[Possibilities of «therapeutic retargeting¼ of 3-hydroxypyridine and succinic acid derivatives due to their dopaminergic action]. / Vozmozhnosti «terapevticheskogo perenatselivaniya¼ proizvodnykh 3-oksipiridina i yantarnoi kisloty, obuslovlennye ikh dofaminergicheskim deistviem.

The review is devoted to a comparative analysis of the clinical efficacy of the original domestic derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) in comparison with the results of an experimental study of their dopaminergic action. The position that the dopaminomimetic activity of emoxipin, reamberin and mexidol largely determines their anti-ischemic, antihypoxic, insulin-potentiating neuroprotective, nootropic and antidepressant potential has been substantiated. A comparative analysis of the safety profile of emoxipine, reamberin and mexidol was carried out, taking into account potential and real side-effects caused by iatrogenic deviations from the eudopaminergic state. It has been shown that mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate), which is simultaneously a derivative of 3-hydroxypyridine and succinic acid, has the best balance of efficacy and safety. A generalized assessment of the available data on the successful use of off-label derivatives of 3-hydroxypyridine and succinic acid indicates the advisability of a significant expansion of indications for their clinical use. The authors resume that the «therapeutic retargeting¼ of emoxipin, reamberin and mexidol (i.e. their use for qualitatively new indications) will contribute to progress in the treatment of socially significant and most common diseases.

[Dopaminergic potential of domestic 3-hydroxypyridine and succinic acid derivatives and prospects for their therapeutic «retargeting¼]. / Dofaminergicheskii potentsial otechestvennykh proizvodnykh 3-oksipiridina i yantarnoi kisloty i perspektivy ikh terapevticheskogo «perenatselivaniya¼.

The review is devoted to the assessment of the pharmacological effects of 3-hydroxypyridine and succinic acid derivatives (emoxipin, reamberin and mexidol) from the standpoint of their dopaminergic activity. A systematic analysis of the data has been performed, allowing us to consider emoxipin, reamberin and mexidol as «normalizers of dopaminergic neurotransmission¼, the dopaminergic action of which in its phenotype corresponds to the effects of partial dopamine receptor agonists. The position that the dopaminergic effect, antioxidant and antidepressant potential of drugs containing 2-ethyl-6-methyl-3-oxypyridine (emoxipine and mexidol) are associated with their inhibitory effect on monoamine oxidase-A (MAO-A) has been substantiated. A direct relationship between the stimulating effect of succinate-containing drugs (reamberin and mexidol) on MAO-B, their prooxidant activity, insulin-potentiating and antidepressant effects was analyzed. A hypothesis has been put forward on the general pathological significance of dopaminergic regulation disorders, the correction of which with the 3-hydroxypyridine and succinic acid derivatives can be considered as a promising strategy for improving the complex therapy of socially significant and common human diseases.

[Anxiolytic and antidepressant effects of emoxipine, reamberin and mexidol in experimental diabetes mellitus]. / Anksioliticheskoe i antidepressivnoe deistvie émoksipina, reamberina i meksidola pri éksperimental'nom sakharnom diabete.

AIM: To perform a comparative study of anxiolytic and antidepressant effects of derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) in experimental diabetes mellitus. MATERIAL AND METHODS: An effect of emoxipine, reamberin and mexidol on manifestations of anxiety in 'elevated plus maze' (EPM) and duration of 'desperate behavior' (DB) in Porsolt test in rats with alloxan diabetes during medication course was studied. Alpha-lipoic (thioctic) acid (α-LA) was used as a reference drug. In additional experimental series, an effect of emoxipine, reamberin, mexidol and α-LA on the intensity of hyperglycemia in experimental DM was investigated. RESULTS AND CONCLUSION: All studied medications used in doses equivalent to therapeutic range in humans and administered for 14 days significantly reduced manifestations of anxiety and depression in rats with alloxan diabetes. The most pronounced anxiolytic potential was demonstrated for emoxipine that emerged as the only medication in the study that reduced manifestations of anxiety not only in comparison with 'alloxan diabetes-control' groups but also in comparison to 'intact control'. The intensity of tranquilizing activity of derivatives of 3-oxypyridine and succinic acid was similar to that of α-LA while the thymoanaleptic activity, when the drugs were administered in maximal doses to rats with experimental DM, was higher. Both emoxipine and mexidol as well as α-LA in all studied doses significantly decreased hyperglycemia in alloxan diabetes. Reamberin demonstrated only insignificant tendencies of the same trend.

[The effect of reamberin and alpha-lipoic acid on the tolerance to acute cerebral ischemia in experimental diabetes mellitus]. / Vliyanie reamberina i α-lipoevoi kisloty na ustoichivost' k ostroi tserebral'noi ishemii pri eksperimental'nom sakharnom diabete.

AIM: To study an effect of reamberin and α-lipoic acid (α-LA) on the tolerance of mice with experimental diabetes mellitus (DM) to acute cerebrovascular accident (ACVA) in mice experiments. MATERIAL AND METHODS: The authors studied mice with alloxan diabetes and subtotal and total brain ischemia. In additional experimental series, an effect of reamberin and α-lipoic acid on the tolerance to acute hypoxic hypoxia and intensity of hyperglycemia in experimental DM was studied. RESULTS AND CONCLUSION: The increased vulnerability of animals to ACVA due to hyperglycemia and increased sensitivity to acute hypoxic hypoxia was established. Reamberin and α-lipoic acid administered for 14 days in doses, which are equivalent to therapeutic range in humans, enhance the tolerance to ACVA and acute hypoxic hypoxia in mice with alloxan diabetes. These medications also decrease the intensity of hyperglycemia during concurrent insulin replacement therapy. The increased tolerance to ACVA in mice with alloxan diabetes caused by reamberin and alpha-lipoic acid is associated with an antihypoxic effect of these medications and does not depend on their effect on the intensity of hyperglycemia. Reamberin outperformed α-lipoic acid in the antihypoxic activity, protection against ACVA and the rate of onset of glucose reducing effect in experimental diabetes mellitus.

[ANTIANHEDONIC EFFECT OF 3-OXYPYRIDINE AND SUCCINIC ACID DERIVATIVES].

We performed a comparative study of the effect of original domestic derivatives of 3-oxypyri-dine and succinic acid (emoxipine, reamberin and mexidol) on measures from «sucrose preferen-ce¼ test which is used for assessment of hedonic behavior in rats. а-lipoic acid (а-LA) and amit-riptylin were used as reference medications. For the modeling of anhedonia rats received dexa-methasone (5 mg/kg subcutaneously). We established that threefold administration of emoxipine, reamberin and mexidol in doses that are equivalent to therapeutic range in humans had antianhe-donic effect and increased the measures of «preference¼ and absolute sucrose consumption. This effect was demonstrated in animals that did not receive dexamethasone as well as in rats with dexamethasone-induced anhedonia. Maximal intensity of antianhedonic effect of 3-oxypyridine and succinic acid derivatives was noted after the previous administration of dexamethasone. In rats that did not receive dexamethasone, succinate-containing medications (reamberin and mexidol) exceeded the isolated 3-oxypyridine derivative (emoxipine) in their antianhedonic potential. In case of previous dexamethasone administration 3-oxypyridine and succinic acid derivatives demonstrated equivalent antianhedonic effect that exceeded the effect of reference medications (а-LA and amitriptylin).

[Antidepressant effect of 3-oxypyridine and succinic acid derivatives (experimental study)].

OBJECTIVE: To evaluate antidepressant activity of domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) in rats. MATERIAL AND METHODS: The influence of emoxipine, reamberin and mexidol on duration of desperate behavior of rats in Porsolt forced swim test was studied. Additionally the effect of these substances on the animal's behavior in the open field was evaluated. Amitriptyline and alpha-lipoic acid were used as reference substances. RESULTS: It was established that three administrations of any of the substances in doses corresponding to the therapeutic range in humans reduced the duration of desperate behavior in Porsolt test. Such effect of emoxipine, reamberin, mexidol and alpha-lipoic acid is indicative of their antidepressant activity. Intensity of this activity depends on the effect of these substances on the behavior in the open field. CONCLUSION: Reamberin and alpha-lipoic acid that in maximal doses either had no effect on the orientation behavior in the open field (reamberin) or suppressed it (alpha-lipoic acid) matched amitriptyline in the extent of antidepressant activity. The derivatives of 3-oxypyridine (emoxipine and mexidol) with stimulatory effect on the behavior in the open field demonstrated significantly lower ability to reduce desperate behavior than that of amitriptyline.

[Anxiolytic and antidepressant effects of 3-oxypiridine and succinic acid derivatives in alloxan diabetes].

The effects of 3-oxypyridine and succinic acid derivatives (emoxipine, reamberin and mexidol) on affective disorders in rats with alloxan diabetes were studied. The efficiency of emoxipine, reamberin and mexidol was compared to alpha-lipoic acid, which is considered a "golden standard" in treatment of diabetic neuropathies. Emoxipine, reamberin and mexidol after seven administrations in single doses, that are equivalent to therapeutic range in humans, corrected the anxiety-depressive disorders in rats with alloxan diabetes. Unlike reamberin and alpha-lipoic acid, emoxipine and mexidol corrected the affective status concurrently with the decrease in hyperglycemia. At the same time, emoxipine outperformed mexidol in tranquilizing action (in maximal doses) but yielded mexidol in the antidepressant effect (in minimal doses).

Comparative analysis of the anxiolytic effects of 3-hydroxypyridine and succinic acid derivatives.

Threefold administration of 3-hydroxypyridine derivatives emoxipine and mexidol in optimal doses corresponding to the therapeutic dose range for humans produced an anxiolytic effect and stimulated risk behavior in the elevated plus maze test in rats. These effects were most pronounced after injection of 3-hydroxypyridine derivative emoxipine. Combination of 3-hydroxypyridine cation and succinate anion in the mexidol structure led to attenuation of the anxiolytic effect and less pronounced stimulation of the risk behavior. By the anxiolytic effect and induction of risk behavior, emoxipine and mexidol were close to the reference substance amitriptyline. Reamberin, a succinic acid derivative, had no pronounced tranquilizing properties, but risk behavior induction was similar to that produced by mexidol. In contrast to other test agents, the reference substance α-lipoic acid produced anxiogenic effects and suppressed risk behavior. The obtained results suggest that Russian-made 3-hydroxypyridine derivatives emoxipine and mexidol are promising preparations for the treatment of anxiety disorders.

[The effect of 3-oxypyridine and succinic acid derivatives on obsessive-compulsive activity of mice in marble-burying test].

The effect of domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin, and mexidol) on obsessive-compulsive behavior of mice was studied in the marble-burying test. Additionally the effect of these drugs on the behavior of animals was assessed in the open field test. Amitriptylin and alpha-lipoic acid were used as reference drugs. It was established that single administration of the investigated drugs in optimal doses, corresponding to therapeutic range in humans, inhibits obsessive-compulsive behavior of mice in the marble-burying test. Amitriptylin and alpha-lipoic acid produced similar effects. It is established that emoxipine stimulates the behavior of mice in the open field after single administration. An increase in the emoxipine dose led to decrease of stimulation and gradual development of sedative effect. Reamberin and mexidol, as well as alpha-lipoic acid and amitriptyline, caused sedation in mice tested in the open field. Inhibiting effect of emoxipine, reamberin, mexidol and alpha-lipoic acid on the obsessive-compulsive behavior in mice directly depended on sedative action of these drugs.

[Anxiolytic and antidepressant effects of 3-oxypiridine and succinic acid derivatives in the acute phase of alloxan-induced diabetes in rats].

The effect of derivatives of 3-oxypyridine and succinic acid (emoxypine, reamberin, and mexidol) on the manifestations of anxiety (according to the criteria of behavior in elevated cross plus maze test) depression (according to the criterian of immobility in the Porsolt test) in the acute phase of alloxan diabetes (96 h after alloxan administration) has been studied in rats. The effectiveness of emoxypine, reamberin, and mexidol was compared with that of alpha-lipoic acid (etalon treatment of diabetic neuropathy). It was established that a single administration of 3-oxypyridine and succinic acid derivatives in doses equivalent to the therapeutic range for humans corrected anxio-depressive disorders in the acute phase of alloxan diabetes, while being not inferior to alpha-lipoic acid with respect to the intensity of anxiolytic and antidepressant action. The correction of affective disorders by emoxypine, reamberin and mexidol did not depend on their effect on hyperglycemia in the acute phase of alloxan diabetes. The most pronounced anxiolytic action was observed upon the administration of emoxypine, while the most pronounced antidepressant effect was observed upon the administration of mexidol.

[Insulin potentiating and antidepressant effects of 3-oxypyridine and succinic acid derivatives].

The dependence of the antidepressant action of 3-oxypyridine and succinic acid derivatives (emoxipine, reamberin, and mexidol) on the insulin potentiating activity of these therapeutic agents has been studied in experiments on rats. Alpha-lipoic acid was used as a reference drug. It was established that single administration of emoxipine, reamberin, mexidol and alpha-lipoic acid in optimal doses, corresponding to the therapeutic range in humans, increased the sensitivity of animals to insulin according to the criterion of insulin coma development. Triple administration of the therapeutic agents studied in the same single dose produced an antidepressant effect according to the criterion of "desperate behavior" in Porsolt forced swimming test. Standardization of obtained data by average difference from the control and further correlation analysis demonstrated that the extent of antidepressant action of emoxipine, reamberin, mexidol and alpha-lipoic acid considerably depends on their insulin potentiating activity (r = 0.762, p = 0.004).

[Protective effect of 3-oxypyridine and succinic acid derivatives under conditions of acute alloxan-induced intoxication in mice].

Protective action of 3-oxypiridine and succinic acid derivatives (emoxipin, reamberin and mexidol) was studied in mice under acute alloxan-induced intoxication conditions. All these drugs exhibited protective action with respect to hyperglycemia and hyperglycemia-connected elongation of desperate behavior in the tail-suspension test and reduced activity level on the open field test. Mexidol exceeded emoxipin in the dose range of protecting action with respect to alloxan-induced hyperglycemia and was superior to reamberin in the treatment of desperate behavior in the tail-suspension test.

[The effect of 3-oxypyridine and succinic acid derivatives on the resistance to acute cerebral ischemia].

OBJECTIVE: The effect of original domestic derivatives of 3-oxypiridine and succinic acid (emoxipine, reamberin and mexidol) on the resistance to acute brain ischemia was studied in an experimental mouse models. MATERIAL AND METHODS: We used 260 adult outbred mice. The drugs were introduced intraperitoneally 30 min before the modeling of acute brain ischemia. Each drug was used in 3 three doses: 1/2 of the calculated equivalent of mean treatment dose (EMTD), EMTD and double EMTD. A strangulation model with the assessment of mouse mortality latency and decapitation model with the assessment of agonal respiration (gasping) were used. The efficacy of the drugs was determined by comparison against alpha-lipoic acid that was used as a reference substance in previous studies of antihypoxic activity of emoxipine, reamberin and mexidol. RESULTS AND CONCLUSION: It was established that the derivatives of 3-oxipiridine and succinic acid protected against subtotal ischemia of rostral brain segments (of cerebral hemispheres) as evidenced by the increase in longevity. Emoxipine demonstrated the maximal effect thereby surpassing reamberin and mexidol in the intensity of antiischemic activity. Antiischemic effect of alpha-lipoic acid was comparable to emoxipine. In the model of total brain ischemia, the derivatives of 3-oxipiridine and succinic acid caused the opposite (proischemic) action on the bulbar respiratory center as evidenced by the reduction in duration of gasping. Alpha-lipoic acid did not affect the duration of gasping.

[Experimental study of 3-oxypiridine and succinic acid derivates antidepressant activity in mice].

Effect of Russian 3-oxypiridine and succinic acid derivatives (emoxipin, reamberin and mexidol) on duration of behavioral despair in mice in forced swimming test (by Porsolot) and tail suspension test (by Steru) was investigated. In addition impact assessment of studied medicinal products (MP) on animals' behavior in open field test was performed. Amitriptyline and alpha-lipoic acid were used as reference drugs. It was determined that single delivery of all studied drugs in optimal doses eqvivalent to therapeutic range for human reduces lasting of behavioral despair in Porsolot and Steru tests. This effect of reamberin, mexidol and alpha-lipoic acid indicates their antidepressant action unrelated to stimulatory activity, as far as these MPs like amitriptyline show sedative action in open field test. Reduction of behavioral despair due to effect of emoxipin in relative low doses was associated with increase of mice activity in open field test and so it can't be considered to be antidepressant action per se. Increase of emoxipin dose leads to progressive decrease of its stimulatory effect impact in behavioral despair reduction and induce antidepressant effect in the setting of sedation.

[Cerebroprotective effect of 3-oxypyridine and succinic acid derivatives in experimental diabetes mellitus].

We studied an effect of original domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin and mexidol) on changes in the cellular composition of cortical and diencephalic structures in the rat brain in relation to the hyperglycemia severity in rats with alloxan diabetes. The effect of 3-oxypyridine and succinic acid derivatives was compared with the results of alpha-lipoic acid treatment. We determined that administration of 14 optimal doses of any medication in this study prevented the decrease in neuronal count in the primary somatosensory cortex (Par1 field). This effect was particularly evident after treatment with 3-oxypyridine derivatives (emoxipine and mexidol). Additionally, a two-week administration of emoxipine and mexidol led to a decreased percentage of lipofuscin-positive neurons in the neocortex and field CA1 of the hippocampus. Concurrently, emoxipine and mexidol increased the number of basket neurons as well as oligodendrocytes and microglia in the studied structure of the Ammon's horn. Moreover, these two substances prevented the decrease in the number of astrocytes in the somatosensory cortex and the paraventricular nucleus of the hypothalamus. The cerebroprotective activity of reamberin and alpha-lipoic acid in alloxan diabetes was less effective than that of 3-oxypyridine derivatives. Also, reamberin and alpha-lipoic acid induced undesirable side-effects manifested in the decreased number of pyramid neurons in field CA1 in the hippocampus and the increased number of lipofuscin-positive neurons in the somatosensory cortex and the paraventricular nucleus of the hypothalamus. Changes in the cellular composition of cortical and diencephalic structures resulting from administration of medications used in this study did not depend on the ability of these substances to restrain the hyperglycemia in alloxan diabetes.

[Dynamics of initial manifestations of experimental diabetic encephalopathy].

We established that alloxan diabetes leads to early development of diabetic encephalopathy on the background of marked hyperglycemia. Initial manifestations of experimental diabetic encephalopathy are based on fast progressing loss of neurons and glial cells in the structures of primary somatosensory cortex (field Par 1) and hippocampus (field CAl) between 4th and 17th day after alloxan administration. This is accompanied by accumulation oflipofuscin in neocortex neurons. Manifestations of diabetic encephalopathy on diencephalic level is registered only 10 days after alloxan administration, specifically in paraventricular nucleus where decrease in the number of neurocytes is observed between 10th and 17th day after diabetes induction. Initial manifestations of experimental diabetic encephalopathy correspond to progressing inhibition of orientation and exploratory behavior in animals and decrease of their capacity for conditioning.

[Protective effect of cytoflavin and its components in mice with acute alloxan intoxication].

We have studied the protective effect of cytoflavin and its components (meglumine sodium succinate, riboflavin, inosine and nicotinamide) in mice with acute alloxan intoxication. It is established that cytoflavin and its components possessing in vitro antioxidant activity (riboflavin, inosine and nicotinamide) significantly decrease the hyperglycemic effect of alloxan. The protective effect of cytoflavin in animals with behavioral disorders caused by acute alloxan intoxication is related to the effect of meglumine sodium succinate and inosine, but does not depend on the influence of these substances on free-radical oxidation processes.

Dynamics of lipid peroxidation-antioxidant defense system during alloxan diabetes in rats.

We studied the dynamics of lipid peroxidation-antioxidant defense system in rat model of alloxan diabetes and compared it with disorders of carbohydrate and lipid metabolism. It was found that rats not treated with insulin developed hyperglycemia, hypertriglyceridemia, hypocholesterolemia, and hypotocoferolemia with simultaneous accumulation of circulating LPO products 96 h after the administration of alloxan. The severity of hyperglycemia and hypertriglyceridemia decreased, hypercholesterolemia developed, hypotocoferolemia returned to normal, and the tendency to LPO inhibition was observed in rats 10 days after alloxan administration against the background of previous one-week treatment with insulin. In 17 days after the induction of alloxan diabetes preceded by two-week insulin therapy, the content of lipoperoxides reduced below the normal values with simultaneous progression of hypercholesterolemia, hypertriglyceridemia and the increase in serum fructosamine.

Cerebroprotective effects of emoxipin, reamberin, and mexidol in alloxan diabetes.

The effects of original Russian preparations, derivatives of 3-hydroxypyridine and succinic acid (emoxipin, reamberin, mexidol), on the cellular composition of the cerebrocortical and diencephalic structures were studied and correlations of shifts in the cellular composition with changes in the severity of hyperglycemia in rats with alloxan diabetes were analyzed. The efficiency of 3-hydroxypyridine and succinic acid derivatives was evaluated in comparison with α-lipoic acid. Seven injections of the optimal doses of all the studied drugs prevented the neuron loss in layers I-III of the primary somatosensory cortex. In addition, emoxipin, reamberin, and α-lipoic acid prevented astrocyte loss in the neocortical surface layers and of neurons in the hypothalamic paraventricular nucleus. Reamberin limited microglial infiltration of the hippocampal field CA1. Injection of α-lipoic acid augmented the increase in astrocyte count in the paraventricular nucleus and potentiated the reduction of tigroid granularity of CA1 field neurons. Emoxipin and mexidol caused an increase in the counts of neurons and oligodendrocytes in CA1 field. By contrast, reamberin and α-lipoic acid reduced the counts of neurons and oligodendrocytes, respectively, in this hippocampal zone. More favorable effects of emoxipin and mexidol vs. reamberin and α-lipoic acid on the cellular composition of the hippocampus of rats with alloxan diabetes were explained by more effective correction of hyperglycemia under the effect of 3-hydroxypyridine derivatives.

[The metabolic predictors of depression under diabetes mellitus].

The possibility to detect the depressive disorders in patients with diabetes mellitus is discussed. The comprehensive analysis was applied to the indicators of carbohydrate metabolism, lipidograms and state of system of lipids peroxidation - antioxidant defense. It is established that the development of clinically valuable medium and severe depression under diabetes mellitus is related to the decrease of level of heptane soluble products of lipids peroxidation (diene conjugate) on the background of increasing of concentration of alpha-tocopherol and total content of cholesterol in blood serum. These biochemical indicators reflected the severity of comorbid depression under diabetes mellitus. They had no dependencies of age and gender diabetes mellitus of patients, duration and type of diabetes mellitus. The most informative predictor was established the level of tokoferolemia. Its registration makes it possible to verify the clinically valuable depression under diabetes mellitus with sensitivity level of 70.5% and specificity level of 64.1%.