Method of treating and preventing cognitive disorders associated with exposure to production-induced manganese from external environment in children aged 5 through 10 years old

FIELD: medicine.

SUBSTANCE: method involves a combined administration of the preparations Enterosgel, Kudesan and Pantogam. Enterosgel is administered orally in the form of gel 30 minutes before meals in a dose of 1 teaspoon two times a day for 7 days. Kudesan is also administered orally during meals before noon in an age dose of: 10-16 drops (15-24 mg) in the children aged 5 through 7 years old, 16-20 drops (24-30 mg) in the children aged 8 through 10 years old, pre-dissolved in a small amount of boiled water or other beverage of room temperature, once a day in the course of 30 days. Pantogam is administered orally 15-20 minutes after meals in an age dose of: 500 mg 2 times a day in the children aged 5 through 7 years old, 500 mg 3 times a day in the children aged 8 through 10 years old in the course of 30 days.

EFFECT: complex administration regiment provides the effective correction of cognitive disorders in the given group of children by a synergetic detoxification, antioxidant and neuroprotective action of its components.

3 cl, 4 tbl

 

The invention relates to medicine, namely to Pediatrics, and can be used for the treatment and prevention of cognitive impairment in children living in the zone of influence of the enterprises of the chemical profile in terms of air pollution by manganese.

The relevance of the proposed method is determined by the prevalence of cognitive impairment in children in areas with high loads of chemicals of industrial origin, in particular manganese, chronic accumulation in the body above a certain norm has a toxic effect.

Cognitive impairment is a collective designation of disorders of higher cerebral function due to disorders of the processes of obtaining, processing and analyzing information. To cognitive functions include attention, memory, psychomotor coordination, speech, gnosis, praxis, account, thinking, orientation, planning and control of higher mental activity. In pediatric practice cognitive disorders can be the consequence not only of pathological conditions (hypoxic brain damage, birth injury) or illness (meningitis, meningoencephalitis, hydrocephalus, stroke, etc.), but also to be a result of prolonged exposure to neurotoxic chemicals. In the last th�s the problem of cognitive disorders in children is increasingly viewed in connection with the environmental impact of chemical factors of anthropogenic origin, with neurotropic properties.

The prior art is widely known ways of enhancing cognitive function, comprising administering to the patient a neuroprotective drugs: for example, fenotropil, Amarone that have a complex effect on the metabolic processes and blood circulation in the brain (Gusev E. I., Hecht, A. B., Gapton V. B., Tinopai E. V. Rehabilitation in neurology. Training. allowance. - M., 2000., 327 S.); or the introduction to a mammal sodium succinate bis[(2-hydroxyethyl)-]N,N,N-trimethylamine], which improves various cognitive functions mammals without the development of side effects (Patent RF №2281766); or the combined administration of Melatonin in an amount of from 0.01 mg to 50 mg and Memantine in an amount of from 0.01 to 100 mg in organic lesions of the Central nervous system (CNS) of various origins (Patent RF №2493838).

The disadvantage of these known methods is that the applied treatment and prevention aimed at restoring the CNS lesions of various origins, excluding the effects of chemical toxicants, namely heavy metal - manganese, on the occurrence of cognitive impairment. In addition, these known methods are aimed at treating adults and not appropriate for children.

Also known Method of prevention and correction of violations of the basic functions of the Central nervous� system with lead intoxication in prenatal and early postnatal periods (Patent RF №2410107), according to which the administered drug Beliz-2 at doses of 0.3 ml per 1 kg of body weight throughout pregnancy or within 7 days before delivery and 7 days postpartum. This method provides effective protection of the brain from lead intoxication by reducing the intensity of free radical oxidation and increasing the survival of neurons of the cerebellum. And while this known method and is applicable in the territory, characterized by environmental exposure to heavy metals - lead, however, it is not recommended to treat children up to 18 years.

It is known use in the Method of treatment and/or prevention of neurotic and neurosis-like States, the States associated with oxidative stress, organic psihosindroma, due to a violation of cerebral circulation, discirculatory encephalopathy, traumatic brain injury, intellectual-mental disorders of various origins, withdrawal syndrome, acute violations of cerebral circulation, intoxication caused by antipsychotics (Patent RF №2385722), pharmaceutical neuroprotective, antioxidant, antihypoxic, anti-apoptotic and membrane-protective composition containing 100-250 mg of 3-hydroxypyridine or its pharmaceutically acceptable derivative, or pharmaceutically acceptable salt of this derivative, 400-500 mformation acceptable derivative of magnesium and 10-50 mg of pyridoxine or its pharmaceutically acceptable derivative, and additionally contains 10-50 mg of nicotinamide and 15-30 mg of a substance selected from idebenone or ubiquinone.

However, this known method cannot be used for the treatment of children, because a number of drugs (3-oxypyridine and its derivatives) are contraindications for children, and the content of pyridoxine in the composition is one or two orders of magnitude higher than a child's dose. In addition, the known method is actually aimed at the prevention and treatment of functional and organic disorders of the Central nervous system and does not affect treatment and prevention in children, cognitive impairment, providing only indirect effects on intellectual and memory disorders of different origins.

Also known a method for the treatment of children with cerebral asthenic syndrome (CAS) (Patent RF №2290869), according to which therapy based on the data comprehensive examination of a child. When the bioelectrical activity of the brain at rest is below 40 μv and failed to restore her background values after the function loads within 3 min on electromagnetic brain scan (EEG), based on the deviation neurotransmitter ensure the brain by 10% or more, violations of enzyme activity with decreased utilization of glucose and the synthesis of creatine phosphate on the EEG install the CA, due to oxybiotic gipergennogo, and injected amino acids, enzymes, iron supplements, vitamins, hepatoprotectors for 1 month, then nootropics, particularly Pantogram, and sedation, followed by transcranial micropolarization with taking antihypoxants and multivitamins with minerals.

The disadvantage of this known method is insufficient to restore children's cognitive functions associated with exposure to manganese because known treatment is aimed at correction of severe organic damage of the Central nervous system that are not associated with exposure to metals, not the technology of elimination of toxic substances.

While the prior art have not been identified, the known methods of treatment and prevention in children, cognitive impairment associated with environmental exposure to manganese anthropogenic origin, so to make the choice closest analogue to the claimed object is not possible.

The technical result achieved by the invention is to ensure the effective treatment and prevention of cognitive impairment in children, due to the high degree of recovery of a broad range of cognitive functions and increase resistance of the organism to manganese, and in improving medical care for children living in areas with �inflammatory by environmental manganese exposure anthropogenic origin.

The technical result is achieved by the proposed method of treatment and prevention in children 5 to 10 years of cognitive impairments associated with environmental exposure to manganese anthropogenic origin, by prescription of medicines, namely, that carry out the combined use of children following medicines: "Enterosgel" in the form of oral gel 30 minutes before a meal 1 teaspoon twice a day course of 7 days; "Qudesan" during oral food intake in the first half of the day in a dosage of age: 5 to 7 years 10 to 16 drops (15-24 mg), 8 to 10 years 16 to 20 drops (24-30 mg), pre-dissolved in a small amount of boiled water or another beverage at room temperature, once a day the course of 30 days; "Pantogram" oral 15-20 minutes after eating, in a dosage of age: 5 to 7 years - 500 mg 2 times a day, from 8 to 10 years - 500 mg 3 times a day course of 30 days.

At excess concentrations of manganese in the blood of a child to two reference concentrations the rate of the combined use of these drugs is carried out 2 times a year.

At excess concentrations of manganese in the blood of a child more than two of the reference concentrations the rate of the combined use of these drugs is carried out 3 times a year.

The specified technical result�is achieved at the expense of the next.

To understand the substance of the matter should be clarified that diseases of the nervous system in children living in conditions of pollution of the environment of chemical substances with neurotrophic mechanism, in particular manganese, tend to have more early development, rapid progression and the increasing resistance to medical treatment.

Compounds of manganese in the intake of atmospheric air and almost completely absorbed in the blood, hematogenous reach the Central nervous system (CNS), easily pass the blood-brain barrier due to facilitated diffusion, active cation transport, endocytosis in endothelial cells of the brain. In the CNS manganese accumulates in the structures of the extrapyramidal nervous system (basal ganglia and nuclei of the brain stem) in the medial segment pallidus and the reticular part of the substantia nigra. In some cases, suffer the cortex of the frontal and parietal lobes, cerebellum and hypothalamus. With lesions of the basal ganglia is disrupted the functioning of the cortical-subcortical circles and PELLICANO-stem connections, afferentation frontal and brainstem structures from the basal ganglia. The accumulation of manganese in brain tissue leads to a decrease in the number of neurons and gliosis, the development of a variety of asthenoneurotic, autonomic, cognitive path�'s and neurological disorders.

The development of cognitive impairment associated with environmental exposure to manganese as a rule, precedes manifestation and asthenic asthenic-neurotic syndrome. The clinical signs of these syndromes, initiated by long-term exposure to manganese compounds are weakness, fatigue, reduced physical and mental disability, physical activity, and increased sleepiness. Characterized by muscular hypotonia, hyperhidrosis, hypomania, lability of heart rate and blood pressure, sensitive disorders. Further and asthenic asthenic-vegetative manifestations are added signs of intellectual-mental disorders, extrapyramidal disease (bradykinesia, a moderate increase in muscle tone, coordination disorders).

Manganese disrupts the metabolism of biogenic amines, a number of oxidative enzymes, inhibits and activates adrenergic cholinergic system, increases acetylcholine in the synapses of the basal ganglia and hypothalamus. Manganese affects the synthesis and Deposit of dopamine, changes the balance of acetylcholine and dopamine, resulting in decreased muscle tone, impaired precision, dexterity and smoothness of voluntary movements, the development of vegetative disabilities�TBA. System effects of manganese include a hypofunction of the endocrine glands, functional insufficiency of the liver, vasomotor insufficiency, decreased blood supply to the brain (in the pool vertebroplasty-basilar arteries) and total cerebral blood flow. Manganese acts on neurotransmitter signaling pathways, metabolism of glutamate and gamma-aminobutyrate acid in the CNS. Manganese promotes the release of large amounts of glutamate in the extracellular space. Glutamate is a major excitatory neurotransmitters in the cortex, hippocampus, striatum and hypothalamus; involved in the regulation of memory processes, is a member of small and medium-regulatory peptides of the brain, such as glutathione. Great is his power role, since glutamate is a supplier of a-Ketoglutarate component citrate cycle. Excess glutamate is removed by astrocytes, mainly glutamate/asparate transport protein (GLAST). Adverse effects of manganese associated with the suppression function of astrocytes, which removes excess amounts of glutamate from the extracellular space, and, as a consequence, the violation of the mediator of exchange.

Thus, influencing the exchange of neurotransmitters and neurotransmitters, manganese compounds will contribute to the abnormalities in both the processes of inhibition and opened�routes in the Central nervous system, the formation of syndromes of asthenia and/or hyperosmolality, the development of cognitive disorders and autonomic dysfunction.

In addition to neurotoxicity of manganese has a systemic effect, which is based on his expressed oxidative properties. Manganese acts as a cofactor oxidases that catalyze oxidation-reduction reactions in the human body, is involved in the processes of formation of free radicals. In sub-toxic doses, it separates the processes of tissue respiration and oxidative phosphorylation. Sub-toxic doses of manganese mitochondrial damage the device, which exacerbates the process of cell damage. Oxidative degradation of cell membrane of red blood cells leads to changes in its membrane potential, transport properties, permeability, disruption of the balance of intracellular trace elements.

Thanks to the combined use of medicines, recommended by the proposed method, high efficiency recovery of cognitive dysfunction in children living in poor environmental conditions in terms of environmental exposure to manganese.

Moreover, in the proposed method, it is recommended to use in combination with the following drugs:

ENTEROSGEL® (Enterosgelum dulcis), the international trade name� - polymethylsiloxane polyhydrate. Registration number: R N003719/02-28.03.2012. Code ATX: AV. Pharmacotherapeutic group: Chelators. Registration number mprm-003840/09. Chemical composition: the hydrogel metalquimia acid. Code ATC AVC. Enterosgel is not only pronounced sorption, but also a detoxifying effect. Has a globular porous silicone matrix (molecular sponge), hydrophobic nature, which is characterized sorption effect in relation to medium molecular toxic metabolites (molecular weight from 70 to 1000). It selectively adsorbs from the contents of the intestine and the blood of endogenous and exogenous toxic substances. Enterosgel helps to accelerate the repair processes in the mucous membranes, does not affect saprophytic microflora, promotes parietal digestion and stimulates peristalsis. Improves the function of the detoxifying organs - the liver and kidneys. Enterosgel in terms of the body of chemically inert, non-toxic and harmless, is not absorbed in the intestine, excreted unchanged within 12 hours, has the organic nature of the surface and is fully compatible with the tissues and substrates of the body, not cause atony. Applied to children from the 1st year of life.

QUDESAN® (Kudesan); Code ATX: SEW in the form of droplets, the act�VNOM substance: ubidecarenone 30 mg, auxiliary substances: alpha-tocopherol acetate - 4.5 mg; ascorbyl palmitate 1 mg; macrogol glycerylmonostearate (Cremophor RH-40) - 105 mg; sodium benzoate 2 mg; citric acid (food grade) - 1.6 mg; purified water up to 1 ml. drugs, cardiotonic, antioxidant. Ubidecarenone (coenzyme Q10, ubiquinone) is a naturally occurring substance, which is a vitamin-like coenzyme. Ubidecarenone is an endogenous substrate that participates in the transfer of electrons in the transport chain redox processes, in the process of exchange of energy in the reaction of oxidative phosphorylation in the respiratory chain of mitochondria of cells. Participates in the processes of cellular respiration by increasing the synthesis of ATP. Have clinically significant antioxidant activity. Protects the lipids of cell membranes from peroxidation. Reduces the area of myocardial damage in conditions of ischemia and reperfusion. Ubidecarenone prevents prolongation of the QT interval, improves exercise tolerance. Due to the endogenous synthesis of fully ensuring the needs of the body to the coenzyme Q10only occurs before the age of 20. The concentration of coenzyme Q10reduced in elderly patients and in a variety of diseases in both adults and children. Indications for the use of children in the composition of the�e combination therapy for the following diseases: chronic heart failure; dilated cardiomyopathy; arrhythmia; chronic gastroduodenitis, chronic pyelonephritis; metabolic nephropathy; migraine; neurocirculatory dystonia, hereditary neurodegenerative diseases, congenital myopathies, muscular dystrophy; diseases associated with metabolic disorders (asthenic syndrome, the recovery period after a serious illness and surgery); in the period of preparation for heart surgery (coronary artery bypass grafting, congenital and acquired heart defects) on the recommendation of a doctor; to improve adaptation to increased physical activity; to prevent and compensate for a deficiency of coenzyme Q10.

"PANTOGAM®" (Pantogam), Code ATX: N06BX. Calcium salt guantanomo acid - neuroprotector, has neurometabolic, neurotrophic and neuroprotective properties. Contains gamma-aminobutyric acid (GABA), which increases brain resistance to hypoxia and exposure to toxic substances, stimulates anabolic processes in neurons, combines a moderate sedative effect with a mild stimulant effect, has anticonvulsant effect, reduces the excitability of the motor while simultaneously streamlining of behavior. Enhances mental and physical performance. The mechanism of action is due to direct in�eniem of Pantogam on GABAB-receptor-channel complex.

Empirically it was found that only the use of a comprehensive scheme of application of the above medicines ensuring synergy in the achievement of the technical result due to the improvement processes of cellular respiration and energy production, provide antioxidant action, normalization of the bioelectrical activity of the brain, recovery of intellectual-mnestic functions of the brain, as well as through the provision of GABA-ergic alfahydroacids effect, while ensuring high efficiency in reducing homeostatic conditions and improve indicators of autonomic regulation and cognitive dysfunctions.

Studies have shown that the use of these drugs individually or in the scheme of the two funds is not achieved in children reduction of cognitive disorders associated with exposure to manganese.

When implementing the proposed method perform the following operations in the following sequence:

- produce a selection of the area for the risk of the formation of children's cognitive dysfunctions: industrialized areas with high anthropogenic load, in particular with a high load of chemical factors of the habitat, namely manganese;

- diagnosed in children � aged 5-10 years, long resident in the said territory and chronically exposed to the toxicant - manganese, the presence of cognitive impairment associated with exposure to manganese, as follows:

(a) conduct of clinical diagnosis by medical specialists ' examination: the pediatrician and neurologist, to identify signs and asthenic asthenic-neurotic syndrome (irritability, tearfulness, headache, fatigue, sweating, anxiety, sleep disturbances, weakness, intolerance of transport, night sweats, memory impairment, dizziness, emotional lability, poorer performance); clinical signs of toxicity (pallor, periorbital shade, marble pattern of the skin, cold clammy hands and feet, dry skin, tachycardia or bradycardia);

b) continue to perform neuropsychological testing of children and establish the child the presence or absence of cognitive impairment, through the study of cognitive functions: memory (verbal, visual); praxis (motor control function) is a spatial, dynamic, reciprocal, kinesthetics; gnosis (perception) test what items are hidden"; attention and speed of mental activity (test "set marks") (A. R. Luria, 1973; Cemernica E. G., 1985; Chomsky, E. D., 005; S. A. V. et al., 2005);

b) next, in the sample of blood of these children establish the manganese content (by atomic absorption spectrometry ("Aanalyst 400 PERKIN ELMER, USA, registration number in the State register №38267-08);

g) in the case of manganese more than the reference level (0,011±0,004 µg/cm3) conduct subsequent laboratory and diagnostic examination of the child by establishing all of the following clinical and laboratory parameters: the level of digestion of lipids in the blood serum, the level of malondialdehyde MDA in plasma and the levels of 8-hydroxy-2-deoxyguanozine 8-OHdG in urine, characterizing the activity of oxidative processes; the level of glutathione peroxidase GPO, the level of Cu/Zn-superoxide dismutase Cu/Zn-SOD, the level of antioxidant activity of the CCA serum characterizing the state of the antioxidant system; the level of glutamate and the levels of γ-aminobutyric acid in the serum, which are the neurotransmitters; the content of hormones of the pituitary-adrenal axis: the level of adrenocorticotropic hormone ACTH, cortisol and serotonin levels in the serum, characterizing the neuroendocrine regulation, the level of cyclic adenosine monophosphate camp and cyclic guanozinmonofosfata cGMP characterizing the state within�gunning for energy security. All these indicators are defined standardized biochemical and immunoassay methods using biochemical "Konelab 20" (ThermoFisher, Finland) and enzyme immunoassay "Infinite F50 (Austria, Tecan) analyzers. As criteria for evaluation of abnormalities of clinical and laboratory indicators of age-related physiological levels, and the content of manganese - reference levels (N. TCI, 2003);

d) is further carried out correlation analysis between clinical and laboratory parameters and the content of manganese in the blood of a child using a logistic regression model, according to which calculate the probability of a negative change in the marker of the response of the organism (the above clinical and laboratory parameters) when exposed to the body of the marker of exposure (manganese). Identifying and evaluating the relationship between changes in clinical and laboratory parameters in children and the concentration of manganese in the blood is based on the calculation of odds ratios (OR) and its confidence interval (DI). The criterion of the presence of "manganese concentration in the blood is an indicator of response" OR is≥1. Rationale markers of response is performed based on the parameter estimates of dependence of the index change of the odds ratio from the concentration of manganese in the blood, described by a regression model in the form of exponential�Oh functions. As the criterion for statistical hypothesis testing is used the Fisher test (F). Differences are considered statistically significant at probability p≤0.05;

(e) when establishing the correct relationship: the high content of manganese in the blood more 0,029 mg/DM3with not less than 50% of these clinical and laboratory parameters, with their next characteristics: - increased compared to age-related physiological norms levels of hydroperoxides of lipids, MDA, 8-OHdG, glutamate, ACTH, cortisol, cGMP, is reduced compared with age-physiological levels of norms Glpo, Cu/Zn-SOD, SLA, γ-aminobutyric acid and camp, diagnose the presence of cognitive disorders associated with exposure to manganese.

- Provide complex treatment of children with identified cognitive impairment associated with exposure to manganese, by combined use of children following medicines: "Enterosgel" in the form of oral gel 30 minutes before a meal 1 teaspoon twice a day course of 7 days; "Qudesan" during oral food intake in the first half of the day in a dosage of age: 5 to 7 years - 10 to 16 drops (15-24 mg), 8 to 10 years 16 to 20 drops (24-30 mg), pre-dissolved in a small amount of boiled water or another beverage at room temperature, od�n times a day the course of 30 days; "Pantogram" orally 15-20 minutes after eating, in a dosage of age: 5 to 7 years - 500 mg 2 times a day, from 8 to 10 years - 500 mg 3 times a day course of 30 days.

An example implementation of the proposed method of treatment of children suffering from cognitive impairment caused by environmental exposure to manganese

- choose environmentally unfriendly territory for high-load chemical factors of the habitat. This site was chosen Chusovoi, Perm territory, characterized by the presence of chronic aerogenic exposure of the population to emissions components Chusovoy metallurgical plant (CMP). In particular, manganese is one of the priority components of emissions in atmospheric air of industrial enterprise (its concentration in the air exceeded the maximum permissible concentration by 2.2 times);

- randomly selected group of children living on this territory for a long time (e.g. not less than 4-5 years) in the zone of influence of emissions of "CMP". As a result, we selected 89 children from organized child care institutions and school students residing in the zone of influence of emissions components "CMP", including 42 boys (47% of the surveyed children), 47 girls (53% of the surveyed children) - supervision group. The age of the examined children �5-10 years left. Formed a comparison group of 87 children aged 5-10 years who lived in areas where there are no recorded violations of hygiene standards on the concentrations of manganese.

- next, for the purpose of comparison and evidence of the influence of manganese on the occurrence of cognitive impairment, all children from both groups were in clinical diagnosis: examination of medical specialists: pediatrician and neurologist, to identify signs and asthenic asthenic-neurotic syndromes and clinical signs of toxicity; they have determined the content of manganese in blood were determined by clinical and laboratory parameters. The data of the observation group and the comparison group are shown in table 1.

The data in table 1 show that the children of the observation group are characterized by cognitive impairment associated with exposure to manganese. Therefore, in the future, they were treated according to the proposed method, the scheme of realization of which is given in table 2.

Data on the effectiveness of the treatment by the proposed method children with cognitive impairments associated with manganese, are shown in table 3.

The data in table 3 show that after treatment by the proposed method has been improving all kinds of indicators�her children suffering from cognitive disorders under the influence of manganese: and clinical diagnostics indicators, and indicators of neuropsychological testing, and clinical and laboratory parameters. Thus there was a reduction in the frequency of complaints asthenic-neurotic 1.4 times, the clinical manifestations of autonomic dystonia 1.2 times, symptoms of General intoxication 1.3 times. Increased the average score on a test of attention and rate of activity with 4,01±0,72% to 5,42±0,45 respectively, p=0.05, by the test that evaluates visual gnosis, 4,63±0,43 to 5.9±0,62 respectively, p=0.04, decreased by the test on kinesthetically praxis from 1.59±0.44 to 0,58±0,29, p=0.01. The number of children who completed the task, increased by 1.4, 1.6 and 1.3 times, respectively.

Revealed positive dynamics of clinical and laboratory parameters. A reduction of the level of digestion of lipids in the serum (with 325,44±23,72 mol/DM3to 223,41±21,31 mol/DM3, p=0.001) and MDA (3,54±0,117 mol/cm3to 2.11±0.08 µmol/cm3); the concentration of 8-OHdG in the urine decreased with 148,94±31,32 ng/cm3to 78,66±9,22 ng/cm3(p=0.001). At the same time, we observed an increase of the antioxidant defense processes: the activity of PPO in serum reached 38,81±2,31 ng/cm3(source - 30,95±3,36 ng/cm3, p=0.04), a Cu/Zn-SOD 62,219±2,653 ng/cm3(source 36,448±2,156 ng/cm3, p=0.001). General�th antioxidant status reached 259,27±25,33 mol/DM 3(source 125,64±to 8.38 mol/DM3, p=0.001). The level of glutamate decreased to 101,79±8,24 mmol/DM3(source - 148,87±16,76 mol/DM3, p=0.001), and the content of gamma-aminobutyric acid in the serum increased to 0,088±0,011 mol/DM3(source - 0,046±0,013 mol/DM3, p=0.001). Cortisol decreased from 791,63±127,39 nmol/cm3to 512,34±93,77 nmol/cm3respectively, p=0.03, and serotonin levels in the blood increased from 66,81±11,17 ng/ml to 97,118±18,02 ng/ml, p=0.03. The content of ACTH in the blood decreased from 11.2±2.3 pmol/l to 7.6±0.6 pmol/l, p=0.03. After the course the level of camp is reached 7,15±1.2 pmol/cm3(source 4,14±1.67 pmol/cm3, p=0.02), and cGMP level is decreased to physiological and amounted to 3.38±0.77 pmol/cm3(original 5,6±2,78 pmol/cm3, p=0.04). Increased resistance of the body to the accumulation of manganese (a decrease in the content of manganese in 12 months by 40-50%, despite the fact that children who have undergone treatment, continued to live in conditions of environmental exposure to manganese).

In the subgroup of children not receiving treatment according to the proposed method, the essential dynamics of the above studied parameters are not set.

According cardiointervalography the number of children with indicators of atonia significantly increased to 46% (in 2.5 times, p=0.04), while in the subgroup of children not receiving treatment, the number d�TEI with vagotonia increased 1.3-fold (p=0.05).

Obtained during the research data showed that the proposed method of medicamentous correction in children 5-10 years of cognitive impairment due to chronic exposure to manganese, concomitant use of drugs with metabolic effect, improves the processes of cell respiration and energy production, providing an antioxidant effect, normalizing the electrical activity of the brain, righting intellectual-mnestic functions of the brain, as well as providing the GABA-ergic, alfahydroacids effect, is pathogenetically justified and shows high efficiency against homeostatic disturbances, indicators of autonomic regulation and cognitive dysfunctions.

For evidence of synergistic effects in the present method it is three drugs in this dose, below is a table 4, reflecting the clinical efficacy in the follow-up period (12 months) under different medication for the treatment and prevention of cognitive dysfunction in children exposed to chronic prolonged exposure to manganese territory of residence.

Studies have shown and the data are shown in table 4, the effect of the proposed method is not a consequence of simple days�Vija used drugs, and shows a clear positive synergy pharmaceuticals for the treatment and prevention of cognitive disorders in children (the sum of effects of individual drugs in the same doses gives the effect is significantly less pronounced than with the combined application recommended in the claimed method three drugs).

Complex specialized medical and preventive care to children with cognitive impairment associated with environmental exposure to metals of anthropogenic origin (manganese), extends the standard approaches to prevent progression of cognitive impairment, includes an additional set of medical interventions based on pathogenetically substantiated conjunction elimination (chelators), neuroprotective (nootropics) and normalizing the redox processes (antioxidants) drugs.

Thus, the proposed method of treatment and prevention in children 5 to 10 years of cognitive impairments associated with environmental exposure to manganese anthropogenic origin, has pronounced effects and promotes recovery of cognitive functions, and can be recommended for treatment of children with cognitive dysfunctions, long-term living in industrialized areas and have elevated levels of b�ashridah manganese.

1. Method of treatment and prevention in children 5 to 10 years of cognitive impairments associated with environmental exposure to manganese anthropogenic origin, by prescription of medicines, characterized by the fact that you are doing the combined use of children following medicines: "Enterosgel" in the form of oral gel 30 minutes before a meal 1 teaspoon twice a day course of 7 days; "Qudesan" during oral food intake in the first half of the day in a dosage of age: 5 to 7 years 10 to 16 drops (15-24 mg), 8 to 10 years 16 to 20 drops (24-30 mg), pre-dissolved in a small amount of boiled water or another beverage at room temperature, once a day the course of 30 days; "Pantogram" oral 15-20 minutes after eating, in a dosage of age: 5 to 7 years - 500 mg 2 times a day, from 8 to 10 years - 500 mg 3 times a day course of 30 days.

2. A method according to claim 1, characterized in that when exceeding the concentration of manganese in the blood of a child to two reference concentrations the rate of the combined use of these drugs is carried out 2 times a year.

3. A method according to claim 1, characterizes�, at excess concentrations of manganese in the blood of a child more than two of the reference concentrations the rate of the combined use of these drugs is carried out 3 times a year.



 

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3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an immunomodulatory composition for injection into a mammal. The immunomodulatory composition for injection into a mammal containing a hydrolysate prepared by acid and/or enzymatic hydrolysis of one or more bioresources specified in a group consisting of bivalve molluscs, annelids, leeches, and water taken in certain proportions. A method for preparing the immunomodulatory composition for injection into a mammal. A method of treating a pathological condition in a mammal in need thereof involving the injections of the immunomodulatory composition into the above mammal. Using the composition for normalising metabolism into the mammal in need thereof.

EFFECT: composition enables extending the range of products with immunomodulatory activity for injections.

19 cl, 7 tbl, 7 ex

FIELD: veterinary medicine.

SUBSTANCE: method of treatment of calves with Simuliidotoxicosis is that 40% solution of urotropine is administered intravenously to calves at a dose of 1.5 ml per 10 kg of animal body weight.

EFFECT: improvement of efficiency of the method.

FIELD: medicine.

SUBSTANCE: group of inventions relates to veterinary and medicine, in particular to obtaining and application of biopreparations for immunotherapy of ecopathologies. The group of inventions includes obtaining a protein antigen from a mixture of anatoxins from three enteropathogenic virulent strains of a pathogen of escherichiosis of calves E.coli No. 378, 379, 380 by their growing on Hottinger medium with further addition of 0.4-0.5% formalin, following thermostating for 10-12 days and cooling the mixture of anatoxins with a sterile solution of aluminium hydroxide, after that obtaining radioantigen from E.coli "PL-6" by growing cultures on a meat infusion agar with further washing away a biomass by a physiological solution and irradiation of the obtained suspension with a concentration of 1.2·1010 m.c./cm3 on a gamma-installation in a dose of 140-150 Gr with following thermostating and extraction of radiotoxin with 70% acidified with 0.05% hydrochloric acid to pH 5.5 ethanol, following evaporation of the exractant to the initial volume, after that, obtaining protein-cadmium radioantigen first by preliminary dechlorination of cadmium chloride, obtaining cadmium hydroxide, addition into the obtained 2.7% solution of the antigen of 0.77% solution of cadmium hydroxide in a ratio of 1:1 with following thermostating at a temperature of 37°C for 30 minutes, evaporation and dissolution of the residue to 12.8% concentration, further obtaining protein-cadmium radioantigen by an addition of 1.2% solution of a mixture of three anatoxins of E.coli and 12.8% solution of cadmium radioantigen in a ratio of 1:9, conjugation of components at room temperature for 8-10 hours, standardisation by a dry substance to 10% concentration and pouring into vials, and storage at a temperature of 4-6°C. The group of inventions also relates to a method of treating radiation, chemical and/or bacteriological damage to an organism by introduction of 10% solution of complex protein-cadmium radioantigen.

EFFECT: application of the group of inventions is effective in treatment of radiation, chemical and/or biological damage.

4 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and particularly to preparations for a therapy of oncological diseases, treatment of allergy, prevention and health improvement. The invention represents a method for preparing fraction 4 (ADP-f4) and fraction (ADP-f5) adaptogenic Dorogov's preparations, characterised by the fact that a primary product is a fraction 2 antiseptic Dorogov's stimulator (ADP-f2) to be thermally treated.

EFFECT: implementing the given invention provides the more effective prevention and eliciting anti-stress reactions for the purpose of improving the functional state of organism and increasing a resistance in an activation therapy.

2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and veterinary science and aims at increasing the radioresistance in mammals. In the period of 12 hours to 20-30 minutes before a radiation exposure and immediately thereafter, 0.11% oil preparation of chlorophyll is introduced into the mammals. Linseed oil is used as an oil base. The preparation is introduced in a dose of 11-12 mg/kg intramuscularly.

EFFECT: method enables increasing the radioresistance and survival rate in the mammals.

1 tbl, 1 ex

Enterosorbent // 2538669

FIELD: chemistry.

SUBSTANCE: invention represents enterosorbent in form of pill, which contains colloidal silicon dioxide, microcrystal cellulose, dextrose, sodium croscarmellose, pharmaceutical talc and magnesium stearate, and components in enterosorbent are in specified ratio in wt %.

EFFECT: increase of sorption capacity and considerable reduction of production process due to reduction of granulate drying operation.

2 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to conjugate for photodynamic diagnostics or therapy of cancer, to method of obtaining conjugate and to conjugate-containing composition, intended for diagnostics or therapy of cancer. Conjugate in form of nanoparticles with size 100-250 nm represents acetylated biologically compatible polysaccharide - chondroitin sulfate, bound by means of ester bond with phthalocyanine-based compound of formula . Conjugate is obtained by acetyation of chondroitin sulfate, dissolution of chondroitin sulfate in organic solvent and addition of phthalocyanine-based compound of said formula and catalyst to chondroitin sulfate.

EFFECT: obtained is conjugate for photodynamic diagnostics or therapy of cancer.

7 cl, 16 dwg, 2 ex

Antimicrobial gels // 2535013

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, particularly to aspects covering antimicrobial compositions, and described antimicrobial compositions, antimicrobial silicone gel based on the above antimicrobial composition, a wound dressing and methods for preparing them. Among other things, the antimicrobial compositions contain at least one alkenyl- and/or alkynyl-substituted polysiloxane, at least one polysiloxane containing silicone-linked hydrogen atoms, and at least one hydroxylation catalyst, at least one hydrophilic ingredient, at least one silver salt.

EFFECT: invention can be used for preparing a drug preparation to be used in treating burns, scars, bacterial infections, viral infections and/or mycotic infections.

19 cl, 5 dwg, 8 ex, 6 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery and can be used in treating lymphorrhea following femoroinguinal lymphadenectomy for skin melanoma. Polysorb MP sterile powder is insufflated into the prepared postoperative wound cavity in the wound edge diastasis. The powder is spread with a dry gauze swab along the whole surface of the wound pocket. That is followed by tight wound tamponade. As the dressing is soaked, Polysorb MP is completely evacuated, and the other dressing is applied until lymphorrhea is terminated.

EFFECT: method provides terminating lymphorrhea in the given category of patients by generating the complexes of silicone oxide and tissue liquid proteins, which create an occlusion of lymphatic vessels lumen.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of pharmaceutics, namely represents a thixotropic preparation of a smearing consistence, which assists in healing wounds and improves characteristics of a postepithelially formed tissue.

EFFECT: invention describes a method of considerable increase of solubility of useful active substances in siloxane-matrix-forming preparations.

20 cl, 1 dwg, 4 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: claimed is a silicon-zinc-containing glycerohydrogel, possessing a wound healing, regenerative and antibacterial activity, a composition of which corresponds to formula kSi(C3H7O3)4·ZnC3H6O3·xC3H8O3·yH2O, where 1≤k≤4, 7≤x≤26, 20≤y≤100, obtained by interaction of tetraglycerolate of silicon in excess of glycerol Si(C3H7O3)4·xC3H8O3, where 0,5≤x≤10, monoglycerolate of zinc in abundance of glycerol ZnC3H6O3·6C3H8O3 and water in molar ratio Si(C3H7O3)4:ZnC3H6O3:C3H8O3:H2O equal to (1÷4):1:(7÷26):(20÷100) at a temperature of 20-40°C and intensive mixing.

EFFECT: claimed silicon-zinc-containing glycerohydrogel possesses the wound healing, regenerative and antibacterial activity, is simple to obtain and convenient in application.

1 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrido[2,3-b]pyrazine derivatives of general formula (I), wherein radicals and symbols are specified in the patent claim. The given compounds inhibit the enzymes ERK, ERK1, ERK2, PI3K, PI3Kalpha, PI3Kbeta, PI3Kgamma, PI3Kdelta, PI3K-C2alpha, PI3K-C2beta, PI3K-Vps34p.

EFFECT: invention refers to a pharmaceutical composition to be used for preparing the drugs applicable first for treating malignant and other diseases implying the pathological cell proliferation.

10 cl, 3 tbl, 66 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a composite enterosorbent of a silicone polymer specified in a group containing methyl monosilane acid xerogel or methyl monosilane acid hydrogel, differing by the fact that contains at least one ingredient specified in a group: lactulose, inulin, lignin, fructooligosaccharide, alginic acid in the form of pharmaceutically acceptable salts, chitosan, pectin, gum resin, beta-glucan in the amount of 0.1 to 10 portions per 1 weight portion of monosilane acid hydrogel or xerogel.

EFFECT: invention provides creating an agent to provide normalising the intestinal microflora and relieving the manifesting intoxication.

3 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel tetrahydroisoquinolin-1-one derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is: lower alkylene-OH, lower alkylene-N(R0)(R6), lower alkylene-CO2R0, C5-6cycloalkyl, C6-10cycloalkenyl, aryl, heterocyclic group, -(lower alkylen, substituted OR0)-aryl or lower alkylene-heterocyclic group, where the lower alkylene in R1 can be substituted with 1-2 groups G1; cycloalkyl, cycloalkenyl and heterocyclic group in R1 can be substituted with 1-2 groups G2; aryl can be substituted with 1-2 groups G3; R0: identical or different from each other, each denotes H or a lower alkyl; R6: R0, or -S(O)2-lower alkyl, R2 is: lower alkyl, lower alkylene-OR0, lower alkylene-aryl, lower alkylene-O-lower alkylene-aryl, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-aryl, -C(O)N(R0)-lower alkylene-aryl, aryl or heterocyclic group, where the aryl in R2 can be substituted with 1-3 groups G4; R3 is: H or lower alkyl, or R2 and R3 can be combined to form C5-alkylene; R4 is: -N(R7)(R8), -N(R10)-OR7, -N(R0)-N(R0)(R7), -N(R0)-S(O)2-aryl or -N(R0)-S(O)2-R7, R7 is: lower alkyl, halogen-lower alkyl, lower alkylene-CN, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-C(O)N(R0)2, lower alkylene-C(O)N(R0)N(R0)2, lower alkylene-C(=NOH)NH2, heteroaryl, lower alkylene-X-aryl or lower alkylene-X-heterocyclic group, where the lower alkylene in R7 can be substituted with 1-2 groups G1; aryl, heteroaryl and heterocyclic group in R7 can be substituted with 1-2 groups G6; X is: a single bond, -O-, -C(O)-, -N(R0)-, -S(O)p- or *-C(O)N(R0)-, where * in X has a value ranging from a bond to a lower alkylene, m is: an integer from 0 to 1, p is: is 2, R8 is: H, or R7 and R6 can be combined to form a lower alkylene-N(R9)-lower alkylene group, R9 is: aryl, R10 is: H, R5 is: lower alkyl, halogen, nitro, -OR0, -N(R0)2, or -O-lower alkylene-aryl, where the group G1 is: -OR0, N(R0)(R6) and aryl; group G2 is: lower alkyl, lower alkylene-OR0, -OR0, -N(R0)2, -N(R0)-lower alkylene-OR0, -N(R0)C(O)OR0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)N(R0)2, -N(R0)C(=NR0)-lower alkyl, -N(R0)S(O)2-lower alkyl, -N(lower alkylene-CO2R0)-S(O)2-lower alkyl, -N(R0)S(O)2-aryl, -N(R0)S(O)2N(R0)2, -S(O)2-lower alkyl, -CO2R0, -CO2-lower alkylene-Si(lower alkyl)3, -C(O)N(R0)2, -C(O)N(R0)-lower alkylene-OR0, -C(O)N(R0)-lower alkylene-N(R0)2, -C(O)N(R0)-lower alkylene-CO2R0, -C(O)N(R0)-O-lower alkylene-heterocyclic group, -C(O)R0, -C(O)-lower alkylene-OR0, C(O)-heterocyclic group and oxo; under the condition that "aryl" in group G2 can be substituted with one lower alkyl; group G3 is: -OR0; group G4 is: halogen, CN, nitro, lower alkyl, -OR0, -N(R0)2) -CO2R0; group G5 is: halogen, -OR0, -N(R0)2 and aryl; group G6 is: halogen, lower alkyl which can be substituted with -OR0, halogen-lower alkyl which is substituted with -OR0, -OR0, -CN, -N(R0)2, -CO2R0, -C(O)N(R0)2, lower alkylene-OC(O)R0, lower alkylene-OC(O)-aryl, lower alkylene-CO2R0, halogen-lower alkylene-CO2R0, lower alkylene-C(O)]N(R0)2, halogen-lower alkylene-C(O)N(R0)2, -O-lower alkylene-CO2R0, -O-lower alkylene-CO2-lower alkylene-aryl, -C(O)N(R0)S(O)2-lower alkyl, lower alkylene-C(O)N(R0)S(O)2-lower alkyl, -S(O)2-lower alkyl, -S(O)2N(R0)2, heterocyclic group, -C(-NH)=NO-C(O)O-C1-10-alkyl, -C(=NOH)NH2, C(O)N=C(N(R0)2)2, -N(R0)C(O)R0, -N(R0)C(O)-lower alkylene-OR0, -N(R0)C(O)OR0, -C(aryl)3 and oxo; under the condition that the "heterocyclic group" in group G6 is substituted with 1 group selected from a group consisting of -OR0, oxo and thioxo (=S); where the "cycloalkenyl" relates to C5-10 cycloalkenyl, including a cyclic group which is condensed with a benzene ring at the site of the double bond; the "aryl" relates to an aromatic monocyclic C6-hydrocarbon group; the "heterocyclic group" denotes a cyclic group consisting of i) a monocyclic 5-6-member heterocycle having 1-4 heteroatoms selected from O, S and N, or ii) a bicyclic 8-9-member heterocycle having 1-3 heteroatoms selected from O, S and N, obtained via condensation of the monocyclic heterocycle and one ring selected from a group consisting of a monocyclic heterocycle, a benzene ring, wherein the N ring atom can be oxidised to form an oxide; the "heteroaryl" denotes pyridyl or benzimidazolyl; provided that existing compounds given in claim 1 of the invention are excluded. The invention also relates to a pharmaceutical composition based on the compound of formula (I), use of the compound of formula (I) and a method of treatment using the compound of formula (I).

EFFECT: obtaining novel tetrahydroisoquinolin-1-one derivatives which are useful as a BB2 receptor antagonist.

11 cl, 302 tbl, 59 ex

FIELD: medicine.

SUBSTANCE: declared invention refers to medicine. The anti-tuberculosis preparations are cancelled, while Ursosal 20 mg/kg is single administered per os, and Enterosgel 10-15 g for 3 days. Then, a dose of Ursosan is reduced to 12-15 mg/kg a day with underlying reinitiation of the anti-tuberculosis preparations, and the Ursosan therapy is continued until the ALT value appears to be below an upper limit of normal.

EFFECT: method under invention enables higher clinical effectiveness in the drug-induced liver injury in children.

1 tbl, 3 dwg, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a therapeutic agent for treating or preventing neuropathic pain containing active ingredients in the form of a cyclohexane derivative presented by the following formula, or its pharmaceutically acceptable salt, and a calcium channel α2δ ligand which represents pregabalin or gabapentin.

EFFECT: therapeutic agent possesses the synergistically increased analgesic action in a dose which prevents any side effects of the calcium channel α2δ ligand, and which prevents any side effects of the agent on the central nervous system .

3 cl, 5 dwg, 5 tbl, 4 ex

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