal for both cases, and the hydrodynamic fields looked similar except for the temperatures of the zones located ahead and behind the jet injection. The chemical reaction zone, indicated by OH radicals, was more intense for the pure hydrogen case, occupying a narrow region along the oblique shock wave line. In contrast, the use of a hydrogen/nitrogen jet mixture resulted in a significantly wider flame front zone. This suggests that the presence of nitrogen in the mixture diluted the hydrogen concentration, leading to slower combustion. The study shows that the flow properties and reactivity of the mixture significantly changing with the dilutions of the fuel composition. [ABSTRACT FROM AUTHOR]

The article provides an overview of mathematical studies performed by Vladimir Alexandrovich Kondratiev, on the 70th anniversary of his birth. Included are studies on: the oscillation and nonoscillation conditions for solutions of ordinary differential equations; elliptic equations in domains with angular and conical points; and a problem with oblique derivatives.