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The antiradical and NO-inhibiting activities of beta-hydroxy(ethoxy) derivatives of nitrous heterocycles (3-hydroxypyridine, 5-hydroxybenzimodazole, and 6-hydroxy(alkoxy)-benzothiazole) have been studied. The antiradical activity has been studied using a homogeneous hydrophilic chemiluminescent system, and the quenching constants (Ki) have been determined. For the most reactive compound, 4-methylthiobenzimidazolyl-3-hydroxypyridine, Ki = 4.5 x 105 M(-1). The NO-inhibiting activity was estimated on a model of the endotoxin shock of experimental animals using a spin trap of nitric oxide radicals based on complexes of iron with sodium diethyldithiocarbamate. It was found that the compounds at doses of 0.25-1 mmol/kg have both the inhibitory and stimulating action on the production of nitric oxide in the liver of animals. The results obtained suggest that some derivatives of nitrous heterocycles can be used as effective antioxidant preparations.

Photoprotective activity of heteroaromatic compounds (derivatives of 3-hydroxypyridine, amino-6-hydroxybenzothiazole, and 5-hydroxybenzimidazole) was studied in the system of UV-induced cardiolipin peroxidation. Although all three compounds had the antioxidant effect during free radical oxidation of luminol, only derivatives of amino-6-hydroxybenzothiazole and 5-hydroxybenzimidazole inhibited the process of UV-induced lipid peroxidation. The 3-hydroxypyridine derivative did not inhibit UV-induced cardiolipin peroxidation, which was probably related to degradation of this compound under the influence of UV light and formation of degradation products that cannot inhibit free radical processes.

In extreme conditions like a new situation, bright light, open space, immobilization, height (the open field and lifted cruciform labyrinth test) and a conflict between an unavoidable action and fear of painful mexidol at the doses of 50 and 100 mg/kg of a body weight eliminates anxiety and fear in rats, recovers adequate reactions and the orientative-trying behavior, and lessens aggressiveness. Mexidol extends life span of mice in acute hypoxic conditions. Mexidol is highly competitive with diazepam as an anti-stress agent and excels it as an anti-hypoxic agent; in contrast to diazepam, mexidol does not cause sedation and myorelaxation. Based on these findings, mexidol can be prescribed to humans to maintain efficiency in all kinds of extreme situations.

The authors have studied mexicor's efficacy in a comprehensive treatment of 25 patients suffering from atherosclerosis obliterans of the lower extremities with grade II-III ischaemia. The state of the vascular bed and the degree of arteries' narrowing were assessed by means of colour duplex scanning of the lower limb arteries using the unit Vivid 7 manufactured by the Company <>. The angiographic examination of the vessels of the lower extremities was carriedout on the angiographic complex manufactured by the Company Siemens Multistar T.O.P. The volume of the filling of the vessels of the lower limbs was evaluated by the parameters of the rheogram registered on the rheograph 4RG-1A. It was determined that the inclusion of mexicor (5-6% ml intravenously dropwise, 300 mg/day) into the standard therapeutic regimen significantly increased the efficacy of the conventional management of atherosclerosis obliterans of the arteries of the lower limbs, accelerating regression of the main clinical symptoms of ischaemia, increasing the distance of pain-free walking, correcting dyslipidaemia, and excreting an antioxidant action.

The goal of this work was to study the expression of tumor necrosis factor alpha (TNFalpha), sphingomyelin cycle activation, and lipid peroxidation (LPO) processes after the removal of a cholestatic factor in the liver subjected to different durations of cholestasis. Restored bile flow after a 9-day hepatic cholestasis normalized sphingomyelinase (SMase) activity and levels of TNFalpha and LPO products. The removal of a cholestatic factor after a 12-day cholestasis did not normalize the studied parameters: SMase activity and the levels of TNFalpha and LPO products remained much higher compared to control. A significant positive correlation between TNFalpha expression, SMase activity, and LPO rate has been revealed. The obtained data indicate that hepatocyte apoptosis after bile outflow restoration in late cholestasis can be due to the activation of the sphingomyelin cycle, LPO, and TNFalpha expression. The synergistic interaction can sharply increase the proapoptotic capacity of each of these factors since TNFalpha activates SMase and LPO, SMase activity depends on the LPO rate, while ceramide, an SMase-produced secondary messenger of apoptosis, can induce oxidative stress.

Mexidol (100 and 200 mg/kg) and diazepam (1 and 2 mg/kg) exhibit a dose-dependent antistressor effect in the pain expectation stress test in rats (conditional emotional reflex). The effect is manifested by the normalization of both motor and somatovegetative characteristics. Paracetamol in a dose of 50 and 100 mg/kg does not possess antistressor properties. Both mexidol and paracetamol increase the threshold of pain sensitivity in the test with electric stimulation of tail in rats. Diazepam does not reduce the pain threshold in this test. The combined administration of mexidol or diazepam with paracetamol does not change the antistressor effect as compared to that of each drug alone. Mexidol, but not diazepam, enhances the effect of paracetamol on the pain threshold.

Aim: To study mexicor effects on functional activity of beta-cells, insulin resistance, lipid metabolism and lipid peroxidation in patients with diabetes mellitus (DM) type 2., Material and Methods: Twenty patients with DM type 2 participated in a double blind randomized trial of mexicor vs placebo. Before and after therapy the following parameters were studied: plasma glucose before meal, immunoreactive insulin, glycosilated hemoglobin, cholesterol, triglycerides, LDLP and HDLP cholesterol, malonic dialdehyde, dienic conjugates, superoxide dismutase, catalase, glutathione peroxidase and alpha-tocopherol., Results: Mexicor significantly improved compensation of carbohydrate metabolism by glucose and glycosylated hemoglobin in the blood, insulin resistance value, lipid metabolism and lipid peroxidation in activation of antioxidant enzymes., Conclusion: Mexicor in therapy of DM type 2 improves carbohydrate and lipid metabolism, lipid peroxidation, activates antioxidant defence enzymes, functional activity of beta-cells, reduces insulin resistance.

Experiments with rats showed that three out of 12 3-hydroxypyridine derivatives (ethyl-methyl hyd- roxypyrine succinate, SK-132 and IBCP-2 - had an anti-motion sickness effect stronger than of scopolamine, the reference vestiboloprotector. The anti-motion sickness effect of ethyl-methyl hydroxypyrine was also demonstrated in experiments with cats. Apparent anti-motion sickness effect of ethyl-methyl hydroxypyrine (mexydol) was found in 69% of healthy male volunteers which is comparable with the effect of scopolamine (62%). In experiments with immobilized cats (myorelaxation drugs) the microelectrode technique and microontoiphoresis of physiologically active substances revealed that ethylmethyl hydroxypyrine influences the majority of neurons in the medial vestibular nucleus (61%). Suppression of cell spontaneous activities in more than one half of cases can be stopped completely or attenuated significantly by bicucculine, a specific GABA(A)-receptor antagonist. In 42% of neurons ethyl-methyl hydroxypyrine subdues the response to vestibular stimulation which is likely to underlie the anti-motion sickness effect.

The method of spin probe and scanning electron microscopy were used to study the effects of some new synthetic antioxidants and bioregulators, the derivatives of 5-hydroxybenzimidazole, on the membrane structure and morphology of erythrocytes. Analysis of EPR spectra and electron micrographs revealed that the derivatives with various side substituents affect the membrane structure and shape of erythrocytes in a concentration-dependent manner, the effect correlating with the hydrophobic properties of the side derivatives. It was shown that all the compounds in the concentration range 1.10(-7) - 1.10(-3) M exhibit the echinocytogenic action, the most profound effect being found in the compound with benzyl- and ethoxygroup in sites 2 and 5, respectively. Our data suggest that nonelectrolytes, the derivatives of 5-hydroxybenzimidazole, are located in the outer monolayer of erythrocyte membrane.

On model of experimental diabetes in rats the possibility of correction of impairments of lipid, carbohydrate and albumin metabolism by SEMOP in a dose of 25 or 5 mg/kg, dimephosphone (100 mg/kg) and alpha-tocopherol (25 mg/kg) has been Advantage of SEMOP consists in its ability to decrease a level of total protein and albumin of blood of animals with experimental diabetes.

Effects of the natural antioxidant hydroxymethylethylpyridine succinate (mexidol) on the electrophysiological and hemodynamic cardiac parameters were studied on narcotized mongrel cats with experimental thoracotomy and acute myocardial ischemia, as manifested by sinoatrial node automatism, conduction, effective refractory period, and excitability of myocardium. The rate of contractility (dp/dtmax) in the left ventricle and the arterial pressure level (p) were monitored using a special differentiating device. The antiarrhythmic activity of mexidol was studied by ECG. The cardioprotective effect of the drug is manifested by normalization of the electrophysiological parameters during operation (accompanied by artificial lung ventilation, thoraco- and pericardiotomy). The positive effect was also observed in operated animals with acute ischemia model. The prophylactic administration of mexidol in a dose of 7 mg/kg prevented the cardio-depressant consequences of acute ischemia and reduced the risk of ventricular arrhythmia during coronary artery occlusion.

Administration of toxic doses of means specific tuberculostatics chemotherapy to rats caused development of medicinal damages of liver, kidneys, and pancreas. Use of 2-ethyl-6-methyl-hydroxypyridine succinate (SEMOP) and S-adenosyl-L-methionine reduced manifestations of pathological effects of tuberculostatics an organism of laboratory animals. There was clear dose-dependence of SEMOP effects. The highest cytoprotective effect was observed at the SEMOP dose of 50 mg/kg. Antioxidant properties of SEMOP determined it membrane protective effects.

The influence of mexidol on the acute toxicity and electrophysiological effects of nibentan, propranolol, and verapamil was experimentally studied. It was found that mexidol potentiates the ability of propranolol and verapamil to inhibit automatism of the sinus node and suppresses the ability of all the three drugs to increase the refractory period of myocardium. It is suggested that these effects are related to the action of mexidol upon ion channels.

Effects of 21 phenyl ethyl-substituted derivatives of 3-oxypyridine (3-OP), 6 adamantine derivatives of pyridine (PD) and actoprotectors bemithyl and bromanthane on physical performance (PP) were evaluated during treadmill testing of mice in ordinary conditions and following vibration. It was stated that in ordinary conditions PP was improved by eleven 3-OP derivatives and 3 adamantine PDs; nine 3-OP derivatives and 3 adamantine PDs had a positive effect following vibration. The actoprotective effect of the compounds depends on their chemical composition, dose and a background. A phenyl ethyl-substituted 3-OP derivative (code CK-132) administered in ordinary conditions and following vibration surpassed significantly the other compounds tested or compared with (bemithyl and bromanthane) in this experiment with regard to the spectrum of effective doses (5-100 mg/kg) and the actoprotective activity (PP improved by 32 to 110%). The compound (code CK-132) can be further test validated as an actoprotector against the impacts of vibration.

The effect of the antioxidant mexidol and two new derivatives of 3-oxypyridine, namely LBK-10 and LBK-39 on the circulation of blood and metabolism of the brain in the postischemic period was studied in acute experiments on narcotized cats under conditions of autohemoperfusion of the cerebral vessels with a stable volume of blood. Therapeutic injection of mexidol and LBK in a dose of 20 mg/kg inhibited the development of the no-flow phenomenon and restored the ischemia damaged metabolism in the brain tissues. LBK-10 reduced the lactate content in the blood flowing from the brain and contributed to constriction of the cerebral vessels.

The influence of mexidol (3-hydroxy-6-methyl-2-ethylpyridine succinate) and its structural components (3-hydroxy-6-methyl-2-ethylpyridine and sodium succinate) and pyridoxine hydrochloride on carbohydrate content and lipid peroxidation was studied in the mouse liver under conditions of stress. Under stress conditions mexidol and pyridoxine exerted positive effects on peroxidation processes; mexidol also normalised glycogen content in the liver.

The decrease of sorbitol dehyidrogenase activity and the increase both of aldoso reductase activity and sorbitol concentration in aorta or eye lens under experimental diabetic angiopathy have been shown. The structural and functional alterations in erythrocytes membranes under angiopathy studied by spin- and luminesoense probes confirm the hypothesis on the major role of membrane pathology processes in the pathogenesis of diabetic mellitus. Pharmacological correction of diabetic angiopathy by glucophag or new antioxidant LBK-78 normalized the studied diversions on the membranes level.

Comparative study of the main pharmacokinetic characteristics and evaluation of the bioavailability of two experimental tablet forms of the new nootropic nooglutil in relation to the substance of the drug were conducted on rabbits. The nooglutil content in plasma samples was determined by high performance liquid chromatography. Significant advantage of one tablet of the drug containing tween-80 was demonstrated. Bioavailability of this drug form of nooglutil in relation to the substance of the drug was 104.3%.

Biochemical, morphological and electron-microscopic readings of blood serum, liver, aorta and brain vessels, and in crystalline lens were investigated in intact and experimental animals during the process of experimental diabetes mellitus formation. The experimental diabetes mellitus was induced by L-adrenaline implementation and atherogenous load. Characteristics of lipid metabolism, peroxide lipid oxidation, sorbitol way of glucose metabolism, glucose and insulin levels conform to diabetes mellitus. Diabetic lipid metabolism impairments were accompanied with changes in microcirculation--a cause of diabetes mellitus complications. These data were supported by morphological and electron-microscopic readings. The results of the study confirm the hormone hypothesis of diabetic complications and stress (high adrenaline level) factors of Diabetes Mellitus pathogenesis.

Acute experiments on nembutal anesthetized rats showed improvement of cerebral blood flow autoregulation in the postischemic period under the effect of mexidol and the new 3-hydroxypyridine (3-HOP) derivatives LBK-10 and LBK-38 administered for prophylactic and therapeutic, purposes. The role of dopaminergic activity, solubility in lipids, and other factors in the mechanism of the activity of 3-HOP derivatives is analysed.

Emoxypin is a medicinal drug from the group of 3-oxypyridines. We studied the capacity of emoxypin to affect the spontaneous level of micronuclear aberrations in the hepatocytes (to decrease or increase it by exerting a mutagenic effect) using the micronucleus test, as well as the capacity to modulate (enhance or weaken) the effects of nitrosomethylurea and X-irradiation. The results obtained do not suggest cytogenetic activity of emoxypin. The nature of "spontaneous" micronuclear aberrations in the liver are discussed, as well as the causes of their age-related increase and adequacy of this model to search for antimutagens.

The influence of synthetic antioxidants (AOs) on hypothalamo-hypophyseal neuro-secretory system (HHNS), sympatho-adrenal system and microcirculatory bad in early stages of atherogenesis in rabbits (Anichkov's model) was studied. Correction of lipid metabolism and lipid peroxidation (LP) activation by AOs was accompanied by disappearing of structural changes in regulatory and microcirculatory systems, regression of atheromatosis in great arteries. Stabilization effect of AOs on neurons and erythrocytes membrane structures was noticed. Some distinctions in mechanism of action between mexidol and fenbutol were found. Thus, regulatory and microcirculatory disturbances, which appear on early atherogenesis stages and is the basis of chronic noninfectious pathology in different target-organs is reversible, for example trough LP correction.

A rabbit model of peroxide atherosclerosis was used to examine the new psychotropic drug Mexydol for its angioprotective properties. The agent was found to inhibit atheroarteriosclerotic manifestations such as hyperlipemia, activated lipid peroxidation, lower activity of the antioxidative system and to produce protective effects on the local vascular mechanisms of atherogenesis, by diminishing the severity of aortic lesion.

The antioxidant capacity of copper chelates with coumarins has been studied by the method of iron-induced chemiluminescence. All substrates studied were potent antioxidants, comparable to butylated hydroxytoluene. The mechanism of the antioxidant action of these copper-coumarin chelates was similar to that of Cu-Mn-superoxide dismutase, with a coumarin part of the complex being involved as a free radicals trap.

Trials in white rats have shown, that intravenous injection of pituitrin (10 U/kg), challenging marked pulmonary edema, resulted in decrease of general lipids in them, as well as cholesterol, phospholipids and free fatty acids with accumulation of lipid peroxidation (LP) products. Preliminary administration of antioxidant emoxipin prevented the decrease in the level of general lipids, phospholipids and fatty acids, promoted a further decrease in cholesterol concentration in them and strongly inhibited lipid peroxidation processes. All this was combined with the development of more pronounced pulmonary edema. Intratracheal administration of a strong inductor of LP--Butyl hydroperoxide has never resulted in the development of pulmonary edema in white rats. These and earlier obtained data ground the statement, that LP--products are not pathogenic in the development of pulmonary edema. Inhibition of their formation may increase its development due to intensification of the signal from the receptor towards intracellular effector systems.

The antiradical activity of coumarine reductones was investigated by the method of inhibition of Fe2+ induced chemiluminescence of egg-yolk lipoproteins. All coumarines studied exhibited high antioxidant activity. The dependence of chemiluminescence intensity on the antioxidant concentration shows that coumarines reductions resemble their chemical analog--ascorbic acid rather than the lipid antioxidant butilated hydroxitoluene (ionol).

The psychopharmacological activity of a new compound--ONK-10--N-5(hydroxynicotinoyl)-L-glutamic acid was studied. It was shown in experiments on mice and rats that the compound possesses the pronounced antiamnestic and antihypoxic effects, does not disturb the conditioned reflex activity and the orientation behavior, has no anxiolytic activity and anticonvulsant properties, causes no disorder of movement coordination, is low toxic. ONK-10 is superior by its antiamnestic and antihypoxic effects to piracetam, meclophenoxat, demanol aceglumate and is not inferior to aniracetam.

The experiment on white rats has revealed that water-soluble antioxidant-emoxipin, having obvious membrane modulating effect, does not influence the rate of watering and congestion of the lungs, the speed of reabsorption of fluid from lung tissue, the permeability of the capillary-alveolar barrier both in the blood-tissue direction and vice versa. Preliminary introduction of emoxipin increased the amount of edema fluid in the lungs when noradrenaline, centrogenic and especially vasopressin pulmonary edema developed, but in did not influence the development of vagotomic pulmonary edema. Stimulation of adenylcyclase or introduction of prostacyclin slowed down the development of centrogenic and vasopressin edema of the lungs. On the basis of these data it can be concluded that the intensification of pulmonary edema after emoxipin introduction is connected with its antioxidant activity.

The experiments on rats have shown that the elaboration of conditioned drinking reflex in T-maze during administration of 2-ethyl-6-methyl-3-hydroxypyridine antioxidant with an anti-stress effect was accompanied by the development of state dependent learning. However, its formation was slower, as compared to state dependent learning in response to the known psychotropic drugs. The replacing test with the injection of bicuculline, picrotoxin, Ca valproate, Ro-15-1788, benactyzine, Cleregil, etc. during state dependent learning made it possible to establish the role of GABA and cholinergic systems in the formation of state dependent learning and in the development of disorders in emotional behavioural reactions after long-term administration and withdrawal of 3-hydroxypyridine.

Experiments on mice and rats were made to study the effect of inhibitors-antioxidants (3-hydroxypyridine derivatives) on the central nervous system. It was established that 3-hydroxypyridine derivatives (50 to 200 mg/kg) possess a broad spectrum of psychotropic effects. They cause normalization of behavior in conflict situations, exert an antiaggressive and anticonvulsant action (antagonism with corazol), are capable of potentiating the hypnotic effect of barbiturates, and of suppressing the animals' motor activity if given in high doses. Most compounds under study have antihypoxic and antiamnestic effects.

The effects of L-tocopherol and synthetic antioxidants on synthesis of prostaglandins, thromboxane B2 and prostacyclin in different layers of the kidney against the background of chronic administration of polyene antibiotics (amphotericin B, levorin, nystatin) were studied in the experiments on aged rats. It was concluded that synthetic antioxidants regulate synthesis of these biologically active substances and also are able to protect the organ from the damaging effect of polyene antibiotics.

The effect of six 3-oxypiridine derivatives (at a concentration of 10(-3) and 5 X 10(-3) M) on cyclic nucleotide level in human platelets and platelet aggregation was studied. Five 3-oxypiridine derivatives were shown to depress platelet aggregation, four of them causing the increase in cAMP platelet level. The correlation between antiaggregation activity of 3-oxypiridine derivatives and their ability to rise cyclic nucleotide level in human platelets is discussed.

Effect of different substances, such as known radioprotectors, inhibitors of free radical processes from the class of 3-oxipyridines and methanol on the characteristics of X-chemoluminescence of human serum albumin solutions and glycyl-triptophane is studied. Possible causes of various effects of added substances on X-chemoluminescence are considered: reactions of the additives with hydroxyl radicals, with primary free radicals and peroxid radicals of protein and peptide. In most substances studied protection is partially concerned with their reactions with hydroxyl radicals and partially with the reaction between additives and free radicals of peptide and protein. When methanol and inhibitors of the 3-oxipyridine class are used as acceptors the reaction between acceptors' free radicals and protein molecules makes a large contribution which results in a decrease of protection. Kinetic data and rate constants of reactions qualitatively describing the effects under study are obtained.