RU2493836C1 - Pharmaceutical combination for prevention and treatment of chronic disorders of vegetative regulation of heart rhythm and method of prevention and treatment by means of pharmaceutical combination - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely, to cardiology, and deals with treatment and prevention of chronic disorders of heart rhythm. For this purpose introduced is pharmaceutical combination, which includes pyritinol, glutamic acid and ubiquinone with the following component ratio for different age groups, in grams per one intake: pyritinol - 0.05-0.2; glutamic acid - 0.125-0.5; ubiquinone - 0.005 - 0.02.

EFFECT: application of such combination ensures correction of chronic disorders of heart rhythm, developing at the background of impairment of sympathetic-adrenalin and parasympathetic influences on myocardium with predominance of parasympathetic influences on heart.

5 cl, 3 dwg, 3 ex

Description

The invention relates to the chemical-pharmaceutical industry and medicine, namely to cardiology, and relates to a pharmaceutical combination for the prevention and treatment of cardiac arrhythmias that develop against a background of dysregulation of the heart rhythm in the form of changes in the ratio of sympathetic-adrenal and parasympathetic effects on the myocardium with a lack of sympathetic and relative or absolute predominance of parasympathetic influences on the heart.

In Russia, diseases of the circulatory system over the past three decades are leading among the causes of death. One of the main pathophysiological mechanisms of sudden and premature death are heart rhythm disturbances. An effective resource for the prevention of chronic disabling diseases of the cardiovascular system should be considered effective treatment of chronic cardiac arrhythmias manifesting at a young age.

Heart rhythm disturbances, such as heterotopic (supraventricular and ventricular) tachyarrhythmias and impaired sinus node function, occupy one of the first places in the structure of cardiovascular pathology in childhood and adolescence. Among the variety of rhythm disturbances, chronic tachyarrhythmias (paroxysmal and non-paroxysmal tachycardia) and bradyarrhythmias (impaired sinus node function) have the greatest clinical significance in young people. It is they who most often cause early disability and are most often associated with a risk of sudden cardiac death. In most cases (up to 80%) in young people, they develop in the absence of signs of organic heart damage, but can also occur as a complication of organic heart damage: congenital heart defects, cardiomyopathies, carditis, swollen hearts, and others. The main pathophysiological mechanisms of the development of rhythm disturbances are represented by intracardial and extracardial mechanisms.

Intracardial mechanisms of the development of heterotopic arrhythmias include structural anatomical and / or electrophysiological changes in the myocardium that contribute to the appearance of pathological electrophysiological mechanisms of cardiac excitation: additional pathways for conducting an impulse, foci of abnormal automatism, trigger zones. The direct pathophysiological mechanisms of the occurrence of heterotopic tachyarrhythmias are most often the circulation of the excitation wave in the myocardium, the so-called rientri mechanism. Extracardial mechanisms of the development of heterotopic tachyarrhythmias include impaired neurovegetative regulation of the heart rhythm. The role of mediators of the autonomic nervous system in the formation of the rientri chain is experimentally shown. The emergence and maintenance of the autonomic basis of arrhythmia can be caused at a young age by a violation of the maturation and functioning of the autonomic centers of rhythm regulation. Extracardial and intracardial mechanisms are in interaction. In each clinical case, their contribution to the occurrence and maintenance of arrhythmia is individual. The impact of risk factors is mediated by their effect on the humoral regulation of cardiac activity and myocardial metabolism.

The autonomic nervous system plays an integral role in modulating electrophysiological processes in the myocardium as a result of complex effects at the level of pre- and postganglionic sympathetic and parasympathetic fibers, extra- and intracardiac ganglia, and humoral effects on cardiomyocytes. The connection between neurovegetative regulation of the heart and local changes in cellular electrophysiology, leading to the development of a wide range of rhythm disturbances, from impaired normal heart rate variability to the development of clinically significant cardiac arrhythmias, has been proved [S. Rapa et al, 2010]. Experimental studies with stimulation of the hypothalamus, stellate ganglia have shown that along with a change in the morphology of the cardiac conduction system, arrhythmogenesis largely depends on the neurogenic effects on the heart. The implementation mechanism is usually associated with efferent vagal and sympathetic influences on the electrophysiological properties of the myocardium and the cardiac conduction system. In this case, stimulating sympathetic influences are given leading significance. In the works of L.V. Rosenstrauch and co-authors obtained convincing experimental confirmation of the development of atrial tachycardia rientri under the influence of vagal stimulation [Role of the vagus nerves in the development of supraventricular arrhythmias. Cardiology, 5, 1994, 1997].

In parallel with experimental studies, clinical observation data has been accumulated, the results of which indicate that a significant part of rhythm disturbances, such as dysfunction of the sinus node, supraventricular tachycardia, supraventricular and ventricular extrasystoles, in young patients without organic myocardial damage are impaired neurogenic regulation heart rate with absolute or relative, due to functional insufficiency of the sympathetic department willow nervous system, the predominance of parasympathetic influences [Schwartz P.J., Zipes D.P. / Autonomic modulation of cardiac arrhythmias // in Cardiac Electrophysiology. 2004. From Cell to Bedside, 4th Edn, eds Zipes D.P., Jalife J., editors. Philadelphia: W. B. Saunders; 300-314]. Such rhythm disturbances are considered to be vagosensitive [Coumel P, Attuel P, Lavallée J, Flammang D, Leclercq JF, Slama R. / The atrial arrhythmia syndrome of vagal origin // Arch Mal Coeur Vaiss. 1978 Jun; 71 (6): 645-56].

Arrhythmias are prone to a chronic course, they are a contraindication for sports, in combination with other pathological conditions, they significantly worsen the prognosis of diseases, with prolonged existence they contribute to the development of circulatory failure, arrhythmogenic myocardial dysfunction and can further lead to disability of patients, limiting their social adaptation, disrupting quality of their life.

Currently, medication and interventional methods of treatment are used to treat rhythm disturbances.

Drug treatment of disorders is based on the use of class I-IV antiarrhythmic drugs, the purpose of which is to influence the intracardial mechanisms of rhythm disturbance, namely, to block the electrophysiological substrate of arrhythmia. Antiarrhythmic drugs are prescribed on the basis of individual selection, by sequential administration of several drugs until a clinical effect is obtained, for a long time. They have many side effects mainly on the nervous, cardiovascular and endocrine systems, including in the form of impaired function of internal organs, often have the so-called proarrhythmogenic effect - they induce previously undetectable rhythm and conduction disturbances, in most cases they inhibit the function of the main pacemaker - sinus node. The effectiveness of treatment with antiarrhythmic drugs decreases over time, and after their cancellation, rhythm disturbance is restored. The appointment of antiarrhythmic drugs in young patients who do not have a structural pathology of the heart is carried out only for health reasons - in the presence of a high risk of arrhythmogenic myocardial dysfunction, heart failure and sudden cardiac death [V.G. Kukes / Clinical Pharmacology // Moscow: GEOTAR-Media, 2006. S.312-365].

With increased parasympathetic effects on the heart rhythm, a solution of atropine sulfate is used [Mashkovsky M.D. Medicines 14th edition. M .: New wave, 2003]. However, this drug is used only in emergency cases and has a number of significant limitations in use due to the development of adverse reactions, including in the form of cardiac arrhythmias.

A known method of treating non-paroxysmal supraventricular tachycardia of the return type in children [SU 1463219, IPC A61B 5/0402]. To reduce the treatment time and prevent complications, the child undergoes an electrocardiographic study before and after 20-30 minutes after the administration of isadrine at a dose of 0.15 mg / kg body weight. If arrhythmias disappear or decrease, they are treated with glutamic acid and pyriditol in age dosages. In the absence of changes after administration of isadrine or worsening of arrhythmia, antiarrhythmic drugs with an adrenergic blocking effect are treated.

A known method of treating sick sinus syndrome [RU 2220718, IPC A61K 31/165]. The method involves administering a β-blocker, atenolol is used as a β-blocker and is prescribed to patients who do not have symptoms of cerebrovascular / systemic circulatory disorders, and after conducting a medical vegetative blockade, the heart rate decreases and the recovery time of the sinus node function increases by less than 280 ms, at a dose of 12.5 mg in the morning and evening, daily orally for 2 weeks, then the dose is increased to 25 mg 2 times a day, course 6-24 months. However, this method, along with a positive effect in the form of a decrease in the activity of replacement rhythm sources in tachy-bradycardia syndrome, is associated with a risk of complications in the form of aggravation of bradycardia, the development of atrioventricular blockade and cardiac arrest in patients with impaired sinus node function when exposed to beta-blockers.

In recent years, given the side effects and lack of effectiveness of antiarrhythmic drugs, great importance has been attached to surgical intervention methods of treatment - radiofrequency catheter ablation of arrhythmogenic zones [Modern methods of interventional treatment of supraventricular tachyarrhythmias in children / S.A. Thermoses, M.A. Shkolnikova // Russian Bulletin of Perinatology and Pediatrics. - 2005. - Volume 50, N 2. - S.26-34]. This method is high-tech and expensive and can only be performed in an x-ray specialized center. In 2-10% of cases, complications associated with damage to the normal structures of the heart are noted - perforation, damage to the coronary arteries, development of iatrogenic blockade. In some cases, as a result of these complications, implantation of an artificial pacemaker may be required. Relapses after interventional treatment of heterotopic arrhythmias in young people reach 10-15%. The use of this method of treatment in young patients with vaginal-dependent arrhythmias is limited, since the manifestations of rhythm disturbances often spontaneously decrease or stop against the background of sedation or during anesthesia, which does not allow performing an intervention. In these cases, the patient is anesthetized, interventional with an intracardiac electrophysiological examination of the heart, but the treatment procedure is not performed, and after the study, the rhythm disturbance recurs. In addition, it should be borne in mind that even in the case of the successful elimination of the morphological substrate of a vegetatively dependent rhythm disturbance, the extracardial mechanisms of arrhythmia continue to function, which increases the likelihood of another rhythm disturbance developing on this basis.

From the above analysis it follows that due to the complexity of the mechanisms of arrhythmogenesis, including both intracardial and extracardial factors;

the lack of effectiveness and unobvious significance of known medication antiarrhythmic drugs in young people with rhythm disturbances in the absence of organic heart damage and a high representation of such patients in the general structure of arrhythmias in young people, the problem of developing drugs that contribute to the normalization of neurogenic regulation of heart rhythm with the subsequent elimination of the vegetative basis of arrhythmia remains relevant.

Improving the effectiveness of the treatment of patients with chronic cardiac arrhythmias is one of the main tasks of modern cardiology and requires the search and development of new effective and safe medications.

The creation of a new pharmaceutical combination is necessary to solve one of the urgent problems of cardiology - the treatment of rhythm disturbances in young people and the prevention of the development of subsequently socially significant diseases of the cardiovascular system.

The problem to which the invention is directed is to expand the arsenal of drugs for the prevention and treatment of chronic heart rhythm disorders and to develop a method for the prevention and treatment of chronic heart rhythm disorders, in the pathogenesis of which the decisive role is played by disorders of the autonomic regulation of heart rhythm with the formation of vaginal arrhythmias in individuals young age.

The technical result of the invention is the correction of chronic disorders of the autonomic regulation of the heart rhythm, which developed against the background of a violation of the ratio of sympathetic-adrenal and parasympathetic effects on the myocardium with a lack of sympathetic and relative or absolute predominance of parasympathetic effects on the heart.

This problem is solved by the claimed group of two inventions, united by a single inventive concept.

To solve this problem, a pharmaceutical combination for the prevention and treatment of chronic disorders of the autonomic regulation of heart rhythm includes pyritinol, glutamic acid and ubiquinone in the following ratio of components for different age groups, g for one dose:

pyritinol 0.05-0.2 glutamic acid 0.125-0.5 ubiquinone 0.005-0.02

To solve this problem, a method for the prevention and treatment of chronic disorders of the autonomic regulation of heart rhythm involves the oral administration of the specified pharmaceutical combination twice a day for 2-3 months.

In a particular embodiment, the oral administration of the pharmaceutical combination is carried out simultaneously in the form of separate dosage forms.

In another particular embodiment, the oral administration of the pharmaceutical combination is in the form of a single dosage form.

In another particular embodiment, the oral administration of the pharmaceutical combination is repeated, if necessary, after 2-6 months.

The proposed dosages of the components of the pharmaceutical combination are based on the recommended single age-related dosages of each of the drugs included in the pharmaceutical combination, taking into account the possibility of use in patients of different age groups. A pharmaceutical combination is prescribed twice a day in the morning and afternoon hours, since its administration is accompanied by increased activity of the peripheral part of the sympathetic nervous system, which is undesirable in the evening. A stable therapeutic effect in the form of an increase in the level of autonomic regulation of the heart rhythm and the disappearance of vaginal-dependent cardiac arrhythmias is achieved, as a rule, when the pharmaceutical combination is administered orally for 2–3 months. When an incomplete positive effect is achieved in the form of a partial elimination of cardiac arrhythmias, repeated courses of treatment are recommended after 2-6 months.

Figure 1 presents a fragment of a synchronized ECG-EEG (electrocardiogram-brain electroencephalography) monitoring in a patient with chronic non-paroxysmal tachycardia with wide QRS complexes. A tachycardia volley with a wide QRS complex on an ECG (A) appears 2.5 s after the development of a generalized volley of a 6-A wavelength slow wave activity on an EEG (B).

Figure 2 presents the dynamics of the ECG of the patient Marina M. before and after treatment

A - ECG fragment before treatment: lower atrial tachycardia is recorded,

B - ECG fragment during treatment: sinus rhythm, arrhythmia is not recorded.

Figure 3 presents the time synchronization of the pharmacological action of ubiquinone, glutamic acid (glutamate) and pyritinol when administered to experimental animals (rats); the introduction of the pharmaceutical combination was carried out in the form of a single dosage form.

The creation of the claimed pharmaceutical combination was made possible by studying the effect of this pharmaceutical combination, including pyritinol, glutamic acid and ubiquinone, on the subtle mechanisms of heart rate regulation in patients with various types of cardiac arrhythmias.

Pyritinol acts on presynaptic m 1 - cholinergic receptors of the central parts of the autonomic nervous system, m 1 - cholinergic receptors of preganglionic neurons of the sympathetic autonomous system, neuropeptide receptors on postganglionic neurons of the sympathetic part of the autonomic nervous system. Pyritinol is a nootropic drug that stimulates metabolism in the central nervous system (CNS), improves cerebral circulation. Pyritinol improves metabolic processes in the brain, increases brain resistance to hypoxia, glucose uptake and metabolism, nucleic acid metabolism, activates cholinergic transmission to the central nervous system, and has mild, gradual stimulating and antidepressant effects. Moreover, as a single drug does not have serious clinical significance in the treatment of autonomic dystonia, in particular, accompanied by a violation of the heart rhythm.

The biological targets of glutamic acid (glutamate) are receptors of neuropeptides, GABA-A and GABA-C of extrasynaptic membranes of the membranes of the postganglionic neurons of the sympathetic part of the autonomic nervous system, which stimulates the central neurotransmitter processes. Glutamic acid and its analogues are used as medicines, as a rule, in complex therapy: in case of chronic insufficiency of amino acid metabolism, vegetovascular dystonia, reactive states that occur with the phenomena of exhaustion, depression. In pediatrics, they are used for mental retardation, the consequences of intracranial birth injury. As a single drug, glutamate has no serious therapeutic value in the treatment of autonomic dystonia, as well as cardiac arrhythmias.

Ubiquinone is an essential component of electron transport chains, it provides the combination of electron transport and oxidative phosphorylation, participates in the mitochondrial chain of electron transport as a coenzyme, regulates prooxidant-oxidative homeostasis, participates in the removal of protons from the mitochondrial matrix and their subsequent release into the intermembrane space. Ubiquinone is used in various conditions associated with metabolic disturbances in the myocardium, in particular with heart failure, arrhythmias, arterial hypertension, as well as in the period of preparation for heart operations - aorto-coronary artery bypass grafting, in case of heart defects. Children are prescribed for prophylaxis and as part of complex therapy for diseases of the cardiovascular system: arrhythmia, chronic heart failure, children with congenital heart defects in preparation for heart surgery and for rehabilitation in the postoperative period, to improve adaptation to increased physical exertion in athletes.

Each of the active substances used is known and the composition of the preparations is included. Pyritinol - Pyriditol, Enerbol and Encephabol. Glutamic acid - L-Glutamic acid, Glutamic acid and Epilapton. Ubyquinone - Kudesan and Ubyquinone compositum.

The data of examinations and observations of 180 patients with heterotopic tachyarrhythmias and 150 patients with impaired function of the sinus node aged 3 to 50 years were analyzed, including medical history, general clinical examination in a cardiology clinic, electrocardiography in 12 standard leads, echocardiography to exclude organic damage heart, a comprehensive assessment of the state of the autonomic nervous system, including determination of the initial autonomic tone, autonomic reactivity and autonomic obesity biscuit activity; electroencephalography (EEG) at rest and during functional loads (indifferent sound stimulus, hyperventilation); combined monitoring of EEG-ECG at different periods of the day in order to determine the nature of neurogenic effects on heart rate and the occurrence of arrhythmias; medicinal tests with vegetotropic drugs - atropine, obzidan, isoproterinol and a dosed physical exercise test were performed for patients with chronic non-paroxysmal supraventricular tachycardia in order to assess the dynamics of arrhythmia, the number and duration of tachycardia volleys, determine the maximum changes in heart rate (HR) of the sinus rhythm. 24-hour Holter ECG monitoring included the analysis of rhythm and conduction disturbances, the construction of a heart rate trend (pulsogram) and a heart rate histogram, and an assessment of heart rate variability. It was shown that one of the leading pathophysiological mechanisms of the occurrence and maintenance of chronic supraventricular tachyarrhythmias in young people without organic heart diseases is a violation of the ratio of sympathetic-adrenal and parasympathetic effects on the myocardium with a lack of sympathetic and relative prevalence of parasympathetic influences. During the test with physical activity, arrhythmias disappeared or significantly decreased at the height of the load in most patients, which proved the vagosensitive nature of arrhythmias. A positive effect was also achieved when conducting a medical test with isadrine (isoproterenol) 0.15 mg / kg sublingually (not more than 7.5 mg once). After 20-30 minutes from taking the drug on the background of stimulation of sympathetic effects on the heart, arrhythmias significantly decreased or disappeared. The achieved effect was short-lived and disappeared after the termination of the load or upon withdrawal of the drug.

Four levels of evidence have been obtained of the relationship between the studied arrhythmias and a decrease (absolute or relative) in the level of sympathetic effects on the heart (in vivo, in vitro).

I. When conducting stress tests with physical activity, these arrhythmias disappear or significantly decrease at the height of the load in most young patients.

II. A drug test with beta-adrenergic agonist isoproterenol leads to a significant reduction or disappearance of arrhythmia in most patients without organic heart damage after 20-30 minutes from taking the drug.

III. As a result of EEG-ECG monitoring in patients with vaginally dependent chronic supraventricular tachyarrhythmias, the relationship of electrophysiological changes in the myocardium with changes in brain bioelectric activity was established. The relationship of arrhythmia with neurogenic effects is especially demonstratively confirmed by simultaneous EEG and ECG monitoring in patients with a recurrent form of chronic non-paroxysmal tachycardia, when tachycardia volleys on the ECG were preceded or accompanied by volley wave activity on the EEG in 68% of cases (Fig. 1).

IV. In the experiment on frog heart preparations, the appearance of “excitability” zones in the atrial myocardium under the influence of acetylloline, which initiate the emergence and maintenance of arrhythmias based on the circulation of electrical excitation in the myocardium around these zones, is shown.

The data obtained indicate the protective role of the normal tone of the sympathoadrenal system as a factor that stabilizes the heart rhythm in individuals without organic lesions of the cardiovascular system.

The research results confirmed the role of autonomic disorders in the occurrence and maintenance of rhythm disturbances. The stimulating effect on the autonomic regulation of the rhythm with an increase in the tone of the sympathetic part of the autonomic nervous system under conditions of activation of metabolic processes in the myocardium will allow patients with vaginal-dependent arrhythmias to restore heart rhythm.

250 patients with chronic cardiac arrhythmias in the absence of signs of organic heart damage (180 patients with heterotopic tachyarrhythmias from 3 to 50 years old and 70 patients with sinus node syndrome from 12 to 38 years old) with manifestations of autonomic dysfunction with a predominance of vagotonia, in which chronic tachycardia or manifestations of the sinus node weakness syndrome disappeared or significantly decreased during the test with physical activity and / or against the background of a drug test with isoproterenol, simultaneously Pyritinol was prescribed at a daily dose of 0.1-0.4 g with glutamic acid at a daily dose of 0.25-1.0 g, depending on age, lasting 2-3 months and ubiquinone 0.01-0.04 g.

During therapy, patients' well-being improved, their working capacity increased, fatigue disappeared, complaints of sensations of weakness - manifestations of asthenic syndrome disappeared.

From the side of the heart rhythm in patients with chronic non-paroxysmal tachycardia of the return type, on average, the number and duration of tachycardia volleys significantly decreased after an average of 2-4 weeks, subsequently, sinus rhythm was restored in 77% of patients. Chronic non-paroxysmal tachycardia of a constant type was largely refractory to this therapy, due to the electrophysiological substrate of tachycardia, eluding neurovegetative influences, which required the appointment of antiarrhythmic therapy.

The condition of patients with paroxysmal tachycardia during treatment is regarded as a significant clinical improvement - the disappearance or significant reduction of seizures in combination with a decrease in their duration and ease of relief.

In 80% of patients with impaired sinus node function, manifestations of sinus bradycardia decreased, periods of sinoatrial blockade according to Holter monitoring disappeared, periods of slipping and replacing rhythms were not recorded, the duration of pause rhythms decreased, which allowed us to establish the restoration of the normal level of functioning of the sinus node.

At the same time, it was noted that when prescribing a course of therapy with pyritinol, glutamic acid and ubiquinone, the patients disappeared complaints of a neuro-vegetative nature, such as dizziness, increased fatigue, poor tolerance of transport, stuffy rooms, which confirmed the initial presence of neurocirculatory dystonia with a predominance of parasympathetic reactions. The disappearance of the symptoms of the so-called “vaginal-dependent” disorders of the gastrointestinal tract - constipation, dyspeptic phenomena. Thus, therapy with the use of three drugs - pyritinol, glutamic acid and ubiquinone in specially selected dosages gives a distinct clinical effect with various variants of neurocirculatory dystonia and rhythm disturbances, which developed against the background of impaired neurogenic regulation of the heart rhythm with a predominance of vagotonia.

The combined use of pyritinol, glutamic acid and ubiquinone in age dosages was proposed for the first time in patients with rhythm disturbances that developed against a background of autonomic dysfunction in the absence of an organic heart pathology. With simultaneous administration in physiological dosages, a positive clinical effect was obtained that cannot be achieved by the separate use of any of these drugs. These patients suffered from chronic rhythm disturbances for many months and years. More than 50% had a disability, with the development of minimally invasive arrhythmias surgery - more than 70% go to radiofrequency catheter ablation, since the appointment of antiarrhythmic drugs is accompanied by side effects and complications, and the therapeutic effect disappears when the antiarrhythmic drug is canceled. A minimally invasive surgical procedure helps restore rhythm, but up to 15% have relapses or the development of new arrhythmias already in the first year after surgery, which indicates the need to eliminate the autonomic basis of arrhythmia.

The use of a combination of drugs with a nootropic, nootropic effect (pyritinol and glutamic acid), in combination with stimulation of metabolic and antioxidant processes in the myocardium (ubiquinone) helps to correct neurovegetative disorders and restore the protective function of the sympathoadrenal system.

A study of the pharmacokinetic characteristics of the proposed pharmaceutical combination. Animal experiments and surgical procedures were performed as follows.

The study was performed on male Wistar rats weighing 250-300 g. Animals under sterile conditions under anesthesia (pentobarbital, 50 mg / kg ip) implanted a catheter into the femoral vein for subsequent blood sampling. A day after the operation, on an empty stomach, the pharmaceutical combination was administered into the stomach on an empty stomach through a probe in the following doses: ubiquinone 10 mg / kg, glutamic acid 300 mg / kg, pyritinol 100 mg / kg. The rats of the first group (n = 7) were given a pharmaceutical combination in the form of a mixture of powders, and the rats of the second group (n = 7) were given a single suspended dosage form (powder of the pharmaceutical composition in the form of a suspension in a 0.2% methylcellulose solution). Blood sampling (0.3 ml each) was carried out before administration of the drug and 2, 3, 4, 5, 7, 9, 24, 36, and 48 hours after administration. Blood samples were centrifuged, blood plasma was taken, frozen and stored at minus 20 ° C until quantitative analysis. For two days after administration of the pharmaceutical combination, the animals were not fed without restricting access to water.

The following pharmacokinetics parameters were determined and calculated for the powder and the suspended form of the pharmaceutical combination: Tmax - time to reach maximum concentration, Cmax - maximum concentration value, AUCo-t - area under the concentration-time pharmacokinetic curve, Cmax / AUCo-t - relative speed suction. For the solubilized form, the following was calculated: f is the relative bioavailability of the studied dosage form relative to the comparable one, determined by the ratio AUCo-t, T / AUCo-t, R, f is the relative degree of absorption determined by the ratio Cmax, T / Cmax, R. Values of the pharmacokinetics parameters were calculated by model-independent methods. The value of Cmax and the time of its achievement were determined from the actual concentration values. The area under the pharmacokinetic curve (AUCo-t) was calculated by the trapezoidal method. The bioavailability of ubiquinone was calculated by comparing the areas under the time-dependence of the concentration of ubiquinone in blood plasma, constructed for two groups of rats. The bioavailability of glutamate and pyrithiniol was calculated using a calibration curve of drug concentrations in the blood.

The obtained values of the time to reach the maximum concentration of ubiquinone in plasma (80-90 min), glutamic acid (glutamate) and pyritinol (30-40 min) indicate that the absorption of both ubiquinone and two other components in the gastrointestinal tract in pharmaceutical combinations are relatively faster than each of the components individually. Moreover, the time to reach the maximum concentration and the relative absorption rate of the powder of the pharmaceutical combination and its suspension did not significantly differ. At the same time, when using the suspended form, the average concentrations of the three components of the pharmaceutical combination in plasma during the day after administration were significantly higher than after administration of the powder. The maximum concentration in blood plasma after taking the suspended form was approximately 3.3 times higher, and the area under the concentration-time curve was 2.6 times larger compared to the powder.

The conducted studies allow us to draw the following conclusions.

When used in the form of a single dosage suspended form of a pharmaceutical combination, there is a significantly greater synchronism of action of the components of the drug compared to their separate use. This allows you to synchronize the therapeutic effect of all three components of the pharmaceutical combination and confirm the higher effectiveness of the drug compared to the separate use of its components.

The bioavailability of all three components of the pharmaceutical combination in the composition of a single dosage suspended form relative to the mixture of the powders of the components was 264%, and the relative degree of absorption was 329%, which indicates a higher bioavailability of the pharmaceutical combination in the composition of a single dosage suspended form compared to the use of three dosage components in as a mixture of powders, i.e. separate dosage forms.

A pharmaceutical combination of three well-known components has a qualitatively new therapeutic effect with the restoration of the protective function of the sympathoadrenal system by acting on the vegetative centers of heart rhythm regulation against the background of increased antioxidant protection due to the combination of the neurometabolic effect of pyritinol, which has a stimulating effect on the m1-cholinergic receptors of the central autonomic departments nervous system and preganglionic neurons of the sympathetic autonomic system, as well as on the counter of neuropeptides in postganglionic neurons of the sympathetic autonomic nervous system, glutamic acid, which is a moderate inducer of the neuropeptide GABA-A and GABA-C dependent receptor of both the central parts of the autonomic nervous system and extrasynaptic portions of the membranes of the postganglionic neuronavic nervous system and the vegetative nervous system involved in the mitochondrial chain of electron transport as a coenzyme by regulating prooxidant-oxidative homeostasis. The use of such a pharmaceutical combination was accompanied by partial or complete normalization of the heart rate in 78% of young patients without the use of antiarrhythmic drugs.

Comparative pharmacokinetic studies of the separate administration of drugs - ubiquinone, pyritinol and glutamic acid and a pharmaceutical combination containing these three components in male Wistar rats weighing 300-400 g showed that the introduction of a pharmaceutical combination has clear advantages in the form of concentration synchronization due to increased bioavailability of ubiquinone and reducing the rate of absorption of glutamic acid, which is potentially promising in terms of obtaining clinical effects through the use of lower doses of prep Ratov.

The main innovative feature of the proposed pharmaceutical combination is the emergence of a qualitatively new therapeutic synergistic effect from a combination of three known components, namely: correction of neurovegetative disorders with restoration of the protective function of the sympathoadrenal system by affecting vegetative centers of heart rhythm regulation against the background of increased antioxidant defense, as a result of which the drug helps to restore normal rhythmic driving functions by increasing the level with impatient effects on the myocardium and sinus node in patients suffering from cardiac arrhythmias, which developed against the background of impaired neurovegetative regulation of the heart rhythm.

The following are examples of the implementation of the invention.

Clinical example 1.

Roman, 5.5 years old. It was observed by a pediatrician at the place of residence in connection with complaints of increased irritability, difficulty falling asleep, excessive sweating in a dream, motion sickness in transport. At the age of 2, for the first time at the Filatov Children's Hospital in Moscow, against the background of poisoning, they heard a heart rhythm disturbance. At the age of 3.5 years, in 2006 he was consulted by a family doctor - a survey was recommended to exclude heart rhythm disturbances. An electrocardiogram (ECG) against a background of pronounced blue owl arrhythmia with a heart rate of 92 - 53 per min revealed ventricular extrasystole. In 2007, he was examined in a specialized department of cardiac arrhythmias. During the initial examination, there was a pronounced vegetative lability, a decrease in the ability to concentrate. In the vegetative status, signs of dysfunction of the parasympathetic department of the autonomic nervous system prevailed. Parents paid attention to periods of increased excitability, followed by increased fatigue, weakness, increased sweating at night, and motion sickness in transport. Heredity is burdened by cardiac arrhythmias - the supraventricular extrasystole is revealed in the child's father. As a result of a cardiological examination, organic damage to the cardiovascular system was ruled out. When examining resting ECG on a cuneiform position, there is sinus bradycardia with a heart rate of 56-70 per min (less than 5 percentiles of the age distribution of heart rate), single ventricular extrasystoles. On the ECG against the background of minimal physical activity (10 squats), the ventricular e / systole disappears According to the 24-hour Holter ECG monitoring, sinus bradycardia, the maximum pause of the rhythm reached 1524 ms (with the norm up to 1300 ms), 14000 ventricular extrasystoles were recorded, mainly in evening and night time (nocturnal circadian type of arrhythmia).

Diagnosis: ventricular extrasystole, sinus bradycardia, vegetative-vascular dystonia according to the vagotonic type.

Given the lack of data for organic pathology of the heart and the established vagos-dependent nature of arrhythmia (the prevalence of arrhythmias at night, the disappearance of rhythm disturbances during stimulation of the sympathetic part of the autonomic nervous system against minimal physical exertion), treatment was prescribed according to the proposed method: pyritinol 0.05 g 2 times per day, glutamic acid 0.25 g 2 times a day, ubiquinone 0.006 g - 2 times a day. Against the background of treatment, a pronounced positive dynamics was observed on the part of health: it became calmer, sleep improved. On the ECG after 2 months - pronounced positive dynamics, ventricular extrasystole is not detected, the frequency of the basic sinus rhythm has increased and corresponds to the 25th percentile of the age distribution of heart rate. Holter monitoring showed positive dynamics in the form of a decrease in extrasystole from 14000 / day to 8947 / day. A second course of treatment is recommended, after which the amount of I extrasystole decreased to 391 / day. During the follow-up examination after a year and after 2 years at the place of residence, ventricular extrasystole is not registered, heart rate is normal. The child is active, has no complaints, is engaged in the sports section without load limitation.

Clinical example 2.

Marina M., 14 years old. Once she underwent a syncopal state at the age of 11 years (during combing during the period of emotional excitement in the morning), several times before this, pre-syncope conditions were observed in stuffy rooms. When analyzing electrocardiograms from the age of 8, it was noted that episodes of the lower atrial rhythm were recorded on all ECGs presented against the background of sinus bradyarrhythmia. She was engaged in sports aerobics from the age of five for 5 years with a training regimen 4 times a week for 4 hours. Was examined in to clarify the causes of syncope. On the ECG recorded episodes of the lower atrial rhythm (figa), heart rate sinus rhythm at the lower border of the age norm (bradyarrhythmia). According to Holter monitoring, up to 80% of the time at night and up to 30% in the daytime are recorded atrial rhythm (nocturnal circadian type of arrhythmia), the minimum heart rate of sinus rhythm is 50 per minute. According to ECHO cardiography - additional trabeculae in the cavity of the left ventricle. A stress test was carried out - rhythm disturbances on the background of dosed physical activity were not recorded.

Diagnosis: Chronic non-paroxysmal supraventricular tachycardia of the return type, impaired function of the sinus node. Syncopal states of vasovagal origin.

Given the lack of data for organic pathology of the heart and the pronounced vagal-dependent nature of arrhythmia (the prevalence of arrhythmias at night, the disappearance of rhythm disturbances during stimulation of the sympathetic part of the autonomic nervous system during exercise), treatment was prescribed according to the proposed method: pyritinol 0.1 g 2 times day, glutamic acid 0.5 g 2 times a day, ubiquinone 0.0075 g - 2 times a day. On the background of treatment after 3 months. marked positive dynamics was observed according to ECG; the lower atrial rhythm was not recorded; according to Holter monitoring, episodes of supraventricular tachycardia at night did not exceed 20% of the volume of cardiocycles during this period of the day. It was recommended that a second course of treatment for the proposed method for 2 months. After 4.5 months from the start of therapy during the follow-up examination at the place of residence, there are no complaints, no syncope and pre-syncope, no rhythm disturbances were detected. According to the ECG sinus rhythm, there are no rhythm disturbances (Fig.2 B); according to the results of Holter monitoring - sinus rhythm, rhythm disturbances are not registered. During the follow-up examination after 1.5 years at the place of residence - rhythm disturbances according to ECG and Holter monitoring were not registered. The patient is allowed to do sports aerobics.

Clinical example 3.

Olga G., 35 years old. She complained of a sensation of interruptions in the region of the heart, attacks of weakness, dizziness, poor exercise tolerance, poor transport tolerance, and a tendency to hypotonic reactions. When analyzing electrocardiograms from the age of 30 years, pronounced sinus bradycardia with a heart rate of 42-50 per min, periodically sinoatrial blockade, episodes of replacement atrial rhythm with a heart rate of 100-120 per min are recorded. She was engaged in swimming, but began to note episodes of weakness after visiting the pool. Passed examination in to clarify the diagnosis at the place of residence. The diagnosis is a violation of the function of the sinus node, tachy-bradycardia syndrome. According to Holter monitoring, up to 60% of the time at night and up to 50% in the daytime are recorded atrial rhythm (mixed circadian type of arrhythmia), the minimum heart rate of sinus rhythm is 30 per minute. According to ECHO cardiography, no pathology was detected. A stress test was carried out - in the end - an alternation of the sinus rhythm with a heart rate of 40 per minute and lower atrial tachycardia with a heart rate of 110 per minute. At the height of the load, the lower atrial tachycardia is not recorded, single supraventricular extrasystoles are noted, the heart rate of the sinus rhythm increased to 90 per minute. Diagnosis: Syndrome of weak sinus node (tachy-bradycardia) of vasovagal origin.

Given the lack of data for the organic pathology of the heart and the pronounced vagal-dependent nature of arrhythmia (the disappearance of heterotopic tachycardia during stimulation of the sympathetic autonomic nervous system during exercise), treatment was prescribed according to the proposed method: pyritinol 0.1 g 2 times a day, glutamic acid 0, 5 g 2 times a day, ubiquinone 0.0075 g - 2 times a day. Against the background of treatment, after 3 months, pronounced positive dynamics was observed according to ECG data: the lower atrial rhythm according to ECG and Holter monitoring was not recorded. Surveillance at the place of residence, follow-up examination after 6 months was recommended. During the control examination at the place of residence, it does not show complaints, does not note bouts of weakness and dizziness, and no rhythm disturbances have been detected.

As can be seen from the examples, the use of the proposed pharmaceutical combination eliminates heart rhythm disturbances that developed against the background of a violation of the ratio of sympathetic-adrenal and parasympathetic effects on the myocardium with a lack of sympathetic and relative or absolute predominance of parasympathetic effects on the heart.

A pharmaceutical combination can be administered separately in the form of separate dosage forms, however, a single dosage form containing three active substances in its composition is much more convenient in use. No less important is the fact that taking such a drug will be safer for the body due to the lower total amount of excipients. In addition, the production and use of one drug instead of three is more economical for both the drug manufacturer and the patient. The pharmaceutical combination may be in the form of tablets, coated tablets, hard gelatine capsules, granules for the preparation of a suspension or suspension. Each dosage form should contain in its composition the doses of active substances recommended for various age groups.

The present invention provides an expansion of the range of drugs used to treat patients with cardiac arrhythmias on the background of autonomic dysregulation of the heart rhythm; longer therapeutic effect; helps prevent the development of complications; reduce the number of complications and normalize heart rate.

In addition, due to the synergistic effect, the effective doses of the components of the pharmaceutical combination can be significantly reduced, as well as applied less frequently, thereby reducing side effects.

The present invention allows to significantly improve clinical symptoms, prognosis and quality of life in a group of patients with chronic disorders of the autonomic regulation of heart rhythm, to reduce the risk of sudden cardiac death due to the development of life-threatening arrhythmias.

Claims (5)

1. A pharmaceutical combination for the prevention and treatment of chronic disorders of the autonomic regulation of heart rhythm, including pyritinol, glutamic acid and ubiquinone in the following ratio of components for different age groups, g for one dose:
pyritinol 0.05-0.2 glutamic acid 0.125-0.5 ubiquinone 0.005-0.02 2. A method for the prevention and treatment of chronic disorders of autonomic regulation of the heart rhythm, including the oral administration of a pharmaceutical combination according to claim 1 twice a day for 2-3 months. 3. The method according to claim 2, characterized in that the oral administration of the pharmaceutical combination is carried out simultaneously in the form of separate dosage forms. 4. The method according to claim 2, characterized in that the oral administration of the pharmaceutical combination is carried out in the form of a single dosage form. 5. The method according to claim 2, characterized in that the oral administration of the pharmaceutical combination, if necessary, is repeated after 2-6 months.

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