Analgesic and Psychotropic Effects of a New Bradykinin Antagonist.

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.

Pharmacological Effects of a New Indolinone Derivative in Experimental Pneumonitis in Rats.

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).

Anti-Atherosclerotic Action of a New Stimulator of Soluble Guanylate Cyclase in an Experiment.

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.

Pharmacological Effects of a New Soluble Guanylate Cyclase Stimulator in Experimental Ischemic Stroke.

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.

Effects of a New Antithrombotic Drug GRS, a Soluble Guanylate Cyclase Stimulator, on Endothelial Dysfunction in Rats with Myocardial Infarction.

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.

[Effect of the energy metabolism regulator Yantar-Antitox on the system of energy production in rat liver during experimental pathology of beta-oxidation].

Effects of the Yantar-Aantitox (succinic acid preparation) preparation on bioenergetic processes in mitochondria of rat liver during the experimental disorders of beta oxidation process evoked by 4-pentenoic acid have been studied. It is established that the course administration of Yantar-Antitox leads to normalization of disturbed bioenergetic processes in rat liver, which is due to stimulation of the rapid metabolic cluster of mitochondria.

Effects of succinic and glutamic acid combination on energy metabolism in the liver of mice under conditions of hypoxia.

Treatment of mice by a combination of succinic and glutamic acids prevented the metabolic disorders in the liver under conditions of normobaric hypoxia. In addition, the activity of the mitochondrial fast metabolic cluster remained intact and lipid peroxidation was limited.

[Effects of silymarin and its combination with succinic acid on brain bioenergetics in rats with experimental inhibition of beta-oxidation of fatty acids].

In the tests on rats with a model of encephalopathy caused by 4-pentenoic acid (inhibitor of the beta-oxidation of fatty acids), the hepatoprotective agent silymarin increases the respiratory activity in brain mitochondria, improves oxidative phosphorylation coupling and energization, and inhibits lipid peroxidation. Succinic acid (a regulator of bioenergetics) improves the damaged Krebs cycle metabolic pathways and produces an antioxidant effect. The combined use of silymarin and succinic demonstrated more expressed cerebroprotective action as compared to that of each agent administered separately.

[Dependence of the pharmacokinetics of captopril on the type of adaptation reactions in the organism].

The dependence of the pharmacokinetic profiles (PhP) of captopril in the phase of adaptation reactions in the organism has been studied within the framework of randomized, comparative, double cross research of bioeqivalency of captopril (Aspharma Co, Anzhero-Sudzhensk) and capoten (Bristol Myers Squibb Co.; official Russian producer, Akrikhin KhimFarmKombinat). It is established that the maximum bioaccessibility and high concentration of captopril in the blood plasma is determined on the background of physiologically optimum reactions of training and in the zone of quiet activation. These characteristics decrease during the reactions of general adaptation syndrome according to the type of increased activation and reactivation.

Air saturation of the medium reduces the rate of phosphorylating oxidation of succinate in isolated mitochondria.

Rat brain mitochondria were isolated and their respiration was polarographically measured without contact with air oxygen. Gas-saturated experimental mixtures close to the in vivo partial oxygen pressure (normoxic) were compared with the air-saturated, i.e. hyperoxic, mixtures. The rate of phosphorylating oxidation of added succinate under normoxic conditions was found to be 70-100% higher compared with hyperoxic ones. The addition of succinate dehydrogenase activators results in a more than two-fold stronger stimulation of succinate oxidation under normoxia than under hyperoxia. Thiol group donors are shown to stimulate respiration under hyperoxia and not under normoxia. Hyperoxic conditions prevented oxidation of the low succinate concentrations corresponding to the physiological ones.

[The effect of an extract of Baikal skullcap (Scutelleria baicalensis) on succinic acid oxidation by the brain mitochondria in rats with hypoxia]. / Vliianie ékstrakta shlemnika baikal'skogo na okislenie iantarnoi kisloty mitokhondriiami golovnogo mozga krys pri gipoksii.

Oxidative phosphorylation in the mitochondria of rat brain in normobaric hypercapnic hypoxia and preventive administration of Scutellaria baicalensis extract was studied by polarography. Hypoxia causes diminution of energy of the rat brain mitochondria with separation of oxidative phosphorylation and inhibition of the reactions of rapid metabolic cluster of Krebs' cycle. Scutellaria baicalensis extract prevents diminution of energy of the brain mitochondria in hypoxia, inhibits restriction of succinate dependent energy production, and preserves intactness of the mitochondrial membranes.

Cardioprotective effects of trimetazidine and a combination of succinic and malic acids in acute myocardial ischemia.

A mixture of mitochondrial substrates of succinic and malic acids more effectively than antihypoxant trimetazidine prevented functional and metabolic disorders in rat myocardium during acute ischemia: reduces T wave amplitude, QT interval, number and duration of arrhythmias, and restores oxidation-phosphorylation coupling.

Effect of cerebronorm on energy metabolism and lipid peroxidation in rat brain during hypoxia.

Cerebronorm prevents de-energization of mitochondria, limitation of succinate- and NAD-dependent energy production, and oxidation-phosphorylation uncoupling and inhibits LPO processes in the brain of rats under conditions of hypoxia.

Effect of silimarin, succinic acid, and their combination on bioenergetics of the brain in experimental encephalopathy.

In rats with experimental encephalopathy caused by intoxication with 4-pentenoic acid inhibiting beta-oxidation of medium- and long-chain fatty acids, hepatoprotector silimarin inhibited LPO, prevented deenergization and maintained high respiratory activity of brain mitochondria, and increased the rate and coupling of oxidation and phosphorylation. Succinic acid improved oxidation of substrates in motochondria and promoted activation of succinate-dependent ATP generation. Silimarin and succinic acid used together produced a synergistic protective effect on brain mitochondria surpassing the protective effects of individual preparations and prevented LPO activation.

Effects of silymarin (hepatoprotector) and succinic acid (bioenergy regulator) on metabolic disorders in experimental diabetes mellitus.

Silymarin (70 mg/kg) and succinic acid (50 mg/kg) reduce blood glucose and cholesterol concentrations, inhibit LPO, and correct oxidative phosphorylation disturbances in liver mitochondria in experimental diabetes mellitus induced by injection of streptozotocin (65 mg/kg) in rats.

Systemic effects of energy metabolism regulator amber-anti-tox during vibration-induced dysregulation.

Energy metabolism regulator Amber-anti-tox had a systemic effect under experimental conditions of vibration-induced dysregulation. Whole-body vibration was accompanied by nonlinear changes in energy metabolism in the heart, liver, kidneys, and lymphocytes and impairment of intra-systemic inter-organ relationships between mitochondria. Amber-anti-tox prevented vibration-induced de-energization of mitochondria and contributed to the preservation of multidimensional relationships of energy metabolism in vital internal organs.

Protective effect of energy metabolism regulators in alteration of gravitation load under experimental conditions.

Mitochondrial substrate-based preparations corrected disorders, caused by long-term exposure to abnormal gravitation vector in head-down tilt (hanging) test in rats. The preparations produced systemic and polyorgan protective effects consisting in correction of the blood prooxidant/antioxidant balance, energy metabolism in musculus soleus, and minimization of morphological changes in the liver and kidneys.

[Effect of phenobarbital and benzonal on succinate and alpha-ketoglutarate oxidation by rat brain mitochondria]. / Vliianie fenobarbitala i benzonala na okislenie suktsinata i al'fa-ketoglutarata mitokhondriiami mozga krys.

Phenobarbital and Benzonal in anticonvulsive doses depress energy production by brain mitochondria of rats, with phenobarbital inhibiting NAD-dependent respiration and Benzonal oxidation of succinate.

[Succinate oxidation by rat brain mitochondria in experimental convulsions]. / Okislenie suktsinata mitokhondriiami mozga krys pri éksperimental'nom sudorozhnom pripadke.

Corasole-induced convulsive fits are accompanied by the activation of succinate oxidation in the isolated mitochondria, paralleled by the mounting effect of factors limiting succinate dehydrogenase activity. Diverse seasonal sensitivity to corasole correlates with the inhibition of succinate-dependent energy supply for the functional neuronal activity.

[Antihypoxic and antioxidative properties of bemitil]. / Antigipoksicheskie i antiokislitel'nye svoistva bemitila.

The authors discovered antihypoxic properties of the bemitil (pretreatment injections 50 mg/kg intraperitoneally) in the experiments on rats with the circulatory or hypoxic hypoxia. There was limitation of pO decrease and diene conjugates and Schiff bases production increase with the drug in the circulatory hypoxia conditions. Bemitil restricted malondialdehyde accumulation in the rat brain homogenate under the activation of free radicals processes. In the mitochondrial suspension incubation similar effect of the medicine was accompanied with limitation of organelle degradation. Bemitil showed no antiradical activity.