3-hydroxypyridine Derivatives Research Articles

Possibilities of «therapeutic retargeting» of 3-hydroxypyridine and succinic acid derivatives due to their dopaminergic action

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 retargeting» 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.

Method for obtaining supramolecular complex based on 3-ohypyridine derivatives and its application for correction of osteoporosis

Introduction: Currently, there are no safe and ideal medicines for the prevention and treatment of oophorectomy-induced osteoporosis. The development of an effective pharmacotherapy for hypoestrogen-induced osteoporosis is an important task of pharmacology. Materials and Methods: A new supramolecular complex (composition №1) was obtained on the basis of 3-hydroxypyridine derivatives: 2-ethyl-6-methyl-3-hydroxypyridinium 3-pyridinocarbonoate and 2-ethyl-6-methyl-3-hydroxypyridinium N-acetyl-6-aminohexanoate in a ratio of 1:3 by topochemical synthesis. The study of the osteoprotective activity of the supramolecular complex at a dose of 50 mg/kg was performed on 60 white female rats of the Wistar line on a model of hypoestrogen-induced osteoporosis. The effectiveness of the osteoprotective activity of the complex was evaluated on the 57th day of the experiment. Results and Discussion: The new supramolecular complex (composition №1) has osteoprotective activity, which is expressed in improving the indicators of X-ray and histomorphological samples. Oral administration of composition №1 at a dose of 50 mg/kg led to an increase in bone density to values of 2.55±0.02 g/cm3, which is 1.3 times higher than in the control group 1.92±0.01 g/cm3 (p≤0.05) and reduce bone resorption by improving cortical and trabecular bone structures. Conclusion: The obtained data characterize the prospects of studying composition №1 for the correction and prevention of hypoestrogen-induced osteoporosis. Graphical Abstract

Возможность фармакологической коррекции NMDA-индуцированной эксайтотоксичности сетчатки производными 3-гидроксипиридина

Relevance. Glaucoma is the leading cause of blindness worldwide. Among all pathological mechanisms, a special role is assigned to glutamate excitotoxicity, which accompanies a number of pathological conditions of the retina. The aim of this work was to study the pharmacological activity of compounds of 3-hydroxypyridine derivatives in a model of NMDA-induced retinal degeneration. Material and methods. The introduction of the compounds was carried out in the prophylactic mode of administration. 7 days after the model, ophthalmoscopic changes in the fundus and the level of microcirculation were assessed. Research results. According to the results of the study, it was found that the compound LHT 6-20 had the highest activity. Compound LHT 6-20 at a dose of 25.5 mg/ kg in a model of neurodegenerative retinal damage induced by intravitreal administration of NMDA in rats with a prophylactic administration regimen provides an improvement in the fundus picture by 15.4%, relative to the group with a pathology model, which has a statistically a significant difference (p < 0.05), an increase in the level of microcirculation in the retina by 14.1% relative to the group with the model, while the indicator has a statistically significant difference from the group with pathology (p < 0.05), but does not differ from the reference drug (p > 0.05). Keywords: derivatives of 3-hydroxypyridine, NMDA, excitotoxicity, retina, rats, the level of microcirculation, ophthalmoscopy

Protective role of 3-oxypyridine derivatives in rats’ steroid-induced osteoporosis associated with reduced oxidative stress and recovery of nitric oxide formation

From the point of view of the mechanisms for the implementation of pathogenetic links in the development of steroid-induced osteoporosis considered in the paper, the increased risk of the oxidative stress in osteoblasts, as well as the development of the vessels endothelial dysfunction of the microcirculatory bloodstream in the bone tissue, are of particular interest. They lead to the impaired bone tissue trophism and progression of osteoporosis.The aim of the study was research of the osteoprotective effects of a 3-hydroxypyridine derivatives composition on the model of steroid-induced osteoporosis.Materials and methods. To model osteoporosis pathology, the animals (male Wistar rats) were injected with methylprednisolone (MP) at the dose of 5 mg/kg (intraperitoneally) every 5th day for 5 weeks. Аs a non-selective blocker of NO synthase, L-NAME was used at the dose of 25 mg/kg (intraperitoneally). Derivatives of 3-hydroxypyridine (hereinafter referred to as composition No. 1) were administrated at the dose of 50 mg/kg (per os) In all experimental groups, the level of microcirculation and the bone mineral density, as well as the analysis of histomorphological and biochemical samples, were assessed.Results. The study results showed that composition No. 1 (50 mg/kg) has an osteoprotective activity, effectively prevents a decrease in the level of the regional bone tissue microcirculation and in the development of an endothelial dysfunction. That makes it possible to increase the bone mineral density and to slow down the thinning of bone trabeculae. In addition, composition No. 1 (50 mg/kg) reduces the production of reactive oxygen species and increases the NO bioavailability.Conclusion. The data obtained indicate that the studied composition of 3-hydroxypyridine derivatives is considered a promising compound for the prevention and treatment of steroid-induced osteoporosis.

Dopaminergic potential of domestic 3-hydroxypyridine and succinic acid derivatives and prospects for their therapeutic «retargeting»

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 neurotransmission», 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.

Derivatives of 3-Hydroxypyridine in The Correction of Disorders in The Structural and Functional Properties of Erythrocytes in Experimental Acute Destructive Pancreatitis Due to Chronic Ethanol Intoxication

At present, acute pancreatitis only in some areas is a rather well-studied disease of the abdominal organs, however, the destructive forms of this disease have various developmental patterns, complications and, often unfavorable outcomes. The aim of the research is to establish the possibilities to correct the disorders in the functional and structural features of erythrocytes by 3-hydroxypyridine derivatives in experimental acute destructive pancreatitis due to chronic ethanol intoxication. In experimental acute destructive pancreatitis due to a 60-day ethanol intoxication there was a decrease in the content of proteins (a - ? ß -spectrin, ankyrin, anion transport protein, actin, gyceraldehyde-3-phosphate dehydrogenase, glutation-S transferase) and lipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, glycerophospholipids, sphingomyelin, phospholipids, triacylglycerol, sum of mono- and diacylglycerol), an elevated level of band 4.1 and 4.5 proteins, pallidin, dematin, tropomyosin and lipids (lysophosphatidylcholine, cholesterol, it’s esters, non-esterified fatty acids), a disorder in intrinsic cellular metabolism of erythrocytes (an increased concentration of lipid peroxidation products, a decreased activity of catalase, superoxide dismutase, degree of stable metabolites of nitrogen oxide and sorption indicators of membrane) in the erythrocyte membrane. The study has revealed that the greatest efficiency in correction of disorders in the functional and structural feutures of erythrocytes from among the derivatives of 3-hydroxypyridine has a compound ß - hydroxynicotinoylhydrazon 2-methyl-3-hydroxy-4-formyl-5-oxymethylpyrydine dihydrochloride, and the least one - 2-ethyl-6- methyl-3-hydroxypyrydine malate (etoxydol), the administration of 2-ethyl-6-methyl-3-hydroxypyrydine succinate (mexidol) has shown an intermediate result.

Experimental study of new derivatives of 3-hydroxypyridine as pharmacological agents for the correction of ischemic brain injury after intracerebral hemorrhage

Introduction: Limiting the action of secondary injury factors can improve the prognosis in acute cerebral accidents. The aim of the investigation is to study the neuroprotective effects of 3-hydroxypyridine derivatives.
 Materials and methods: The study was performed in Wistar rats. An intracerebral hemorrhage (ICH) model was used. The animals were once administered intraperitoneally with the test drugs 1 hour before the surgery and on the 1st, 2nd and 3rd days. The registration of behaviors and condition of the animals on days 1, 3, 7 and 14 and the morphological examination of the brain were performed.
 Results and discussion: The use of the substances LKhT 4-97 and LKhT 11-02 in the treatment of experimental ICH had a positive effect on the survival rate of the animals and on the resolution rate of pathological signs (p<0.05). Clinical observations were confirmed by the results of analysis of the S100b brain damage marker and morphometry. The efficacy of LKhT 3-15 was largely comparable to that of the reference drug Mexidol. The efficacy of LKhT 01-09 was significantly inferior to that of the reference drug Mexidol. Differences in the neuroprotective effects of the studied substances are related to the metabolism of their various pharmacophores. A hypothetical mechanism for the induction of their neuroprotective effects has been proposed.
 Conclusion: Three of the four 3-hydroxypyridine derivatives under study have a neuroprotective effect, which is manifested in a more rapid resolution of pathological symptoms and less pronounced signs of neurodegeneration.

The effect of new derivatives of 3-hydroxypyridine on the development of brain edema in bacterial purulent meningitis in experimental conditions

Bacterial purulent meningitis (BPM) is one of the most severe infectious and inflammatory diseases of the nervous system, which is characterized by high mortality and frequent development of residual neurological deficits. Edema and swelling of the brain is the most common cause of death in patients with neuroinfections. Most often, brain edema develops in pneumococcal meningitis (PM), which has the highest mortality rate among all bacterial meningitis. The aim of our work was to study the effect of new derivatives of 3-hydroxypyridine, 2-ethyl-6-methyl-3-hydroxypyridinium 2.6-dichlorophenyl (amino)phenylethanoic acid (EMHDA) and bis(2-ethyl-6-methyl-3-hydroxypyridinium) 2.6-dichlo-rophenyl (amino)phenylethanoic acid (B-EMHDA), on the degree of brain edema in the simulation of BPM in experimental conditions.Material and methods. BPM was modeled by injecting a suspension containing Streptococcus pneumoniae at a concentration of 5 x 109 CFU/ml into the subarachnoid space of the brain. The degree of severity of cerebral edema in rats was assessed by determining the content of total water, free and bound fractions in the brain tissue, as well as the hydration coefficient. The lower the hydration coefficient, the more pronounced the cerebral edema. Determination of the content of water fractions in brain tissue and blood was carried out by the thermogravimetric method.Results and discussion. 24 hours after the induction of meningitis, the free water content increases and the amount of bound water decreases. That testifies to the development of cerebral edema. Hydration coefficient in the group treated with EMHDA at a dose of 50 mg/kg, increased by 11.5 % relative to the control group; in the group receiving EMHDA at a dose of 25 mg/kg, increased by 15.3 % compared to the control group (p<0.05). Hydration coefficient in the group treated with B-EMHDA at a dose of 50 mg/kg, increased by 23 % relative to the control group; in the group receiving B-EMHDA at a dose of 25 mg/kg, increased by 26.9 % compared to the control group; and the group receiving B-EM-HDA at a dose of 12.5 mg/kg was 19.2 % higher relative to the control group (p<0.05).Conclusion. Brain edema is least pronounced when using B-EMHDA at all three studied dosages - 50, 25 and 12.5 mg/kg. Injection of EMHDA at doses of 50 mg/kg and 25 mg/kg also helped to reduce the degree of brain edema when modeling BPM in experimental conditions.

Сравнительная эффективность антиоксидантных препаратов в эксперименте in vitro

The aim of this work was to study the antioxidant activity of 3-hydroxypyridine derivatives: Mexidol-Vet® and Emycidin in a model oxidation system. Using the chemiluminescence method, it was found that the introduction of Mexidol-Vet® into the test system at a dose of 1 mg reliably suppresses the amplitude of a fast flash and decreases the formation of photons (light sum value), compared with the test system / placebo and the test system / Emicidin. The antioxidant activity of Mexidol-Vet® is significantly higher than Emicidin by 28.1%.

ADDITIVE NEUROPROTECTIVE EFFECT OF 3-HYDROXYPYRIDINE DERIVATIVES AND HUMAN ERYTHROPOETIN ANALOGUE ON A HEMORRHAGIC STROKE MODEL IN RATS

The correction of free radical oxidation processes is one of the most promising strategies of neuroprotection in acute cerebrovascular disorders.The aim of the study is an experimental study of the neuroprotective effects of 3-hydroxypyridine and erythropoietin derivatives, as well as their combined use.Materials and methods. The study was performed on 109 male Wistar rats. The neuroprotective effect of the substances was studied on a hemorrhagic stroke model. The study drugs were administered to the animals intraperitoneally. Carbamylated darbepoetin was administered three times in advance at the dose of 100 µg/kg within intervals of 3 days, the last injection took place 1 hour before the operation (the total dose was 300 mg/kg). Etoxidol was administered once 1 hour before the surgery at the dose of 50 mg/kg. The survival rate, behavioral features and the state of the animals on the 1st, 3rd, 7th and 14th days were recorded, and the morphological assessment of the brain was carried out.Results. The investigated substances had a positive effect on both the survival rate of the animals during the first day and on the 14th day. The best survival rates on the 14th day were recorded in the group of a combined use of ethoxydol and carbamylated darbepoetin (75%). Thus, in this group of rats, a faster recovery of neurological disorders was already distinguished from the first day on. By the 7th day, more than 50% of the rats receiving the combination of the studied drugs, had had a slight neurological deficit (up to 3 points on the McGrow scale); by the 14th day there had been only minor changes in the neurological status in the rats of this group. A pronounced neuroprotective effect of the combination of 3-hydroxypyridine and erythropoietin derivatives has been confirmed by a histological examination of brain slices – a more rapid decrease in the size of perifocal edema and microcirculation disorders, less damage to neurons and glial elements, and faster processes of resorption and organization of hemorrhage. A macroscopic examination of the brain sections stained with triphenyltetrazolium chloride of the dying rats, showed that perifocal necrosis had been the main cause of high mortality in the control group after the 3rd day.Conclusion. As a result of the experiment, the nephroprotective effect of the studied derivatives of 3-hydroxypyridine and erythropoietin has been proved. Moreover, the combination of these drugs has shown a greater neuroprotective activity than their isolated use. The additive effect of these drugs was due to their action mechanism resulting from the synergism of various structures and components of the cells.

The Effect of 3-Hydroxypyridine and Succinic Acid Derivatives on Hippocampal Monoamine Oxidase Activity in Rats with Alloxan-Induced Diabetes

The effect of the original, domestically manufactured, derivatives of 3-hydroxypyridine and succinic acid (emoxipine, reamberin and mexidol) on the dynamics of monoamine oxidase (MAO-A and MAO-B) activity was studied as compared with the hippocampal level of biogenic amines (serotonin and dopamine) during the first two weeks of alloxan-induced diabetes in rats. It was shown that during this period the hippocampus develops a buildup of dopamine and serotonin against the background of unchanged MAO-A and MAO-B activities. It was established that a 14-day administration of emoxipine, reamberin and mexidol in animals with alloxan-induced DM at doses equivalent to the human therapeutic range prevented an increase in paleocortical serotonin and dopamine levels. Succinate-containing drugs (reamberin and mexidol) induced a parallel decrease in the MAO-B activity in the Ammon’s horn of diabetic animals. Mexidol, which is a co-derivative of 3-hydroxypyridine and succinic acid, induced additionally decreased the hippocampal MAO-A activity. In terms of the severity of the above effects, reamberin and mexidol were not inferior to α-lipoic acid which was used as a reference drug. An isolated derivative of 3-hydroxypyridine (emoxipine), in contrast to reamberin, mexidol and α-lipoic acid, promoted normalization of paleocortical serotonin and dopamine levels but did not affect hippocampal MAO-A and MAO-B activities in rats with alloxan-induced DM. 3-hydroxypyridine derivatives (emoxipine and mexidol), in contrast to reamberin and α-lipoic acid, induced no transient increase in MAO activity and monoamine levels in the hippocampus of diabetic rats. These results are consistent with the previously demonstrated superiority of emoxipine and mexidol over reamberin and α-lipoic acid in the intensity of their cerebroprotective effects in alloxan-induced DM.

ИССЛЕДОВАНИЕ ПРОТИВОГИПОКСИЧЕСКИХ СВОЙСТВ НОВЫХ ПРОИЗВОДНЫХ НИКОТИНОВОЙ КИСЛОТЫ

Two of the five new nicotinic acid derivatives proved to have the antihypoxic properties in tests with mice exposed to acute normobaric hypoxic hypoxia with hypercapnia. Specifically, LKhT 4–19 (100 mg/kg) extended lifetime of the animals by 11 %; LKhT 6-19 doses of 50 and 100 mg/kg extended lifetime by 23 and 34 %, respectively. The antihypoxic effect of LKhT 6–19 (50 mg/kg) outperformed in 1.2 times mexidol (substance of comparison) at the similar dose and was highly competitive at the dose of 100 mg/kg. For reference, mexidol is a 3-hydroxypyridine derivative (ethylmethylhydroxypyridine succinate incorporating, similar to the substances in question, the pyrydine heterocycle). Besides, LKhT 6–19 (100 mg/kg) outperformed mexidol at the similar dose in 1.1 times.

Neuroprotective effects of taurine and 3-hydroxypyridine derivatives in the intracerebral hemorrhage model in rats

Introduction: At present, the problem of pharmacological correction of free radical processess emerges full-blown. The aim of the study is an experimental study of the neuroprotective effect of taurine and 3-hydroxypyridine derivatives.
 Materials and methods: The study was performed in Wistar rats. The neuroprotective effect of the substances was studied in the intracerebral hemorrhage model.
 Results and discussion: The administration of the studied substances had a positive effect on the survival of the animals within the first day (50% of rats died in the control group, 30% – in the Mexidol- and Ethoxidol-treated groups, and 20% – in LKhT 3-17-treated group). Within the first day after the surgery, all rats with stroke had severe neurological disorders. However, by the 3rd day, the Ethoxidol- and LKhT 3-17-treated rats had a lower neurological deficit. By Day 14, all groups of animals treated with the test substances had a lower severity of post-stroke disorders than those in the control group, which was evident as a 1.5-time lower McGraw Stroke Index score. LKhT 3-17 substance showed the most pronounced neuroprotective effect.
 Conclusions: The studied derivatives of taurine and 3-hydroxypyridine have a neuroprotective effect, which is manifested in the lower severity of neurological disorders,a more rapid reduction in the signs of neurodegeneration and accelerated hemorrhage processes.

The Effect of 3-Hydroxypyridine and Succinic Acid Derivatives on the Activity of Monoamine Oxidases in the Brain Cortex of Rats with Alloxan-Induced Diabetes

Abstract—We studied the effects of original Russian 3-hydroxypyridine and succinic acid derivatives (emoxypine, reamberin, and mexidol) on the dynamics of activity of monoamine oxidases (МАО-А and МАО-B) and correlated them to the levels of biogenic amines (serotonin and dopamine) in the brain cortex during the first 2 weeks of alloxan-induced diabetes in rats. An injection of 3-hydroxypyridine derivatives for 7 or 14 days (emoxypine and mexidol) to the alloxan-induced diabetic rats at doses that are equivalent to the treatment range in humans prevented an increase in the activity of cortical МАО-А and dopamine deficiency. The strengths of the effects of emoxypine and mexidol were comparable to the effect of the reference agent α‑lipoic acid. The isolated succinic acid derivative (reamberin) attenuated the activity of МАО-А in the neocortex of rats with alloxan-induced diabetes but caused a transient decrease in cortical serotonin and dopamine levels at the early stages of experiments and failed to correct dopamine deficiency by the end of experiments. A course of injection of the studied drugs for 7 and 14 days increased cortical МАО-B activity; this increase was not associated with a parallel shifts in monoamine levels in the brain cortex of rats with alloxan diabetes. The changes in the activity of cortical МАО that were induced by the drugs were not associated with their effect on the level of circulating corticosterone and hyperglycemia in rats with alloxan-induced diabetes.

COMPARATIVE ANALYSIS OF ACTOPROTECTIVE PROPERTIES OF NEW CHEMICAL COMPOUNDS

Aim. This study was aimed at searching and investigating new substances among phenylethyl derivatives of 3-hydroxypyridine, which exhibit a high actoprotective activity under the conditions of normoxia and acute hypobaric hypoxia.Materials and methods. New compounds of phenylethyl derivatives of 3-hydroxypyridine under the SC code (n = 23) were investigated in comparison with bemethyl and bromantane. The actoprotective activity of new compounds was assessed in experimental animals using a treadmill running test under the conditions of normoxia and acute hypobaric hypoxia. The studied chemical substances and comparative drugs were administered 1 hour prior to exposure of animals to the test. Statistical processing of the obtained experimental results was performed using Microsoft Excel and Statistica for Windows 6.0 software.Results. Among the studied substances, active compounds exhibiting an actoprotective effect have been distinguished. SC-119 chemical substance was revealed, which exceeds the other studied chemicals and bemethyl and bromantane reference actoprotectors in terms of the range of effective doses and actoprotective activity under the conditions of normoxia and acute hypobaric hypoxia.Conclusion. According to the results of the study, the SC-119 compound seems to be a prospective candidate for further research into highly effective actoprotective drugs.

Acute Antidepressant Effects of Derivatives of 3-Hydroxypyridine and Succinic Acid in Experiments on Rats

We report here a comparative analysis of the acute antidepressant actions of derivatives of 3-hydroxypyridine and succinic acid (emoxypine, Reamberin, and Mexidol) developing 30–45 min after single drug doses. The acute antidepressant effects of emoxypine, Reamberin, and Mexidol were assessed from the dynamics of reductions in the duration of “behavioral despair” in rats during 15-min sessions of forced swimming starting 30 min after drug administration. The stimulatory or sedative activities of the study drugs were also assessed, in terms of their influences on behavior in animals in the open field test. All derivatives of 3-hydroxypyridine and succinic acid studied here had acute antidepressant effects. The rate of onset of this effect and the presence of stimulatory or sedative activities depended on the characteristics of the chemical structures of the derivatives of 3-hydroxypyridine and succinic acid. The 3-hydroxypyridine-only derivative (emoxypine) was less active than the succinic acid derivatives (Reamberin and Mexidol) in terms of the rate of onset of the antidepressant effect and had stimulatory actions after single subantidepressant doses. Reamberin and Mexidol had acute antidepressant effects on the background of concomitant sedative effects.

Correction of Experimental Retinal Ischemia by l-Isomer of Ethylmethylhydroxypyridine Malate.

An important task of pharmacology and ophtalmology is to find specific and highly effective agents for correcting retinal ischemia. The objective of this study is to increase the effectiveness of pharmacological correction of retinal ischemia by using new 3-hydroxypyridine derivative–l-isomer of ethylmethylhydroxypyridine malate. A modification to the retinal ischemia-reperfusion model was used, in which an increase in intraocular pressure is carried out by mechanical pressure (110 mmHg) to the front chamber of the eye for 30 min. The protective effects of l-isomer of ethylmethylhydroxypyridine malate in comparison with Emoxipine as pretreatment, with parabulbar injection, based on the model of retinal ischemia-reperfusion, were estimated by the changes in the ratio of the amplitudes of the a- and b-waves of electroretinography (the b/a coefficient) and ophthalmoscopy. The use of l-isomer of ethylmethylhydroxypyridine malate improves the retinal electrophysiological state after 72 h of reperfusion; in the group of rats treated with l-isomer of ethylmethylhydroxypyridine malate, the coefficient b/a was reliably increased by 9.5%, p < 0.05, in comparison with animals treated with Emoxipine, and by 91.7%, p < 0.05, in comparison with the group with no treatment. Furthermore, it prevents the development of ischemic changes in the retina observed in ophthalmoscopy to a greater extent than Emoxipine.

Photophysical and antimicrobial properties of new double-armed benzo-15-crown-5 ligands and complexes

New double-armed crown ether ligands linked to pyridine derivatives have been synthesized and characterized. These macrocyclic ligands (1–5) have been synthesized by the reactions of 4′,5′-bis(bromomethyl)benzo-15-crown-5 with 3-hydroxy pyridine derivatives. A series of Na+, K+ and Ag+ complexes (1a–5a, 1b–5b and 1c–5c) of the macrocyclic ligands have been prepared from sodium perchlorate, sodium picrate, potassium iodide, potassium picrate and silver nitrate salts, respectively. The most suitable cation Na+ is bound to the 15-crown-5 cavity and 1:1 “filling complexes” are formed (1a–5a) while the K+ cation interacts with the crown ether cavity and forms sandwich-type complexes (1b–5b). The Ag+ complexes (1c–5c) have been obtained with a pyridine moiety of the new crown ethers. New ligands undergo photophysical changes when bonding the cation. The influence of metal cations such as Na+, Li+, K+, Fe3+, Cu2+, Ca2+, Ba2+ and Al3+ on the spectroscopic properties of the pyridine linked to the double-armed crown ether moiety was investigated in EtOH solution by means of absorption and emission spectrometry. The prepared compounds (1–5, 1a–5a, 1b–5b and 1c–5c) were evaluated for antibacterial and antifungal activities against pathogenic microorganisms. The results show that the antimicrobial activity of the synthesized compounds varying a degree of inhibitory effects on the growth of different tested pathogenic strains.

Anxiolytic and Antidepressant Actions of Emoxypine, Reamberin, and Mexidol in Experimental Diabetes Mellitus

Objectives. To conduct a comparative study of the anxiolytic and antidepressant activities of derivatives of 3-hydroxypyridine and succinic acid (emoxypine, Reamberin, and Mexidol) in experimental diabetes mellitus (DM). Materials and methods. The effects of emoxypine, Reamberin, and Mexidol on the signs of anxiety in an elevated plus maze and the duration of “despair” behavior in the Porsolt test were assessed in rats with alloxan diabetes during courses of drug treatment. The reference agent was α-lipoic acid. An additional series of experiments was run to study the effects of emoxypine, Reamberin, Mexidol and α-lipoic acid on the severity of hyperglycemia in experimental DM. Results and conclusions. All study drugs were used at doses equivalent to the human therapeutic range for 14 days and significantly decreased the signs of anxiety and depression in rats with alloxan diabetes. The most marked anxiolytic potential was demonstrated for emoxypine, which was the only one of the study drugs decreasing the signs of anxiety not only in comparison with the alloxan diabetes control group, but also relative to the intact control group. Derivatives of 3-hydroxypyridine and succinic acid were no less effective than α-lipoic acid in terms of the level of tranquilizing activity and were more effective than α-lipoic acid in terms of thymoanaleptic activity when given at the maximal dose to rats with experimental DM. Emoxypine and Mexidol, and also α-lipoic acid, significantly decreased hyperglycemia in alloxan diabetes at all the doses tested. Reamberin displayed only minor trends in this direction.

Effects of Derivatives of 3-Hydroxypyridine and Succinic Acid on Stereotypical Behavior and Catalepsy in Mice

The effects of derivatives of 3-hydroxypyridine and succinic acid (emoxypine, Reamberin, and Mexidol) on the state of cerebral dopaminergic processes were studied using catalepsy and stereotypical “verticalization” (climbing) behavior as criteria in experiments on mice. Single doses of emoxypine, Reamberin, and Mexidol at doses equivalent to the therapeutic range for humans were found to potentiate apomorphine-induced stereotypical behavior and to decrease the cataleptogenic effect of haloperidol. All studied derivatives of 3-hydroxypyridine and succinic acid increased spontaneous catalepsy. Emoxypine and Reamberin stimulated spontaneous stereotypical behavior in mice. The intrinsic cataleptogenic activity of the agents studied here correlated negatively with their influences on spontaneous stereotypical behavior. The nature of changes in stereotypical behavior and catalepsy in response to the test compounds provided evidence of an apparent similarity between their effects on dopaminergic processes and the phenotype of the pharmacological action of partial agonists of dopamine receptors.