Antiarrhythmic drug

 

The invention relates to the field of medicine and relates to anti-arrhythmic drug. The invention lies in the fact that the drug on the basis of salts of gluconic acid contains at least one salt in which the cation is selected from the group consisting of potassium or magnesium. The invention provides acceleration cupping arrhythmias of various etiologies and risk reduction of complications, their prevention and treatment. 7 C.p. f-crystals, 3 tables.

The invention relates to anti-arrhythmic drugs on the basis of salts of gluconic acid, and preferably on the basis gluconate potassium and/or magnesium.

It is well known that paroxysmal cardiac arrhythmias are one of the most important causes of sudden death. There is a particularly high risk of death during ventricular polytopes, group or early ekstrasystolichniy arrhythmias in patients with myocardial infarction in the acute phase and in persons with post-infarction and atherosclerotic cardiosclerosis, or with severe cardiac insufficiency arbitrary etiology (beavers Century A., Kupovina I., Refractory tachyarrhythmias. Kiev: Health, 1994).

Cell ion formation mechanism of arrhythmias may be due to different factoranalysis therapy//Therapeutic archive 1999, 8, S. 67-74).

Indeed, before the attacks of arrhythmia within the myocardial cells, the concentration of Na+and CA2+increases and ions To+and Mg2+decreases with changes in the electrophysiological properties of cardiomyocytes.

However, the known antiarrhythmic drugs, as a rule, narrowly focused on the blockade of ion channels or for Na+(I class), or receptor-mediated channels for CA2+(Class II) or for K+(Class III). To class IV rank drugs are calcium antagonists as such, but to the V class - bradycardias drugs affecting the activity of only the sinus node.

Therefore, the success of cupping and subsequent treatment and prevention of arrhythmias directly depends on the correct choice of doctor of antiarrhythmic drugs that are appropriate for specific patients in specific circumstances.

However, only a long survey, you can determine the status of the Central nervous system, hormonal and electrolyte status, acid-base balance and metabolism the body of the patient, to evaluate the anatomic and functional status of myocardiocytes and by complex electrophysiological studies to establish the type of ion engine paroxysmal funds.

Unfortunately, this is usually not enough time, and doctors rely on their own experience, which raises the inevitable often fatal mistakes.

Thus, the efficiency of the medical relief of paroxysmal arrhythmia does not exceed 60-70%, prevention of occurrence of repeated episodes of arrhythmias effective only 20-30% of patients, and 12-15% of patients arrhythmia aggravated, or transformed into other, often-fatal form (op cit beavers Century A., Kupovina I., Refractory tachyarrhythmias).

Similar, although not as complete data were obtained in the result of extensive randomized studies CAST and CAST II (1. The Cardiac Arrhythmia Supression Trial (CAST) Investigators //New Engl. J. Med.- 1989, V. 321, pp.406-412. 2. The Cardiac Arrhythmia Supression Trial I (CAST-II) Investigators //Ibid. - 1992, V. 327, pp.227-233). It was found that patients taking antiarrhythmic drugs class I moratsizin and flecainide, respectively in 2 and 3.64 times increased risk of sudden death compared with patients from the control group that these drugs did not accept.

These sad results due to the fact that: no single known antiarrhythmic drug is not able to normalize ion homeostasis in all types of ions, an excess or deficiency of which can has a lot of contraindications to the use; every single well-known blocker of ion channels of any class is able under certain circumstances to aggravate the imbalance of ions in the cardiomyocytes and, contrary to its purpose, to provide proaritmicheskimi action, the severity of which varies in the above 12-15%.

Said it is easy to confirm publicly available reference data (see, for example: Mashkovsky M. D. Medicines. Manual for doctors. 14th edition revised, corrected and augmented. In 2 volumes. Volume 1, M.: LLC "Publishing house New Wave", 2001, S. 357-388).

In particular, the preparation of subclass Ia procainamide hydrochloride (procainamide) can cause such adverse effects as hypotension, collapse, heart blockage and asystole, excitement, insomnia, headache and nausea (vomit), and with long-term use - lupus syndrome. It is contraindicated for long-term use in patients even with mild heart failure.

Another widely used representative of the same subclass - disopyramide (ritilin) has an anticholinergic effect and cause dry mouth, accommodation disorder, and difficulty urinating. He clearly inhibits the contractile spool this subclass is etmozin - can cause dizziness, and in concurrent use with monoamine oxidase inhibitors - even mental disorders. It works briefly, for which patients have to take it up to 6 times per day. On this background it is not uncommon hypotension, conduction disorders and arrhythmogenic effects.

The most common drug of subclass Ib lidocaine (xylocaine) is effective only for arrhythmias due to myocardial ischemia, has a low bioavailability after oral administration, and parenteral capable sharply, up to the collapse, to lower blood pressure and cause drowsiness, anxiety, tinnitus, tongue numbness, visual disturbances, dizziness, and tremor.

The preparation of the same subclass meksiletin (meksitil) is well absorbed when taken orally, however, gives the same side effects as lidocaine. It is contraindicated in syndrome, sick sinus, kidney and liver failure.

The preparation of subclass IC ethacyzin (moricizine) adversely affects the Central nervous system, causing dizziness and/or numbness in various parts of the body, the cardiovascular system, causing hypotension, inhibiting vascular system of the heart and reducing the contractility of the myocardium. In the Yining affects the Central nervous system, causing dizziness, headache, facial flushing, and blurred vision, and on the cardiovascular system, causing hypotension, tachycardia and conduction disorders.

For all drugs class II (-blockers) are characteristic of disorders of the Central nervous system (confusion, depression, weakness), broncho-pulmonary system (bronchospasm, until the development of status asthmaticus), cardiovascular system (hypotension, inhibition of the conduction system of the heart and myocardial contractility, bradycardia, Raynaud's syndrome). These drugs should not be administered in pregnancy and diabetes.

The most popular drug class III amiodarone (cordarone) sometimes breaks: the cardiovascular system, causing hypotension resistant bradycardia, blockade, heart failure, and often fatal arrhythmias associated with prolongation of the QT interval; CNS, causing ataxia, muscle weakness and tremor; bronchopulmonary apparatus, causing interstitial pneumonia/alveolitis or fibrosis of the lungs with often fatal; the gastrointestinal tract, causing nausea, constipation and drug-induced hepatitis; thyroid gland, causing Hypo - or hyperthyroidism; eye and skin (with the effect of photosensitization);

Amiodarone increases the arrhythmogenic effects of drugs of class I (except lidocaine) and alters the metabolism of many drugs.

Another drug class III sotalol (gelugor), along with negative effects, which are inherent in the above-blockers, can cause a decrease in contractility, blockade, tachycardia torsade de pointes associated with prolongation of the QT interval, and expressed bradycardia. From bronchopulmonary apparatus possible bronchospasm and bronchial asthma attacks.

Drugs class IV - calcium channel blockers group fenilalkilaminov (verapamil, gallopamil) adversely affect myocardial contractility, which limits their use in patients with heart failure (especially in the acute phase of myocardial infarction) and during pregnancy. Indeed, calcium antagonists inhibit the function of the sinus and atrioventricular nodes, called bradycardia, hypotension, peripheral edema, increased fatigue and constipation. Therefore, they are usually prescribed in combination with drugs V-class, typical representatives of which are alinidine and FilePanel.

Along with the described synthetic organic the change of the person increases the concentration of potassium ions and/or magnesium. These ions are the main physiological stimulators of the enzyme Na+-K+- ATPase responsible for maintaining electric potential resting cardiomyocytes (see, for example: heart Arrhythmia. Ed. by C. D. Mandela. In 3 volumes. Volume 1, M. : Medicine, 1996, S. 155-188).

Ions To+have a non-specific anti-arrhythmic effect, normalizing the generation of a pulse of the rhythm in the background of oppression automatic activity of ectopic pacemakers, interrupting the circulation of excitation and refractory lining cells in the myocardium. therapeutic efficacy of potassium is almost the same in patients with low and normal concentration in the blood.

The influence of ions To+rhythm depends on the electrical integrity of the myocardium, the initial concentration of potassium in the blood and speed of its change. The last factor is very important for the suppression of the arrhythmia often enough to enter the patient several milligram-equivalents of potassium. With repeated bouts of arrhythmia potassium is administered to normalize the rhythm. Failure of this therapy usually caused by the continued introduction of potassium after the suppression of the arrhythmia.

However, therapeutic effect of application of potassium briefly. Further, the use of chloride ka is e inside the potassium chloride may cause ulceration of the gastrointestinal tract and perforation occurred ulcers.

Antiarrhythmic and protivopellargnoe action of magnesium ions based on their antagonism towards calcium ions and is especially pronounced in cases of arrhythmia, which is due to the wrong use of drugs Ia and III classes and are associated with prolongation of the QT interval. Participating in many enzymatic reactions, ions MD2+play an important role in the regulation of metabolism, including the synthesis of ATP. In addition, magnesium is able to modulate the operation of the receptors and thereby regulate cellular activity.

As for potassium, therapeutic efficacy of magnesium are almost identical in patients with low and normal concentration in the blood.

Prolonged use of magnesium improves the condition of patients with ischemic heart disease and promotes regression of atherosclerosis. In patients with myocardial infarction the use of magnesium reduces the risk of sudden death (Shilov, A. M., Svyatov I. S., Kravchenko centuries, etc. the Use of drugs magnesium for the prevention of arrhythmias in patients with acute myocardial infarction//Russian heart journal, 2002, 1, S. 16-19). Magnesium is capable of regulating coronary blood flow and reduce the negative inotropic effect of ischemia (Chekman I. S. Biochemical pharmacodynamics. Kiev: Health, 1991).

This undesirable effect can eliminate the use of organic salts, namely orotata magnesium (otherwise referred to as magnerot). However, it is also poorly soluble, also has a laxative effect, and the remainder orotovoy acid with long-term use of magnerot contributes to fatty liver and requires medical correction (Smirnov, C. A. Vitamins. M.: Medicine, 1974). The same can be said about the once popular potassium orotate.

A pronounced antiarrhythmic effect on the background of ischemic and reperfusion injury of the myocardium provides Asparaginate magnesium (op cit Chekman I. S. Biochemical pharmacodynamics). It should be noted that it contains the amino acid residue is included in the metabolic processes and can be fully recycled plastic exchanges, and therefore virtually harmless to humans.

Apparently so in clinical practice during the paroxysmal cardiac arrhythmia due to an overdose of sergantov potassium and magnesium, known under the trade names Panangin and asparkam.

However, a pronounced antiarrhythmic effect is usually achieved only by using combinations of Panangin and other antiarrhythmic drugs.

Therefore, there is an acute need for such anti-arrhythmic drugs, which would be practically non-toxic and would not have dangerous side effects. It can be assumed that these drugs should be created on the basis of chemical compounds, which, as aspartic acid, naturally present as anabolics in the normally functioning human body.

Many of these substances can be distinguished gluconic acid, otherwise known as 2,3,4,5,6-pentahydroxyflavanone or 2,3,4,5,6-intoxicatingly acid.

She is a substrate pentose-phosphate pathway of glucose oxidation and normoglycemic conditions serves as a donor pyridine nucleotides that are involved in plastic synthesis. This pentose-phosphate pathway is energetically provides ion pumps, especially in the conduction system of the heart, and in conditions of ischemia and/or myocardial hypoxia pentose-phosphate shunt delivers the substrates of the glycolytic pathway of glucose oxidation, which also contributes nst. - M.: Medicine, 1987, S. 75-76).

It is known that the calcium salt dimethylglycinamide ether gluconic acid (pangamat calcium activates the succinate dehydrogenase with a pronounced antihypoxic and cardioprotective effect in local ischemia (Anisimov C. E. Pangamat calcium. - Kazan, 1965, S. 7). At the same time in experiments on cats, it was shown that the use of pangamate calcium before artificially induced by hypoxia of the myocardium is approximately three times increases the time before the beginning of arrhythmia in comparison with control (C. C., Andreev, A. C. Dokukin, Y. S. Chechulin, Y. C. Bukin. The effect of pangamic acid on hypoxia and heart/brain/Vitamin B15(pangamic acid). Properties, functions and applications. M.: Nauka, 1965, S. 80-90).

Thus, although more than 35 years, no one saw gluconic acid and its derivatives as the basis of practical anti-arrhythmic drugs, closest to the proposed anti-arrhythmic drug to the technical nature should be considered as random drug on the basis of gluconic acid.

Accordingly, the basis of the invention is by choosing chemical compounds on the basis of gluconic acid to create a new class practice is mplexes lipoic action and thereby significantly accelerated least mild asthma arrhythmias of different etiology and would reduce the risk of complications in their prevention and treatment.

The problem is solved by the fact that antiarrhythmic drug on the basis of gluconic acid, according to the invention comprises at least one gluconate in which the cation is selected from the group consisting of potassium and magnesium.

Indeed, as will be shown hereinafter, the practical application of any of the possible combinations of cations potassium and/or magnesium gluconate-anions allows to provide lipoic action regardless of the common causes for disturbing the integrity of cell membranes and, at least, to effectively stop attacks of paroxysmal aritime.

The first additional difference is that the anti-arrhythmic drug is potassium gluconate. This drug is most effective in measuring against the background of excess sodium cations and the cation deficiency of potassium in the bodies of patients.

A second difference is that the anti-arrhythmic drug is gluconate magnesium. This drug is most effective in measuring against the background of cation deficiency of magnesium in the organism of the patient.

The third additional difference is that the anti-arrhythmic drug is a mixture of potassium gluconate and magnesium. Drugs of this type when anitelea to the third difference is in the above-mentioned mixture of one mol of potassium gluconate is not less than 1.0 mol of magnesium gluconate. Preparations of this type are preferred for the prevention and treatment of arrhythmias based on the data about the lack of specific cations of potassium or magnesium in the body of the patient.

Fifth, additional to the fourth difference is that in the above-mentioned mixture of one mol of potassium gluconate falls from 4.0 to 6.0 moles of magnesium gluconate. Preparations of this type are most preferred when rapid (within seconds) the relief of attacks of paroxysmal arrhythmias introduction of a solution of this mixture directly into the bloodstream.

Sixth, additional to the third difference is that the mixture additionally contains at least 1.0 mole of amiodarone on one mol of potassium gluconate, which contributes to the success mild asthma arrhythmia even with the use of mixture per os, and strengthen preventive action.

Seventh, additional to the third difference is that the mixture additionally contains at least 1.0 mol of inosine on one mol of potassium gluconate, which is especially effective for long-term drug prevention arrhythmias arbitrary etiology.

Further, the essence Islaam experiments on laboratory models of arrhythmias of various etiologies and the obtained results compared with the results of the General anti-arrhythmic drugs;
(3) guidelines on the use of drugs of the proposed class for cupping fibrillation and its treatment and prevention.

(1) a Method of obtaining experimental dosage forms
Raw material in all cases served available as a chemical reagent substance gluconate and potassium gluconate magnesium, which had the quality of "chemically pure" (chemically pure), and is available on the pharmaceutical market amiodarone and inosine (Riboxin).

Since in our experiments we used only the solutions for injection, the method of preparation of experimental samples of the following antiarrhythmic drugs according to the invention include the following:
calculation of doses required with application known in the art methods,
batching is selected dry ingredients and
their mixing with isotonic sodium chloride or glucose to obtain 5, 10 or 20% solution for injections.

In experiments with regard to the molar ratio of ions To/MD and additives amiodarone or inosine used pre-prepared solutions with suitable molar concentrations and mixed them before applying them in the required proportions.

Expert it is clear that the preparation of t is/p> (2) Experimental verification of the preparations according to the invention
Antiarrhythmic activity of the preparations according to the invention, the mechanism of their action, the range of possible applications and advantages over the known antiarrhythmic drugs was determined in experiments on models of cardiac arrhythmias with the known pathogenesis in accordance with the procedure established by the Ministry of health of Ukraine (C. A. Bobrov, N. A. Gorchakov, V. N. Simonot etc. //Experimental and clinical study of antiarrhythmic drugs: a practical guide. K.: Pharmacological Committee, Ministry of health of Ukraine, 1995). Such models are based on the introduction of standard arrhythmogenic drugs. Doses of all drugs set forth per 1 kg of weight of a laboratory animal.

Continua model is based on intravenous sulfate solution or bromide aconitine at a dose of 30-40 mg/kg and is characterized by disorders of cardiac activity in the interval between atrial and ventricular ekstrasistolii to ventricular fibrillation, which arise through 1,3-4 min, last more than hours and control lead to the death of most animal parts.

This model is used to detect violations of the permeability of the appropriate drugs in class I, belong to lidocaine and etmozin.

Clerically model based on rapid intravenous solution of calcium chloride at a dose of 200-250 mg/kg and is characterized by ventricular fibrillation and stop breathing, which is caused by the toxic effect of excess ions of CA2+.

This model (taking into account the severity of cardiac activity and the number of surviving animals) allows to evaluate the preventive effect of study drug on the cardiovascular system and the possibility of their inclusion in the I and IV classes. Were used for comparison procainamide hydrochloride at a dose of 20 mg/kg (M. R. Malinov, F. F. Battle, Century Malmud. Nervous mechanisms in ventricular arrhythmias induced by calcium chlorid in rats// Circ. Res. -1953, V. 1, pp. 554-559).

Hloridnaja model is based on intravenous solution of barium chloride at a dose of 4 mg/kg (N. Brasch. Protective effects of Na salicilate against digoxin - and BaCl2-induced arrhythmias in guinea-pigs// Eur. J. Pharmacol. -1984. -V. 2, pp. 297-301).

This model is used to detect violations of the permeability of cell membranes for ions K+and suppression induced by barium chloride arrhythmias allows you to enable investigational drugs in class III, belongs to amiodarone, used for comparison in the dose of 5 mg/kg

Stroganina model is based on intravenous what they abnormalities concentrations of potassium ions, sodium and calcium within cardiomyocytes, and poisons the Central nervous system, causing bradycardia, ekstrasystolichniy fibrillation, paroxysmal tachycardia and ventricular fibrillation that control usually leads to death.

Comparison with amiodarone at a dose of 5 mg/kg allows to rank investigational drugs to the III class.

Memberdeclaration model (UA Patent 43207 (A) based on intravenous fluids such inducer of lipid peroxidation, Svobodnoye-radical oxidation of proteins, as a mixture of ascorbic acid (50 mg/kg), iron sulfate (10 mg/kg) and calcium chloride (100 mg/kg), which is already on the 1st minute, causing conduction disorders and rhythm, ending ventricular fibrillation.

Suppression of arrhythmias in this model (compared to amiodarone at a dose of 10 mg/kg) indicates the prophylactic efficacy of investigational drugs.

All manipulations with animals were performed under eleminal-sodium (40 mg/kg) anesthesia. Electrocardiogram (hereinafter ECG) were recorded in II standard lead from limb. When the analysis took into account:
the number (n) of experimental animals with rhythm disorders,
features of cardiac arrhythmias (especially in terms of the combination "PF" fibrillat the i.i.d. data were statistically processed.

In tables icons (") before the numbers marked evidence of the effectiveness of the known anti-arrhythmic drugs which are recommended by the above method, the MOH of Ukraine as benchmarks for comparison with the efficiency of the tested drugs on the appropriate laboratory model of cardiac arrhythmia (AU).

Icons (*) after the numbers indicate statistical differences p<0.05 compared with control.

According to the results of experiments comprehensively assessed the antiarrhythmic activity of the drugs, the breadth and security of their actions (especially with long-term use and with regard to side effects) and determined isoeffective dose.

In the first series of experiments evaluated the antiarrhythmic activity separately applied gluconate potassium and magnesium. This continua, memberdeclaration and clerically model speakers were tested on adult outbred rats, stroganina model AC - on Guinea pigs and hloridnaja model AC - rabbits (see, respectively, tables 1 and 2).

A cursory viewing of tables 1 and 2 it may seem that separately applied gluconate potassium and magnesium, which are in italics indicate only about the suitability of these and antiarrhythmic drugs related classes.

However, it should be noted that even separately applied gluconate potassium and magnesium, first, have an antiarrhythmic effect on all tested models of speakers and, secondly, considerably less toxic than their known counterparts, and because in normal doses can cause side effects such as hyperkaliemia or hypermagnesemia.

To justify the second advantage on adult outbred rats, experiments were carried out on the evaluation of acute toxicity with the definition of LD50gluconate potassium and magnesium and mixtures thereof.

It was found that LD50pure potassium gluconate at least 2500 mg/kg intraperitoneal injection, and intravenous LD50depended on the time of the issuance of the dose and amounted to not less than 450 mg/kg for 30 s, 580 mg/kg for 1 min and 1100 mg/kg for 3 minutes In all cases exceeding the indicated doses of potassium gluconate death neverovich rats came from a cardiac arrest. Surviving rats for 2-3 h were sluggish. Then their condition did not differ from the control.

Even higher are measures of LD50for pure magnesium gluconate. So, intraperitoneal injection LD50there was a minimum of 2800 mg/kg intravenously also Zawislak, unlike hyperkaliemia, in cases of exceeding the indicated doses of magnesium gluconate death neverovich rats came from respiratory arrest on the background of severe bradycardia. Toxic manifestations intraperitoneal injection was evident after 3-4 minutes the Animals went in a pronounced sedative, sedentary condition, some fell asleep. Breathing was noisy, sparse and deep within 12-30 min developed apnea. Surviving animals within 3-5 h was in a locked state, acquired the initial activity gradually and only after 12-15 h did not differ from control.

LD50mixtures of potassium gluconate and magnesium, which have been tested in the following table 3 molar ratios of from 1/4 to 1/6 in the form of solutions for injection, in all cases intraperitoneal injection did not exceed 56 ml/kg 5% and 28 ml/kg of 10% solution almost regardless of whether he was prepared using sodium chloride or glucose.

In this way, the introduction of the toxicity depended mainly on the concentration of magnesium gluconate, since the toxic manifestations and LD50almost coincided with the data obtained by individual (without potassium gluconate) application.

When nutrire amounted to not less than 7 ml/kg for 30 s, 13 ml/kg for 1 min and 26 ml/kg for 3 minutes

Death neverovich animals (regardless of the method of introduction of the mixture of potassium gluconate and magnesium) occurred, as with the use of pure magnesium gluconate, from patients on the background of severe bradycardia.

Thus, potassium gluconate and magnesium and mixtures thereof belong to class IV toxicity and because in therapeutic or prophylactic dosage is practically safe.

Indeed, conventional pharmacological calculations using the above data show that the lower LD50of the magnesium ion in the composition gluconate can't be worse than 155 mg/kg, while the reference data it is known that:
LD50MgS47H2About equal 770,9 mg/kg, which corresponds LD5075 mg/kg of magnesium ions,
LD50magnesium ions in the composition MgCl26H2About equal with 83.6 mg/kg, and the best known LD50magnesium ions in the composition of the drug "Panangin, which, as stated above, is a mixture of asparaginates potassium and magnesium, does not exceed 140,8 mg/kg

More effective data recovery stable sinus rhythm on the speakers models were obtained by the use of combinations of potassium gluconate and magnesium with various molinist fibrillation regardless of pathogenesis. This is highlighted by the shift to the left and italicized data emphasize that as antiarrhythmic drugs are the most effective mixtures with molar ratios of potassium and magnesium from 1/4 to 1/6.

For some models, and the optimal mixture of potassium gluconate and magnesium ratio K/MD=1/5 was calculated antiarrhythmic index LD50/ED50. So, aconitine model as the value of the ED50which corresponds to short-term restoration of sinus rhythm and is defined by gluconate magnesium as the more toxic component did not exceed 50 mg/kg, that is 8.3% of LD50intravenous and insignificant values of 1.8% from LD50intraperitoneal injection of magnesium gluconate. Therefore, LD50/ED50lies in the interval from a minimum of 12.0 to a maximum of 55.6. The corresponding value LD50/ED50for intravenous administration of magnesium sulfate (literature data) does not exceed 30,8.

From the above it follows that:
a mixture of potassium gluconate and magnesium in the optimum molar ratio is superior to antiarrhythmic activity pangamat calcium and inorganic salts of potassium and magnesium in all studied models of cardiac activity;
the effectiveness of cupping pristupa the Arat on strofantino model speakers and close to their effectiveness on aconitine and cloridrato models AC;
the preventive effect of mixtures of potassium gluconate and magnesium membraneelectrode model speakers is much higher than the known anti-arrhythmic drugs, and close to their effect on chloralkali model speakers.

Below are typical examples of therapeutic and prophylactic antiarrhythmic activity of preparations according to the invention.

Example 1. In Guinea-pig weighing 520 g under eleminal-sodium anesthesia has registered the original ECG showing stable operation of the heart. Then in the femoral vein was introduced a solution of barium chloride at a dose of 4 mg/kg After 15 ECG registered politono ventricular ekstrasystolichniy arrhythmia type bigeminy.

Immediately in the same vein at the rate of 2 ml/kg was injected solution mixture of potassium gluconate and magnesium in doses of 20 mg/kg and 80 mg/kg, respectively. Immediately after injection was marked transition in sinus rhythm with a duration of 2.4 min, after which the arrhythmia resumed. Re-introduction of half the dose of this mixture led to the restoration of a stable sinus rhythm.

Example 2. The rats weighing 150 g under eleminal-sodium anesthesia has registered the original ECG showing stable operation of the heart. Then in the femoral vein of the races is positive slowed cardiac function.

After 2 min in the same vein introduced a solution of ascorbic acid in a dose of 50 mg/kg, and after 1 min - prepared ex tempore ferric sulfate solution at a dose of 10 mg/kg

30 with ECG changes in QRs complex in the form of giant teeth T, indicating damage to cardiomyocytes.

At this point he introduced a solution of calcium chloride at a dose of 100 mg/kg On ECG were isolated ventricular extrasystoles on the background of atrioventricular block. However, after only 40 with cardiac activity became more frequent, and after another 30 resumed normal sinus rhythm.

Through a 3.3 min were isolated ventricular extrasystoles, then the stability of sinus rhythm no longer violated (whereas in the control, i.e. without pre-injection of a mixture of potassium gluconate and magnesium, at the same time, such extrasystoles usually transformed into ventricular fibrillation).

More striking evidence of clinical antiarrhythmic activity were obtained with the introduction of the preparations according to the invention in the face of evidence.

Example 3. In Guinea-pig weight 560 g under eleminal-sodium anesthesia has registered the original ECG showing stable operation grey ventricular ekstrasystolichniy arrhythmia type bigeminy. Immediately in the same vein introduced a solution of amiodarone hydrochloride in a dose of 5 mg/kg anti-Arrhythmic effect on the ECG did not emerge. After 2 min in the same vein at the rate of 2 ml/kg solution mixture of potassium gluconate and magnesium in doses of 20 mg/kg and 80 mg/kg, respectively.

Already during the introduction was registered transition in stable sinus rhythm.

Most of prophylactic antiarrhythmic effect was achieved at a joint simultaneous administration of drugs according to the invention and amiodarone.

Example 4. The rats weighing 160 g under eleminal-sodium anesthesia registered normal ECG. Then in the femoral vein was introduced a solution of amiodarone hydrochloride in a dose of 5 mg/kg and 3 ml/kg of a solution mixture of potassium gluconate and magnesium in doses of 30 mg/kg and 150 mg/kg Marked slowing of the heart.

After 1 min in the same vein introduced a solution of calcium chloride in a shock dose of 220 mg/kg ECG appeared only a single ventricular extrasystoles on the background of atrioventricular block, and after 40 with cardiac activity became more frequent, and after another 30 resumed normal sinus rhythm.

And, finally, had verified the effectiveness of prevention of arrhythmias with the use of the preparations according to izobretennom registered normal ECG. Then in the femoral vein has introduced a solution strofantina dose of 0.25 mg/kg 3.2 min Later on the electrocardiogram was registered politono ventricular ekstrasystolichniy arrhythmia type bigeminy converts to ventricular tachycardia.

Immediately in the same vein introduced a solution mixture of potassium gluconate and magnesium and inosine in doses of 30 mg/kg, 150 mg/kg and 10 mg/kg, respectively. After 45 were recorded episodes of sinus rhythm. In the same vein re-entered the half of the initial dose of this mixture. After 30 seconds, after the introduction of registered transition in sinus rhythm, periodically successive idioventricular rhythm. Gradually, however, episodes of ventricular rhythm is shortened, and after 3 min from the time of the last injection recovered stable sinus rhythm.

(3) Recommendations for use of preparations according to the invention is based on the experimentally established facts:
the practical absence of cholinergic activity gluconate potassium and magnesium,
their very low toxicity in the high single doses and
the ability to increase the antiarrhythmic activity of other anti-arrhythmic drugs with reduced risk of arrhythmogenic effects (osobennosti shown in myocardial infarction for the prevention and treatment of cardiac arrhythmias.

A mixture of potassium gluconate and magnesium appropriate to apply:
first, as a means of edema (preferably by intravenous infusion for 3-5 minutes or drip):
attacks ectopic arrhythmia due to an overdose of cardiac glycosides and
paroxysmal atrial fibrillation, ventricular arrythmia and paroxysmal ventricular tachycardia type "pirouette" (even in cases circulation arrhythmogenic pulses on additional ways) and
secondly, as a means of enhancing efficiency and reduce the risk of arrhythmogenic actions of other antiarrhythmic drugs (especially prolong the QT interval).

Thus, a mixture of potassium gluconate and magnesium, it is expedient to appoint conjunction with cardiac glycosides and/or diuretics group of saluretics for a complete and safe treatment of heart failure.

Similar mixtures are shown as means comprehensive treatment of disorders of electrolyte metabolism to adjust the level of potassium and magnesium.

Of the dosage forms preferred injectable solutions prepared in isotonic solutions of glucose or sodium chloride, and tablets or capsules (which are preferred for the prevention of ariticle and magnesium, amiodarone and inosine and standard dosage forms in the form of solutions for injection and tablets or capsules with well-known pharmaceutically acceptable excipients.

The practical application of such dosage forms will reduce the risk of increased arrhythmia in relieving her attacks and improve the effectiveness of long-term treatment and prevention of arrhythmias arbitrary types.

Indeed, experimental results show that the potassium gluconate and magnesium have a broad spectrum antiarrhythmic activity and have therapeutic and prophylactic antiarrhythmic action on almost all used experimental models of cardiac arrhythmias. This mild asthma arrhythmia some preparations according to the invention is achieved almost from the moment of their introduction, while the known antiarrhythmic drugs (except for significantly less efficient solution of magnesium sulfate) give effect later 1,3-1,5 min after injection.


Claims

1. Antiarrhythmic drug on the basis of gluconic acid, characterized in that it contains at least one gluconate in which the cation select the OIC is potassium gluconate.

3. Antiarrhythmic drug under item 1, characterized in that it is a basis gluconate magnesium.

4. Antiarrhythmic drug under item 1, characterized in that the base is a mixture of potassium gluconate and magnesium.

5. Antiarrhythmic drug under item 4, characterized in that the mixture of one mol of potassium gluconate contains not less than 1.0 mol of magnesium gluconate.

6. Antiarrhythmic drug under item 5, characterized in that the mixture of one mol of potassium gluconate contains from 4.0 to 6.0 mol of magnesium gluconate.

7. Antiarrhythmic drug under item 4, characterized in that the mixture additionally contains at least 1.0 mol of amiodarone on one mol of potassium gluconate.

8. Antiarrhythmic drug under item 4, characterized in that the mixture additionally contains at least 1.0 mol of inosine on one mol of potassium gluconate.

 

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The invention relates to inhibitors of potassium channel, in particular a derivative of tetrahydronaphthalene formula (I) or their pharmaceutically acceptable salts, stereoisomers, crystalline or amorphous forms

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where t is 1; a and b each represent H; R1represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; provided that when R1represents optionally substituted aryl, R1is not dialkoxybenzene; Y2represents (CH2)qwhere q is 0; X2is SO2; R3represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of atom N; R2represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; Y1represents (CH2)pwhere p is 1; NS=SN or ethinyl; X1is C=O or (CH2)nwhere n is 0, 1 or 2; R4represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of carbon atoms and contains nitrogen as heteroatom

The invention relates to compounds of formula (I)

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where R(2) and R(3) independently from each other denote hydrogen, Cl, Br, J, (C1-C8)-alkyl, (C3-C8-cycloalkyl or(5), R(5) - (C1-C8)-alkyl, and one of the two substituents R(2) and R(3) is always hydrogen, however, both Deputy R(2) and R(3) at the same time are not hydrogens, as well as their pharmaceutically acceptable salts

The invention relates to new orthotamine benzoylpyridine formula (1), where R(1) - H, alkyl with 1-8 C-atoms, Xand-(CH2)b-(CF2)c-CF3where a, b, C = 0; one of the two substituents R(2) and R(3) means-O-CO-R(27), respectively, and the other substituents R(2) and R(3) is R(1) where R(27) - alkyl with 1-8 C-atoms; R(4) is hydrogen, alkoxy with 1-4 C-atoms, F, Cl, Br, I; R(5) is hydrogen, and their pharmaceutically acceptable salts
The invention relates to medicine, namely to wound healing tools, and can be used for treatment of burns
The invention relates to medicine and concerns balneological resources used in physiotherapy, balneology and life
The invention relates to cosmetic products and relates to tools used in physiotherapy, balneology and life

The invention relates to medicine, in particular to the pharmaceutical industry for the production of drugs therapeutic and prophylactic purposes, and can be used as an aid in facilitating the regulation of the respiratory system

The invention relates to medicine, in particular to the pharmaceutical industry for the production of drugs therapeutic and prophylactic purposes, and can be used for the prevention and adjuvant therapy of hypotension and vascular dystonia
The invention relates to medicine, namely to create medicines for removal of benign skin tumors (warts, papillomas, condylomas)

The invention relates to medicine, namely to methods for healing the human body
The invention relates to medicine, namely to ophthalmology, and for the treatment of diabetic retinopathy
The invention relates to medicine, in particular to surgery, and can be used for the treatment of purulent wounds
The invention relates to medicine and can be used for the manufacture of therapeutic and cosmetic products in the form of ointments, creams, emulsions, lotions, gels, used as decongestants tools

The invention relates to medicine, specifically to vascular surgery, and relates to methods of conservative treatment of occlusive arterial disease of the limbs
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