Method of treating hyperkinetic disorder in children

FIELD: medicine.

SUBSTANCE: invention concerns medicine and medical technology. A patient is exposed to electrical stimulation generated by the 'simpaticor-01' apparatus. A one-element electrode is placed in a projection of cervical ganglia, while a multiple-element electrode - on a patient's neck. The exposure to the field is paused. A convulsive readiness threshold is assessed. Neurometabolic preparation dosage is specified in accordance with age, while anticolvulsants are dosed as per manufacturer's recommendations. Amplitude, frequency and length of the current pulse field, length of exposure and pauses are specified individually for each patient so that in the process of treatment and later on, the convulsive readiness threshold tends to decrease in the form of reducing a number of paroxysmal sharp and slow waves, as well as elimination of epileptoid activity.

EFFECT: method provides higher clinical effectiveness ensured by combining drug-induced therapy with electrical stimulation of the vegetative nervous system.

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The invention relates to medical equipment, intended for use in psychiatry and neurology and can be used in the outpatient or inpatient setting when the hyperkinetic conduct disorder in children.

Analogues of the proposed method are different ways of drug therapy, psychological correction and methods of non-pharmacological therapy.

It is known that hyperkinetic disorder in children is a clinical syndrome that includes hyperactive behavior impulsive behavior, attention deficit, reduced working memory and impaired development of Executive functions [1-3].

When drug therapy is used psychostimulants, neurometabolic drugs and anticonvulsants.

The clinical effect of drug substitution therapy with use of psychostimulants is based on the model of genetic deterministic lack of neurotransmitters in the frontal veins structures, causing all the symptoms of hyperkinetic disorders [4]. A significant drawback of the use of these drugs is the short duration of effect, lifelong therapy, the formation of numerous side effects, strengthening of addictive behavior (alcohol, nicotine, gambling and other addictions) and the development of other psychos is a mini disorders [5].

In the works of academician G.N. Kryzhanovsky [6] hyperkinetic disorder is considered minimal damage to the fronto-striano-cerebellar structures, which are formed hyperventilatory group of neurons, extending its impact on increasing the number of neurons, which subsequently leads to the formation of pathological systems and relationships. Disorganized fronto-striano-cerebellar connections in the developing brain result in violation of neurotransmitter metabolism, the result included a number of compensatory mechanisms leading to clinical manifestations of hyperkinetic disorder. In this case, in the treatment of hyperkinetic disorders used neurometabolic drugs and anticonvulsants [7, 8]. The use of neurometabolic drugs stimulates the maturation of nerve cells. But long-term use (more than one month) may occur depletion of energy resources neuronal tissue, leading to neuronal cell death [9]. The efficacy of anticonvulsants associated with their influence on the excitability of different neurons [6]. These drugs may long-term (permanent) appointment, however, there are difficulties in determining the effective dose, which is often above the maximum: in this case p is to slivatsa hepatotoxic effect [10].

Reliable information about the concomitant use of psychostimulants, neurometabolic drugs and anticonvulsants no.

The effectiveness of other medicines, biologically active additives, certain diets, etc. is now considered to be refuted or not proven [11].

Psychological correction is achieved by the active use of psychotherapeutic methods, educational and neuropsychological corrections [12]. The effect of psychological correction is poorly defined and quickly disappears in the absence of constant reinforcement [13]. Problem when implementing these methods is the need to change the micro-social environment.

Of non-pharmacological methods, the most widespread methods of biofeedback and electrostimulation. The essence of the techniques using biofeedback, is to "return" to the patient on the computer screen or in audio form current values of physiological parameters defined clinical Protocol. The training is aimed at increasing fast activity in the range of beta 1 rhythm in the suppression of theta activity. The disadvantage of these methods is the complexity of the procedure, necessitated by the formation of individual Protocol and conduct numerous and lasting who's training sessions. In addition, the method requires constant concentration and specific volitional effort of the child, which is difficult doable with hyperkinetic disorder [9].

The analogue of the present invention is a method of transcranial electrical stimulation, which use low-frequency monopolar sequence of current pulses of rectangular form with repetition frequency (77-78) Hz and duration (3.5 to 4.0) MS or a pack of high-frequency pulse repetition frequency (10-12) kHz, the same duration amid constant component at the ratio of the current strength of these signals is 1 to 2. The size of the stimulating current can be set in the range of 1.4 to 1.7) mA. For this purpose the electrodes from frontal and mastoid localization. Safe for the skin, the current density should be no more than (1-2) µa/mm2. The maximum value of current should be no more than 10 mA, the area of the electrodes is not less than 50 cm2. This method of electrical stimulation is carried out (5-10) sessions per month for up to 20-30 minutes each. According to the authors, the method of transcranial electrostimulation provides direct electrical stimulation of endorphin mechanisms of the brain, based on the activation of protective mechanisms of the brain", which fulfill the role of the medial located subcortical structures (nucleus of the hypothalamus, in particular arcuate cores is, allowedprivate medium gray matter of the brain, the core suture bridge and medulla oblongata). Due to the activation intense homeostatic action and normalized the impaired functions of the systems and organs, mainly due to the endorphins (primarily beta-endorphin and serotonin. Through this mechanism are implemented anxiolytic, antistress effects, as well as, presumably, the effect of regeneration of nerve cells [14, 15]. Known methods of electrical stimulation, influencing processes of neurodynamics, transcranial electrostimulation has the best clinical effect: according to psychometric and psychophysiological studies after treatment in 75% of children with hyperkinetic disorder there is a significant improvement within 6 months. The disadvantage is the reduction of the clinical severity of therapeutic effect when re-treatment courses. In addition, it should be noted that effects on subcortical structures that need deep penetration of current impulses in the brain. To do this, increase the amplitude of the current and reduce the area of the electrodes, which may cause irritating effect on the skin and to the state of "overstimulation" exposed areas of the cerebral cortex [16].

A variation of transcranial electrostimulation, used in the treatment of children with hyperkinetic disorder, is a device that uses DC current [17]. However, the effectiveness of treatment in this case is virtually indistinguishable from transcranial electrical stimulation using low-frequency pulse current.

The closest analogue of the claimed method is a method of treating hyperkinetic disorders in children [18], including the introduction of drugs attributable to the actions and anticonvulsants in combination with carrying out percutaneous electrical stimulation of the autonomic nervous system, which perform focused spatially distributed rotating field low-frequency monopolar current pulses, and data evaluation, and electroencephalography. However, the disadvantage is the lack of control over treatment.

The technical result of the invention is to increase the effectiveness of treatment in the form of a significant reduction in the severity of impulsive and hyperactive behavior, improve attention and other Executive functions and the absence of any complications.

The essence of the invention lies in the fact that the claimed method of treatment of hyperkinetic disorders in children combine drug therapy, realized with what omashu attributable to drugs (for example, nootropil) and anticonvulsants (eg, carbamazepine and valproic acid), and electrical stimulation of the autonomic nervous system, which perform focused spatially distributed rotating field low-frequency monopolar current pulses generated between singleton and multiple electrodes; singleton electrode is placed in the projection of the cervical ganglia of the sympathetic nervous system or stellate ganglion, and multi - element electrode on the neck of the patient, and if the singleton electrode have projected the left ganglia, multi-element electrode on the right side of the neck, and Vice versa; multielement electrode consists of several partial galvanically isolated from other conductive elements that connect to the source current; a field effect current pulses alternate with pauses; before each treatment and after its completion estimate the threshold of convulsive readiness of the Central nervous system, which determines when conducting functional stress tests with hyperventilation or photic stimulation in the presence of paroxysmal sharp and slow waves, as well as the disappearance of epileptiform activity of slow waves; dosage neurometabolic drugs are chosen in accordance with the age norms recommended for the TEI manufacturer of the drug, and anticonvulsants - individually based recommended by the manufacturer of the drug dosage to 1 kg of body weight of the patient; amplitude, frequency, and duration of the field current pulse, time effects and pauses chosen individually for each patient so that the treatment process and after its completion, there was an increase in the threshold of convulsive readiness of the Central nervous system in the form of reducing the number of paroxysmal sharp and slow waves, as well as the disappearance of epileptiform activity.

From the analysis of scientific-technical and patent literature, technical solutions of the proposed method for the treatment of sensorineural hearing loss meet the criteria of "novelty" and "technical level".

Figure 1 shows the structural diagram of one of the possible variants of the device that implements the inventive method of treatment for hyperkinetic disorder, and figure 2 - diagram of the algorithm of the proposed method of treatment.

Here presents: patient 1, a neck 2, the cervical ganglia of the sympathetic nervous system and stellate ganglion 3, the bioelectrical activity of the brain 4, 5 EEG analyzer 6 the threshold of convulsive readiness, library 7 performance age norms convulsive readiness evaluator dose of anticonvulsant 8, the current source 9, the controller biotropic parameters is Olya current pulses 10, control duration of procedure 11, single-element electrode 12, the switch 13, the programmer of the law of partial switching of the electrodes 14, the multi-element electrode 15.

Before each treatment and after its implementation are conducting a study of bioelectric brain activity 4 with an electroencephalograph 5, the output of which is connected to one of inputs of the analyzer 6 the threshold of convulsive readiness, a second input connected to the output library 7 indicators of age-related norms of convulsive readiness. The first output of the analyzer 6 the threshold of convulsive readiness is connected to the computer dose of anticonvulsant 8, the data which are used when drug therapy treatments. The second output of the analyzer 6 the threshold of convulsive readiness connected to the first input of the regulator biotropic parameters of the field current pulse 10, the second input is connected to the first output of the current source 9. As biotropic parameters in the controller 10 uses the amplitude, frequency, and duration fields of the current pulses. The second output of the current source 9 is connected to the first input of the switch 13, a second input connected to the third output of the analyzer 6 the threshold of convulsive readiness, and the third input - output device, switching law of partial electrodes 14. The output of the controller biotropic parameters for the I current pulse 10 is connected to the input of the regulator of the length of proceedings 11, the output of which is connected to the element electrode 12 mounted in the projection of the cervical ganglia of the sympathetic nervous system or stellate ganglion 3. The output of switch 13 is connected to a multi-element electrode 15 that is installed on the neck 2 of the patient. In the treatment process combined drug therapy, realized with the help of anticonvulsants (eg, carbamazepine and valproic acid), and electrical stimulation of the autonomic nervous system, which perform focused spatially distributed rotating field low-frequency monopolar current pulses generated between the element 12 and the multi-element electrodes 15. Singleton electrode 12 is placed in the projection of the cervical ganglia of the sympathetic nervous system or stellate ganglion 3, a multi - element electrode on the neck 2 of the patient. Multi-element electrode 15 consists of several partial galvanically isolated from other conductive elements that connect through the switch 13 to turn the current source 9, formed according to the programmer to the law of partial switching of the electrodes 14. The impact of this field of current pulses alternate with pauses. Before each treatment and after analyzing the threshold of convulsive readiness of the Central nervous system, which is determined by the presence of the s paroxysmal sharp and slow waves when conducting functional stress tests with hyperventilation or photic stimulation. Dosage neurometabolic drugs are chosen in accordance with the age norms recommended for children by the manufacturer of the drug, and anti - epileptics individually based recommended by the manufacturer of the drug dosage to 1 kg of body weight of the patient, and the amplitude, frequency, and duration of the field current pulse, time effects and pauses chosen individually for each patient so that the treatment process and after its completion, there was an increase in the threshold of convulsive readiness of the Central nervous system in the form of reducing the number of paroxysmal sharp and slow waves, as well as the disappearance of epileptiform activity.

From 2007 to 2010 on the clinical basis of the Department of psychiatry of the GOU VPO "Ural state medical Academy of the Federal Agency for healthcare and social development" conducted research on the effectiveness of the proposed method for the treatment of hyperkinetic disorders in children.

In the research participated 137 children with hyperkinetic disorder in children aged 6 to 9 years with a randomized sample were divided into 3 groups.

In the first group (37 children) when the treatment was applied monotherapy with nootropil related to neurometabolic preparations: dosage corresponded to the age norm is, and the duration of treatment was (30-40) days. After a two-month break, the course was repeated up to 4 times per year.

In the second group (45 children) when the treatment was applied complex drug therapy with neurometabolic drugs and anticonvulsants. As neurometabolic drugs used nootropil in dosages as in the treatment of children of the first group. As anticonvulsants - prolonged form of carbamazepine, Finlepsin-retard in age-appropriate doses (10-15) 1 mg per kg of body weight per day.

In the third group (55 children) when the treatment was applied complex drug therapy with neurometabolic drugs and anticonvulsants, as in the treatment of children of the second group, and percutaneous electrical stimulation of the autonomic nervous system, which was performed using the apparatus "SIMPATICO-01" on the methodology of the proposed method of treatment. Within one year, conducting two courses transcutaneous electrical stimulation, each of which consisted of 5 treatments. Daily procedure consisted of the following stages: 5 minutes exposure field of the current pulses generated in the device "SIMPATICO-01", projection of the left cervical ganglion, 5 functional minute rest, 5 minutes exposure field of the current pulses in the projection of the right cervical ganglion, 5 minutes functioning of the social peace. Before each treatment and after its completion estimated the threshold of convulsive readiness of the Central nervous system.

Patients were followed for 12 months: every 3 months was analyzed clinical and anamnestic data, the results of psychometric and psychophysiological examination.

The result of the treatment, most children in the third group noted the positive dynamics of the symptoms of hyperkinetic disorders:

- 48 children indicators of hyperactivity, impulsivity and poor attention decreased to almost normal values (values on a scale ADHD-RS-IV had values less than 1,00);

- 52 children showed significant improvements in attention and mental performance.

12 months:

- 52 children marked reduction of high-amplitude slow-wave activity, predominantly theta range, the change in the ratio of alpha and theta rhythm predominance of alpha-activity;

- in 47 children marked stabilization of the alpha rhythm under load, which also indicates an increase of the threshold of convulsive readiness of the Central nervous system.

The above results are valid and confirmed by the high statistical significance in comparison with the figures before treatment (P≤0,01).

Side effects from the use of the proposed method for the treatment of hyperkinetic disorders in children have not been recorded. After the first treatment procedures in 27 children marked increase drowsiness from mild to moderate, mild sedation, which on subsequent treatment stages were not recorded.

Results changes in psychometric assessments hyperkinetic disorders in children (attention problems, hyperactivity/impulsivity, and total score) in subgroups of interest 12 months after treatment are presented in table 1.

Table 1. Dynamics of indicators of ADHD-RS-IV before and after treatment in subgroups of interest

The parameters of psychometric assessment hyperkinetic-
th rasstroistva
Indicators of psychometric assessments on a scale ADHD-RS-IV
Before the treatmentAfter the treatment
The first groupThe second groupThe third group
Impaired attention1,99±0,391,69±0,76*1,57±0,63*1,15±0,39**
Hyperactivity/impulsivity2,17±0,382,07±0,75 1,85±0,50**1,28±0,39**
Total score2,08±0,291,88±0,58*1,71±0,45**1,22±0,29**
Here:
* the significance of differences compared to the figures before treatment, P≤0,05;
** - significance of differences compared to the figures before treatment, P≤0,01.

As follows from table 1, after 12 months in children of the first group of indicators of hyperactivity was 2,07±0.75, and impaired attention was 1.69±0,76: the severity of hyperactive behavior in comparison with the figures before treatment remained virtually unchanged, and the differences between these indices was statistically insignificant (P≥0,05).

Children of the second group after 12 months, the indicators of hyperactivity and impaired attention was significantly decreased, respectively, to values of 1.85±0.50 1,57±0,63 (P≤0,05).

Children in the third group after 12 months, the indicators of hyperactivity and impaired attention was significantly decreased, respectively, to values of 1.28±0,39, and 1.15±0,39 (P≤0,01). Compared with children first and second groups of these changes are significantly larger values.

Figure 3 given the s data on the dynamics of changes of the averaged parameters of the annual monitoring total psychometric scale ADHD-RS-IV in the groups studied. As can be seen from the graphs here, the largest positive dynamics of psychometric and psychophysiological changes observed among children in the third group.

Example case: M, age 6.

Born from the first pregnancy complicated by toxemia in the second trimester, delivery in time, was used forceps delivery. Diagnosis at discharge: PCNS post-hypoxic and post-traumatic Genesis, moderate severity. Spastic tetraparesis, VUI, CMV, balanoposthitis, cardiomegaly.

The first words in 1.5 years, phrase speech to 2.5 years. From birth was seen by a neurologist: received courses protivoanemicheskoe therapy with little positive effect. 3 years have seen a psychiatrist diagnosed with mental retardation.

Grew somatically weakened. Education in conditions of emotional deprivation. In kindergarten has adapted poorly. Up to 6 years about the delay in speech development worked with a speech therapist. The effect is negligible.

In secondary school from the age of 7, the program could not cope. It was noted low cognitive activity, fidgeting, inability, headaches diffuse nature to 2-3 times a week, emotional lability, easy switching of attention with the rapid exhaustion, rapid forgetfulness. Arbitrary operations shall lnost was untargeted and wore impulsive nature. The lessons was passive, were often involved in foreign Affairs. It was recommended that the child's education in the secondary school.

Since 2009, is under the supervision of a staff of the Department of psychiatry of the GOU VPO "Ural state medical Academy of the Federal Agency for healthcare and social development". Parents gave consent to experimental treatment method.

The primary value of hyperactivity scale ADHD-RS-IV - 1,61. Figure 4 and 5 shows the EEG before treatment in the functional state of rest and during hyperventilation, respectively.

Before treatment in the functional state of rest observed on EEG disorganized alpha activity in the form of high amplitude rhythm to 112 µv, irregular, with a predominance of sharp waves, while zonal differences smoothed modulation is not expressed. Expressed a slow rhythm: theta-rhythm of high amplitude to 83 UV, high index 61%, Delta activity amplitude up to 83 MACs index 25%. Often paroxysmal high-amplitude slow waves in theta range. The number of paroxysmal waves on the interval 10 sec average 14. Thus, in this state, in the bioelectrical activity of the brain of a marked change with signs Express interest and instability respecof the ical mid-stem structures, lowering the threshold of convulsive readiness, the delay in the formation of the basic rhythm by age.

During hyperventilation load there has been a sharp increase in the power of theta rhythm (9 times), the amplitude is increased to 240 mV, index - 17%; increase the capacity of the Delta rhythm 27 times, the amplitude is increased to 330 µv, the increase in the index by 47%. Registered frequent discharges diffuse epileptiform activity in the form of spike-wave complexes, the duration to 7 seconds. The number of paroxysmal waves on the interval 10 sec averages 20-21. Thus, on the background of hypoxic load even more decreases the threshold of convulsive readiness, tolerance to stress low.

A comprehensive treatment, including:

- regular intake of anticonvulsants (carbamazepine) in a dosage of up to 400 mg per day, which is selected from a rate of 20 mg per 1 kg of body weight of the patient;

- during the year held on 3 course of treatment attributable to drugs (nootropil) within 30 days, each at a dose of 1600 mg per day, selected in accordance with the age norms recommended for children by the manufacturer of the drug;

two courses of electrical stimulation apparatus "SIMPATICO-01" according to the method of the present invention.

After 1 month after completion of five procedures electrostimulation parents reported improvement of BEGO health, a significant decrease in the frequency and intensity of headaches. Three months was marked stabilization of the background mood, behavior has become more calm, diligent in the classroom. The value of the indicator hyperactivity scale ADHD-RS-IV decreased to 1.22. Six months after the start of treatment, a second course of stimulation, after which the rate of hyperactivity scale ADHD-RS-IV decreased to 0.94; improved attention and planning that emerged in the consciousness of their actions, significantly reduced the number of impulsive actions. The girl was returned to secondary school, where it was adapted.

12 months after the start of treatment observed EEG changes. On the background recording (6) is moderately disorganized alpha activity in the form of high amplitude rhythm to 90 mV, average, fairly regular, zonal differences retained, the modulation amplitude is well expressed. Theta activity is insignificant, amplitude up to 65 µv, index to 25%. Delta activity and beta-activity is practically absent. Paroxysmal activity in the functional state of rest on the EEG is not observed, there are only a few pointed paroxysmal waves. Thus, it is possible to speak about moderate expression is a major change in the bioelectrical activity of the brain in the form of disorganization and slow cortical rhythm with signs of interest in the mid-stem departments. Compared to EEG before treatment positive dynamics, the degree of maturity of bioelectric brain activity similar to age-related norms, the threshold of convulsive readiness in the dynamics considerably increased.

When conducting hyperventilation load (Fig.7) according to EEG increases the power of theta rhythm in 3 times, increasing its amplitude up to 150 µv, index by 10%, increasing the power of the Delta rhythm 5 times, its amplitude up to 220 µv, the increase in the index by 12%. Registered paroxysmal high-amplitude slow waves, the average number 9-10 at the interval of 10 sec. Thus, on the background of hypoxic load compared with those before treatment slightly reduces the threshold of convulsive readiness, but tolerance to stress in the dynamics considerably. There is a smaller number paroxysmal waves, true epileptiform activity is not logged.

After treatment, the patient M:

- indicator hyperactivity scale ADHD-RS-IV decreased from 1.61 to 0.94;

according to the EEG increased the threshold of convulsive readiness of the Central nervous system;

- according to the observations of parents, improved overall health, decreased significantly the frequency and intensity of headaches, stabilized background mood, behavior - increasing patience and perseverance in the classroom, what evidence is the duty to regulate about a reduction of symptoms of hyperkinetic disorder.

Shown in a clinical sample data support the efficacy of the present invention "a Method for the treatment of hyperkinetic disorders in children".

Thus, the above results of clinical testing of the proposed method for the treatment of hyperkinetic disorders in children attest to its high efficiency in a significant reduction in the severity of impulsive and hyperactive behavior, improve attention and other Executive functions that do not lead to any complications.

LITERATURE

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A method for the treatment of hyperkinetic disorders in children, including the introduction of drugs attributable to the actions and anticonvulsants in combination with carrying out percutaneous electrical stimulation of the autonomic nervous system, which perform focused spatially distributed rotating field low-frequency monopolar current pulses, and data evaluation, electroencephalography, wherein the electrical stimulation is performed with a single-element electrode in the projection of the cervical ganglia of the sympathetic nervous system or stellate ganglion, and multi - element electrode on the neck of the patient, and if the singleton electrode have projected the left ganglia, multi-element electrode on the right side of the neck, and Vice versa; however, multi-element electrode consists of several partial galvanically isolated from other conductive elements that are connected to the current source, and the exposure field of the current pulses alternate with pauses; before each treatment and after its completion estimate the threshold of convulsive readiness of the Central nervous system is s, which is determined by the presence of paroxysmal sharp and slow waves, as well as by the presence of epileptiform activity of slow waves when conducting functional stress tests with hyperventilation or photic stimulation; dosage of drugs attributable to the actions chosen in accordance with the age norms recommended for children by the manufacturer of the drug, and anti - epileptics individually based recommended by the manufacturer of the drug dosage to 1 kg of body weight of the patient; amplitude, frequency, and duration of the field current pulse, time effects and pauses chosen individually for each patient so that the treatment process and after its completion when conducting functional stress tests with hyperventilation or photic stimulation was observed enhancement the threshold of convulsive readiness of the Central nervous system in the form of reducing the number of paroxysmal sharp and slow waves, as well as the disappearance of epileptiform activity of slow waves.



 

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3 dwg, 7 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pyrazolo[1,5-a]-pyrimidine compounds according to the invention are specified in a group consisting of: N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-ethylmethanesulphonamide; {2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2,4-difluor-5-[3-(thiophene_2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide and N-{5-fluor-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide.

EFFECT: preparing pyrazolo[1,5-a]pyrimidine compounds, their pharmaceutically acceptable salts and hydrates showing an ability to inhibit GABAA receptors, and applicable for treating and preventing anxiety, epilepsy and sleeping disorders, including insomnia, as well as for inducing a sedative-hypnotic, analgesic and sleeping effects and myorelaxation.

14 cl, 6 tbl, 4 dwg, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention discloses applying 3-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid or its pharmaceutically acceptable salt in preparing a drug for treating or preventing restless leg syndrome in a patient or for improving sleep in a patient suffering restless leg syndrome. There are also described pharmaceutical compositions for treating or preventing restless leg syndrome and for improving sleep in a patient with restless leg syndrome, containing a therapeutically effective amount of 3-{[α-isobutanoyloxyethoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid or its pharmaceutically acceptable salt.

EFFECT: preparing the pharmaceutical compositions for treating or preventing restless leg syndrome and improving sleep in a patient with restless leg syndrome.

31 cl, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to neurology, and can be used in treatment of muscle spasticity in patients with spinal cord injury. For this purpose botulotoxin is introduced into iliolumbar muscle under control of X-ray computer tomography. Introduction of preparation is performed by dorsal access into proximal part of iliolumbar muscle at the level of LII-LIII vertebrae, 2-3 cm more laterally than spinous process. Depth of introduction is 8-10 cm.

EFFECT: method makes it possible to ensure efficient relief of local spasticity of iliolumbar muscle with absence of botulotoxin effect on other groups of muscles due to accurate introduction of preparation into definite region of said muscle.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an amorphous form of N-{2- fluorine-5-[3-(thiophen-2-carbonyl)-pyrazolo[1,5-a]-pyrimidin-7-yl]-phenyl}-N-methyl-acetamide, methods for preparing it.

EFFECT: preparing the pharmaceutical compositions for GABA-receptor inhibition containing said form, and also to using them as a drug for treating and/or preventing anxiety, epilepsy, sleeping disorder and sleeplessness, for induction of sedative-hypnotic effect, for anaesthesia and muscular relaxation and for time modulation required for sleep induction and duration.

12 cl, 4 dwg

Gsk-3 inhibitors // 2449998

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns applying urea derivatives or their pharmaceutically acceptable salts characterised by formula , wherein RB is specified in: while R3, R4, R'2, R'3, R'4, R'5, and R'6 represent hydrogen as GSK-3 inhibitors, pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

EFFECT: preparing the pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

14 cl, 2 ex, 1 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compound, namely to N-(5-chlorfuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane or its pharmaceutically acceptable salts, pharmaceutical compositions for treatment of conditions and disorders associated with dysfunction of central nervous system, containing said compound, as well as methods of treatment. Claimed compound demonstrates selectivity with respect to neuron nicotine receptors of subtype α4β2 in central nervous system (CNS) and bind with them with high affinity.

EFFECT: compound and compositions based on it can be applied for treatment and/or prevention of wide spectrum of diseases and disorders, in particular, CNS disorders.

6 cl, 1 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1, R2 and R3 are independently selected from a group consisting of hydrogen, halogen and lower alkyl containing 1-6 carbon atoms; R4 denotes a residue given in the claim; R5 denotes hydrogen or methyl; R10 is selected from a group consisting of: (i) hydrogen; (ii) (C1-C10) alkyl; (iii) (C1-C10)alkyl, substituted with one or more substitutes independently selected from a group consisting of -N(CH3)2, morpholinyl, (C1-C4) alkoxy, hydroxyl, -CON(CH3)2 and halogen; (iv) monocyclic (C3-C8) cycloalkyl containing one N heteroatom; (v) 9-methyl-9-azabicyclo[3.3.1]nonane; (vi) phenyl; (vii) phenyl substituted with one or more (C1-C4)alkoxy; R11 is selected from a group consisting of hydrogen and (C1-C10)alkyl; or R10, R11 and a nitrogen atom with which they are bonded, together, form a nitric heterocycle or a substituted nitric heterocycle, such as given in the claim. The invention also relates to a pharmaceutical composition, having serotonin type 3 receptor modulating capacity and a method of treating a disorder which depends on serotonin type 3 receptor modulation.

EFFECT: compounds of formula II as serotonin type 3 receptor modulators.

18 cl, 1 tbl, 159 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely dentistry, and aims at treating the patients suffering chewing musculature dysfunction. The 4 types of the chewing muscle state are pre-specified: type 1 - optimal state, type 2 - adaptive compensatory hypertrophy, type 3 - pathological hypertrophy, type 4 - functional decompensation. If observing the type 2 dysfunction, the patient is exposed to current pulses of frequency 15-30 Hz and intensity 8-10 mA. If observing the type 3 dysfunction, the exposure is characterized by frequency 40-60 Hz and intensity 5-8 mA. If observing the type 4 dysfunction, the exposure has pulse frequency 30-40 Hz and intensity 3-5 mA. The therapeutic sessions for the patients suffering the types 2 and 3 are conducted once a day for 15 min. The length for the patient suffering the type 4 dysfunction is 25 min; total number of the sessions is 5-10. The patient is exposed to percutaneous electric stimulation generated by Electronica EPB 50.01 apparatus.

EFFECT: method enables reducing the length of rehabilitation of the patients suffering the chewing musculature dysfunction ensured by selecting percutaneous electric stimulation modes for various types of dystonias.

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely neurology, physiotherapy. A method involves exposure of a patient's spinal cord above thoracic spines T11-T12. The patient is laid on one side with his/her feet supported by rocking frames. An active electrode is applied on skin. The exposure length is 10-20 seconds. The patient is exposed to a square electric bipolar stimulus sequence. The exposure amplitude is 40-70 mA, frequency is 5-40 Hz, and length is 0.5 m seconds. The carrier frequency is 10 kHz.

EFFECT: method provides higher clinical effectiveness ensured by rhythmic alternating activity in flexor and extensor muscles.

1 tbl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medical equipment, namely to devices for electrical stimulation of brains. A stimulation wire has a distal end for tissue stimulation in a target region and contains an array of one or more stimulating elements with one or more sensors each of which provides electric tissue stimulation in the target region and detection of electric signals. After the first wire installation along a path pre-set by non-surgical procedures, the array of the stimulating elements localises the target region and determines the essential stimulation parameters for each stimulating element. The stimulating elements are directly connected with the stimulating elements in accordance with the connection between positions of the sensors and the stimulating elements. The wire is integrated in a stimulation system also having a pulse generator. A method for therapeutic electric tissue stimulation in the target region involving the stages of non-surgical procedures to visualise an approximate target region for stimulation and a path for wire installation; wire installation along the path; detection of electric signals generated by nerve cerebral cells by one or more sensors; localisation of a three-dimensional space and borders of the target stimulation region and tissue stimulation with the use of the individual stimulation parameters.

EFFECT: use of the invention enables higher accuracy of positioning the stimulating electrodes.

17 cl, 8 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment, namely to electrodes for neurostimulation and methods of their application. Neurostimulator contains non-conductive carrier, which has first side and second side, mainly opposite to first side, at least, one first electrode on first side of carrier, at least, one second electrode on second side of carrier, with first electrode being electrically isolated from second electrode, and carrier being provided with, at least, one bypass channel, passing through entire thickness of carrier with possibility of providing circuit of low electric resistance between first and second sides of carrier. Method of nervous tissue stimulation lies in application of neurostimulator.

EFFECT: application of invention makes it possible to increase quality of stimulation due to improvement of its focusing.

32 cl, 14 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment, namely to implants for electromechanical stimulation of internal ear. System of connection with internal ear includes acoustic converter for reciprocal conversion of electric energy and mechanical energy and internal ear catheter, which contains distal tip, made with possibility of vibration interaction with internal ear medium, proximal tip, made with possibility of vibration interaction with acoustic converter, cavity, filled with catheter liquid for transmission of vibration signals between distal tip and proximal tip.

EFFECT: application of invention makes it possible to increase efficiency of implanted prosthetic system.

13 cl, 7 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely - to paediatrics, neurology. A method involves segmented electrical stimulation by means of Lymphavision apparatus. It is added with dynamic proprioceptive correction by means of Graviton reflex-load apparatus. The apparatus comprises a closed waist-foot system and generates conditions for spastic stretching from an upper limb girdle to feet. A procedure length at the first session makes 15 minutes. It is shown to be gradually increased to 20 minutes by the 5th procedure. Further prolongation of the procedure up to 30 minutes is achieved by the last procedure. The therapeutic course is 10 procedures.

EFFECT: method provides higher clinical effectiveness ensured by segmented electrical stimulations and dynamic proprioceptive correction that enables to create the most favourable conditions for improved blood flow and venous outflow through the whole spinal cord centred on the cervical and lumbosacral plexus thereby facilitating the antagonistic muscles and depressing the spastic muscles, allows avoiding physical disability.

3 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to therapy, physiotherapy, balneology. Method includes carrying out respiratory gymnastics, inhalations with mineral water, manual massage of chest, applications of peloids, electric stimulation at the background of drug basic therapy. During electric stimulation impact is performed by high-amplitude pulse current with biological feedback, with frequency 90-100 Hz and gradually increasing current intensity until sensation of painless vibration appears. On the first day impact is performed paravertebrally at the level D1-D7 and along 7-8 intercostal spaces. On the second day impact is performed paravertebrally and on collar area. Peloid therapy is carried out 20-30 minutes after electric stimulation. In first application impact is performed on chest at temperature 38-40°C and 20-30 minute exposure. On the second day of application impact is performed on collar area at temperature 35-36°C. Course of treatment includes 6-7 coupled impacts on each zone.

EFFECT: method increases treatment efficiency and increases remission duration due to expressed local and systemic anti-inflammatory effect.

2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medical technology, in particular to method and device for control of state of patient's autonomous nervous system under anesthesia. Method is realised by device which includes measuring equipment for registration of signal of skin conductivity and control unit. In accordance with the method during interval of measurements signal of skin conductivity is registered, points of local minimums are identified, integration intervals are selected, function of linear inclination, as well as integral are calculated from difference of values of skin conductivity signal and linear inclination function in case, when signal of skin conductivity is higher than values of function of linear inclination, first index of state of patient's autonomous nervous system under anesthesia is calculated. Also, selected is subset of measurement interval values with beginning in the first point of minimum, value of skin conductivity is selected in said point as constant value, integral is calculated from difference of values of skin conductivity signal and said constant value in case, when signal of skin conductivity is higher than said constant value, second index of state of patient's autonomous nervous system under anesthesia is calculated. The larger of the first and the second indices is given as outlet signal, reflecting state of patient's autonomous nervous system under anesthesia.

EFFECT: application of group of inventions will make it possible to improve interpretability of measurement results, as well as will increase convenience and easiness of control of state of patient's autonomous nervous system under anesthesia.

11 cl, 6 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medical equipment, namely to methods and apparatuses for neurostimulation therapy. A neuromimetic apparatus comprises first and second inputs receiving neural signals with the first input receiving signals afferent to a suspected area and the second input - different from the suspected area. The input emitting neural compatible signals efferent to the suspected area. A signal processing unit comprises a forward channel arranged between the first input and output, and a modulation channel receiving signals from the second input and feeding a signal into the forward channel. The forward channel comprises a first sensor, a processor trained to imitate the suspected area functions which is a second neural area, a signal generator feeding signals to the efferent third area suggested to be healthy. A method for substitution of the suspected neural tissue functioning implies the stages of implantation of the neuromimetic apparatus, emission of at least one stimulus based on the processing function, signal control from the first and second inputs, signal sample comparison from the first and second inputs and emission sample adaptation on the basis of the comparison results.

EFFECT: use of the invention enables higher adaptability and flexibility for diagnosing and treating neuromotor outcomes, such as Parkinson's disease.

12 cl, 9 dwg

FIELD: medicine.

SUBSTANCE: invention relates to medical equipment. An apparatus comprises: two data retrieval electrodes placed on a tenth cranial nerve or cerebral portions, two stimulating electrodes placed on the tenth cranial nerve, a stimulation unit, a control unit. The stimulation unit comprises two series switchboards, an operating amplifier, a sigma particle, an analogue-to-digital converter, a microprocessor, a transmitter-receiver. A digital-to-analogue converter, a generator, a switchboard are series connected on a second output of the microprocessor. A magnetoelectric generator is connected to the microprocessor. A power element supplies the unit. The control unit consists of series transmitter-receiver, microcontroller. A real-time clock, a flash memory, USB microcircuit are parallel connected to the microcontroller. The power element supplies the unit. The control unit comprises a permanent magnet separated from the electric circuit by a screening wall in order to eliminate magnetism on the electric circuit.

EFFECT: invention provides higher clinical effectiveness ensured by adaptation of the apparatus to an epileptic seizure.

1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I:

,

where X1 denotes a bond, NR8 or S; Y1 denotes O or NR ; R1 denotes C1-10alkyl, C6-10aryl or a 5-10-member heteroaryl containing 1-3 heteroatoms which are independently selected from N or S; where said R1 is optionally substituted with 0-2 J1; R2 denotes H or C1-10alkyl; each of R3, R4, R5 and R6 independently denotes H or C1-10alkyl; and R7 denotes C1-10alkyl, C3-10cycloalkyl, phenyl, 5-6-member heterocyclyl containing 1-3 heteroatoms independently selected from O and N, - (C1-6alkyl) -(C3-10cycloalkyl), - (C1-6alkyl) - (phenyl) or -(C1-6alkyl)-(6-member heterocyclyl containing 2 heteroatoms selected from O and N); where said R7 is optionally substituted with 0-5 J7; or R3 and R4, together with a carbon atom with which they are bonded, optionally form a 3-4-member saturated or partially unsaturated monocyclic fragment; R3 and R5, together with carbon atoms with which they are bonded, optionally form a 5-member monocyclic fragment; R8 denotes H; R9 denotes H or unsubstituted C1-6alkyl; or R2 and R9, together with atoms with which they are bonded, optionally form a 5-member aromatic monocyclic fragment containing 3 nitrogen atoms; each J1 independently denotes C1-6halogenalkyl, halogen, NO2, CN, Q or -Z-Q; or two J1 together can optionally form =O; Z denotes C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -NR-, -O-, -C(O)- or -SO2-; wherein each Z is optionally substituted with 0-2 J2; Q denotes H; C1-6alkyl; 3-8-member aromatic or non-aromatic monocyclic fragment containing 0-3 heteroatoms independently selected from O, N and S; or an 8-10-member aromatic bicyclic system; each Q is optionally substituted with 0-2 JQ; each J7 independently denotes C1-6alkyl or halogen(C1-4alkyl); each of JQ and J7 independently denotes M or -Y-M; each Y independently denotes an unsubstituted C1-6alkyl, wherein 0-3 carbon atoms are optionally substituted with -O-, -C(O)- or -SO2-; each M independently denotes H, C1-6alkyl, C3-6cycloalkyl; halogen (C1-6alkyl), phenyl, halogen, CN, OH, OR1; or two M together can optionally form =O; R denotes H or an unsubstituted C1-6alkyl; R' denotes an unsubstituted C1-6alkyl. The invention also relates to methods of producing said compounds and a pharmaceutical composition for inhibiting PLK based on said compounds.

EFFECT: novel compounds which can be used in medicine as inhibitors of protein kinase are obtained.

34 cl, 1 tbl, 279 ex

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