CH661208A5 - MEDICINAL PRODUCT WITH ANTI-ARRHYTHMIC EFFECT. - Google Patents

Description

The present invention relates to a pharmaceutical preparation having an antiarrhythmic effect, which is used in various diseases accompanied by cardiac arrhythmias, such as e.g. ischemic heart disease, various types of cardiomyopathy, etc. can be used.

There are various preparations with an antiarrhythmic effect, such as Quinidine, novocainamide (p-aminoben-zoic acid-ß-diethylaminoethylamide hydrogen chloride), obsidane (propanolol), isoptin, moricizine (ethmozin) and others known. These preparations are widely used in medical practice.

However, these preparations have a number of disadvantages, they have an insufficiently high activity, a pronounced hypotensive effect and a short duration of action.

The invention has for its object to provide a new pharmaceutical preparation which has a higher antiarrhythmic activity, a greater duration and breadth of the pharmacological effect and does not lower the arterial pressure.

The pharmaceutical preparation according to the invention with antiarrhythmic activity is new and has not been described in the literature.

The pharmaceutical preparation according to the invention having an antiarrhythmic effect is characterized in that, in addition to a pharmaceutically acceptable carrier as active ingredient, the hydrobromic acid salt of the alkaloid lappakonitin of the formula

H CO

OCH

OH

.V

O

j. HBr

C = 0

NHCOCH

contains.

The preparation according to the invention is preferably administered as an injection or orally in the form of tablets.

Tablets usually contain 0.05 g of the active ingredient per tablet. The tablets preferably contain sucrose and starch as pharmaceutically acceptable carriers.

The preparation according to the invention in the form of injections usually contains 0.5% by weight of active ingredient in the solution, and distilled water is preferably used as the pharmaceutically acceptable diluent. In terms of antiarrhythmic activity, the preparation according to the invention outperforms the particularly widely used antiarrhythmic agents quinidine and novocainamide.

The distinguishing feature of this preparation is its long duration of action, which exceeds the duration of action of quinidine and novocaine amide by more than 10 times. The antiarrhythmic effect of the preparation according to the invention is not accompanied by a reduction in the system artery pressure and by no negative inotropic effect on the heart tissue. The stated properties of the preparation according to the invention are advantageously coupled with its moderate coronary dilation, spasmolytic, local anesthetic, anti-inflammatory and sedative action.

The medicament according to the invention can be used in the following cases:

- Treatment of almost all rhythm disorders of ventricular and supraventricular origin, caused by increased ectopic excitability;

- various types of ventricular extrasystoles in myocardial infarction;

- continuous oral treatment for ventricular and supraventricular extrasystoles and prophylactic relapse prevention treatment for paroxysmal tachycardia and prevention of cardiac arrhythmias;

- in operations on the heart and large vessels;

- after the electro pulse treatment;

- when the atria flicker and flutter, accompanied by ventricular tachycardia;

- with sinus tachycardia and rhythm disturbances with neurosis with hypersympathicotonia, mental and physical tensions, hyperthyroidism;

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- cardiac arrhythmias during cardiogenic shock;

- as a prophylaxis of cardiac fibrillation during myocardial infarction.

The pharmaceutical preparation according to the invention was tested in an experiment on animals and in a clinic on humans.

The antiarrhythmic activity of the preparation was assessed in acute and chronic experiments on rats, rabbits, cats and dogs. Various experimental models of arrhythmia have been used.

The atrioventricular type arrhythmia caused by aconitine is one of the reliable models for predicting the effectiveness of the anti-arrhythmic effect of the new drug preparation in the clinic. The experiments were carried out on anesthetized and non-anesthetized animals. The preparation was administered orally, intramuscularly, intraperitoneally and intravenously 5-15 minutes before or 3-5 minutes after the administration of aconitin.

The duration of the antiarrhythmic effect of the preparation was investigated in rats by injecting aconitin into the vein at 1, 2, 4, 6, 24 and 48 hours after oral administration of the preparation.

It was found that the antiarrhythmic effect of the preparation according to the invention appears from a dose of 0.03 mg / kg. In doses of 0.2 to 0.5 mg / kg, the preparation according to the invention prevents the development of aconitine arrhythmia in 100% of the rats. Re-administration of the same dose of aconitine to the same animals after 5 to 10 days without prior administration of the preparation according to the invention led to the appearance of the arrhythmia in 100% of the rats. Under analogous test conditions, prior intravenous administration of novocainamide at a dose of 60 mg / kg had an antiarrhythmic effect in 50% of the animals.

In the analogous case, the antiarrhythmic effect was observed in 50% of the animals when quinidine was administered at a dose of 20 mg / kg.

The information received regarding the influence of novocaine amide and quinidine on aconitine arrhythmia 2 is consistent with the literature data. Lidocaine and trimecain in doses of 5 to 10 mg / kg prevent the development of aconitine arrhythmia for 3 to 5 minutes and, in doses of 20 mg / kg and above, cause the death of part of the anesthetized rats before the administration of the aconitine. Prophylactic administration of obsidan to rats at a dose of 5 mg / kg delayed the occurrence of aconitine arrhythmia by 5 to 8 minutes in all experimental rats, then an arrhythmia developed in 60% of the animals.

. Doses of 0.1 to 2.5 mg / kg of isoptin could not prevent the development of aconitine arrhythmia.

The preparation according to the invention thus significantly exceeds all antiarrhythmic comparable preparations in terms of its prophylactic effect on the development of aconitine arrhythmia. Its antiarrhythmic index (LDjo / ED5o) is 118.0. This is followed by quinidine and novocainamide, whose antiarrhythmic index is 2.75 and 2.3, respectively.

The antiarrhythmic activity of the pharmaceutical preparation according to the invention when it was administered in developing aconitine arrhythmia (therapeutic effect) was investigated in 110 anesthetized rats. The preparation was administered intravenously 3 to 6 minutes after the arrhythmia developed. It was found that the preparation according to the invention was administered at a dose of 0.1 mg / kg.

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complete restoration of normal sinus rhythm in 50% of the animals 30 to 35 minutes after its administration (in the control experiments the aconitine arrhythmia lasts 120 minutes). Doses of the preparation according to the invention of 0.3 to 0.5 mg / kg lead to complete elimination of the arrhythmia and restoration of the correct sinus rhythm in all animals after 1 to 2 minutes. Under analogous conditions, the novocainamide at a dose of 20 mg / kg restored the normal sinus rhythm in three rats on average for 10 minutes, after which a stable arrhythmia returned. At a dose of 40 mg / kg, the antiarrhythmic effect of novocaine amide was found in 83.3% of the animals. In 50% of the rats, however, the effect lasted for the first 20 minutes, after which a stable arrhythmia returned. The quinidine showed doses of 2.5; 5; 10; 20 mg / kg with developing aconitine arrhythmia no antiarrhythmic activity. The use of lidocaine (5 to 10 mg / kg) under analogous conditions showed a brief (0.5 to 3 minutes), the arrhythmia suppressing effect, after which arrhythmia developed again. The use of trimecain, obsidan and isoptin under analogous conditions also had no great effect. The antiarrhythmic index of the preparation according to the invention LD / ED50 = 59 in the case of developing aconitine arrhythmia significantly exceeded that of the novocainamide following in activity, whose antiarrhythmic index is 6.9. The examination of the antiarrhythmic effect of the preparation according to the invention on non-anesthetized rats and dogs showed that this completely prevents the development of aconitine arrhythmia in 100% of the animals when administered intravenously in from 0.2 to 0.3 mg / kg. In doses of 0.5 and 1 mg / kg, the pharmaceutical preparation according to the invention completely prevents the fatal heart fibrillation which is induced in rats by aconitine. Experiments in dogs and in intact rats have shown that the oral administration of the preparation in doses of 1 to 2 mg / kg completely prevents the development of aconitine arrhythmia in 100% of the animals. Thus, the preparation according to the invention based on the aconitin model of the arrhythmia significantly exceeds the known preparations quinidine, novocainamide, lidocaine, trimecain, isoptin and obsidan in terms of activity, duration (up to 24 hours) and breadth of the antiarrhythmic effect.

The antiarrhythmic activity of the pharmaceutical preparation according to the invention was examined on the model of cardiac arrhythmia induced by barium chloride on 56 anesthetized rats and 16 intact rabbits. The preparation according to the invention injected 10 minutes before the administration of the barium chloride in a dose of 0.1 mg / kg prevented the development of the arrhythmia in 86.6% of the animals. In analogous experiments, the quinine in doses of 10 mg / kg corresponded approximately to the preparation according to the invention in a dose of 0.1 mg / kg with regard to the antiarrhythmic effect. Novocainamide showed the weakest antiarrhythmic activity on the model of cardiac arrhythmia mentioned, which corresponds to the literature.

The influence of the pharmaceutical preparation according to the invention on the cardiac arrhythmia caused by the constriction of the descending branch of the left coronary artery according to the Harris method was investigated in experiments on dogs. The preparation according to the invention was administered intravenously on the first and second day after the operation. Earlier, changes in the phonograph of the electrocardiogram (ECG) were recorded in the dogs before each attempt. The antiarrhythmic effect of the preparation according to the invention in a dose of 0.5

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661208

mg / kg was observed in 86% of the animals. Complete suppression of ventricular extrasystole was found in 100% of the animals at a dose of 1 mg / kg. Complete suppression of ectopic contractions was observed in 3 to 3.5 hours in 40%. Then arrhythmia occurred, the intensity of which could not reach the output phone within 7 hours.

In 60% the duration of the 100% antiarrhythmic effect was significantly longer (over 5 hours) with subsequent gradual recovery of the arrhythmia. In addition to reducing and completely suppressing the arrhythmia, a decrease in the frequency of heart contractions was also found in all experiments. The antiarrhythmic effect occurred 5 to 15 minutes after the administration and was directly dependent on the dose administered. Under analogous test conditions, novocainamide showed an antiarrhythmic effect in doses of 40 to 50 mg / kg. The effect was rapid, but lasted 4 to 7 minutes, after which ventricular extrasystole and tachycardia reappeared. At a dose of 70 to 80 mg / kg, the effect was retained within 30 to 60 minutes.

Quinidine at a dose of 5 to 10 mg / kg had a weak influence on cardiac arrhythmia, caused by the constriction of the descending branch of the left coronary artery in dogs, which is in accordance with the literature.

Thus, the pharmaceutical preparation according to the invention was about 70 times more active than novocainamide in this model of cardiac arrhythmia, significantly exceeding this in the duration of the effect, but is inferior to it in terms of the speed at which the antiarrhythmic effect occurs.

The preparation according to the invention in doses of 0.25 and 0.5 mg / kg (intravenously) completely prevents the occurrence of the arrhythmia caused by the electrical generation of the auricular appendage of the right atrium and the apex of the left ventricle in all animals (7 dogs and 10 cats).

The antiarrhythmic effect of the preparation according to the invention develops 3 to 7 minutes after the administration and remains within 2 to 3 hours. The arterial pressure and the amplitude of the heart contractions remain unchanged. Under analogous test conditions, novocainamide and quinidine in a dose of 10 mg / kg show an antiarrhythmic effect within 2 to 5 minutes in 40% and 30% of the animals, respectively. In a dose of 20 to 30 mg / kg, the effect achieved by using both preparations lasted 20 to 25 minutes. In all doses tested, novocainamide and quinidine reduced arterial pressure by 20 to 70 torr and bradycardia. The antiarrhythmic effect of novocaine amide occurred 1 to 1.5 minutes and that of quinidine 2 to 3 minutes after intravenous administration. Consequently, the preparation according to the invention outperforms the quinidine and novocainamide by 40 times in this model of cardiac arrhythmia in terms of activity. Its antiarrhythmic effect develops more slowly, but lasts significantly longer and is not accompanied by a decrease in arterial pressure in the animals.

The pharmaceutical preparation according to the invention completely reduces or suppresses the arrhythmia caused by adrenaline in dogs in which the descending branch of the left coronary artery was previously constricted.

The maximum effect develops after 5 to 10 minutes and lasts more than 2 hours.

In the above doses, the preparation has no influence on the level of arterial pressure and the level of adrenaline-induced increase in arterial pressure (hypotension).

To determine the influence of the preparation according to the invention on the arterial pressure and breathing, tests were carried out on anesthetized cats and dogs. It was found that the intravenous administration of the preparation according to the invention in doses of 0.05; 0.1; 0.5; 1 mg / kg (that is, in doses that cause a pronounced antiarrhythmic effect, has no effect on arterial pressure and breathing.

Two test series were carried out to determine the negative inotropic effect on the heart tissue:

1) Influence of the preparation according to the invention on the amplitude of the heart contractions of the frog heart isolated according to Straube;

2) Influence of the preparation according to the invention on the strength of the heart contractions in anesthetized (sodium ether, 50 to 60 mg / kg intraperitoneally) rats and guinea pigs.

The results of the first series of experiments showed that the preparation according to the invention in a concentration of IO-6 to 5.10-5 g / ml has no negative inotropic effect. In the negative inotropic effect, quinidine significantly exceeds the preparation according to the invention. Quinidine in a concentration of IO-4 to 3.10-4 g / ml causes arrhythmia in addition to the strong suppression of the amplitude of the heart contractions. In the second series of experiments it was shown that the intravenous administration of the preparation according to the invention in doses of 0.1; 0.5; 1; 2 mg / kg, i.e. in doses that cause a 100% antiarrhythmic effect, does not affect the amplitude of the heart contractions. Thus, in contrast to quinidine, the preparation according to the invention has no negative inotropic effect on the heart.

In order to investigate the character of the effect of the preparation according to the invention on the cardiac conduction system, the ECG changes were examined which arise under the influence of this preparation in anesthetized rats, cats and intact rabbits and dogs. When administered intravenously in doses of 0.05 to 0.25 mg / kg, the preparation had no significant influence on the ECG in rats. At a dose of 0.5 mg / kg, it slows down the atrioventricular conduction and slows down the rhythm somewhat. Doses of 1 to 2 mg / kg increase the intervals PQ, QRS, QT, insignificant R — R, the S wave increases and the amplitude of the T wave increases. Intravenous administration in doses of 4 to 6 mg / kg (doses that are close to lethal and lethal doses) leads to increasing suppression of conduction by the cardiac conduction system. Quinidine and novocainamide also cause severe cardiac arrhythmias in large doses. The EKG changes caused by the pharmaceutical preparation according to the invention show that the preparation lowers the conduction of the myocardium and to a lesser extent the automatism of the atrial node. The effect of the preparation lasts for a long time. Sodium hydrogen carbonate reduces the suppressive effect of the preparation on the line.

The influence of the preparation according to the invention on the coronary circulation was investigated in acute experiments on cats using the method of registering the volume velocity of the coronary circulation. The intravenous administration of the preparation in a dose of 0.1 mg / kg has no effect on the coronary circulation, whereas that in a dose of 0.5 mg / kg in 40% of the animals

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Coronary circulation increased by 15 to 30%. The administration of the preparation in a dose of 1 mg / kg leads to a prolonged increase in the speed of the coronary circulation by 30 to 80%. Thus, in addition to the pronounced antiarrhythmic property, the preparation according to the invention has a moderate coronary dilation effect.

Examination of the influence of the preparation on the ion currents through the somatic membrane of the neurons showed that it selectively interacts with the calcium and potassium channels of the membrane of the molluscs, thereby suppressing the currents flowing in these channels.

The local anesthetic effect of the preparation was examined in 14 intact rabbits. It has been shown to have a pronounced anesthetic effect which is the same as the anesthetic activity of dicain, but exceeds the dicain more than 6 times in terms of the duration of the effect. In the depth of anesthesia, the preparation according to the invention is inferior to dicain. The results of the experiments to determine the ability of the preparation according to the invention to effect infiltration anesthesia showed that 10 to 15 minutes after the intracutaneous administration of the 0.01 to 0.05% and 0.1% solution of the preparation Rabbit anesthesia occurs, which is characterized by an increase in the threshold of pain excitation; the duration of the effect is 20 to 48 hours. Under the same test conditions, the local anesthetic effect of a 0.5% solution of novocaine lasts on average 90 minutes. The preparation according to the invention thus has a pronounced and long-lasting local anesthetic effect.

The medicament according to the invention has a weak central sedative effect, does not significantly influence the central adrenergic and quinolinergic processes and shows a weak serotoninonegative effect.

In doses of 1 to 5 mg / kg, the preparation shows a pronounced anti-inflammatory effect.

The resorptive effect and toxicity of the preparation according to the invention was investigated in mice, rats, rabbits and dogs. In intravenous administration of the preparation according to the invention in doses of 0.01 to 1 mg / kg, intraperitoneal administration in doses of 1 to 5 mg / kg and peroral administration in doses of 5 to 20 mg / kg to various types of animals no significant changes in the general condition of the animals were found. In higher doses, adynamy, inhibition, weakening of muscle tone, decrease in breathing frequency, increase in depth of breathing and decrease in body temperature occur in mice and rats 5 minutes after the administration of the preparation. In sublethal and lethal doses, the preparation causes a more pronounced and intense manifestation of the symptoms described above, which are accompanied by salivation, diarrhea and severe breathing disorders.

When administered intravenously in doses of 5 to 6 mg / kg, the preparation according to the invention leads to the death of the dogs and is fatal to rabbits in doses of 3 to 4 mg / kg.

In doses of 0.5 to 1 mg / kg, it has no effect on the diuresis of the rats; Protein and blood (sample with sulphanyl acid and benzidine sample) are not detected in the urine.

The experiments carried out with 12 guinea pigs and 6 rabbits show that the medicinal product according to the invention has no allergy effect.

The preparation according to the invention does not exercise any doses of 1 mg / kg with a single and continuous administration

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significant influence on the blood content of the rats of sugar, protein and ferment (transaminase, lactate dehydrogenase).

Based on the comparative histological examination of the internal organs of laboratory animals (dogs, rabbits, rats), to which different doses of the preparation according to the invention were administered within 6 months, it can be concluded that the oral administration of the preparation according to the invention to dogs in doses of 1 to 5 mg / kg, intravenous administration to rabbits in doses of 0.1 and 0.5 mg / kg and oral administration to rats in a dose of 1 mg / kg caused no destructive changes in the internal organs and tissues. Continuous administration of the preparation in a dose of 10 mg / kg causes structural changes in the internal organs.

In experiments on 317 pregnant rats, of which 2377 pups were obtained, it was shown that the preparation according to the invention is not a latently teratogenic substance.

On the basis of the macro and microscopic examinations of the internal organs of the control and experimental animals, it was found that the subcutaneous and oral administration of the preparation in doses of 0.5 to 2 mg / kg did not result in any new growth within 6 months when observing the animals within 2 years, as well as no cell and tissue atypy and no anaplasia. Consequently, the pharmaceutical preparation according to the invention has no carcinogenic properties.

In acute experiments on dogs with registration of arterial pressure, breathing and the bioelectric activity of the heart, the effect of sodium hydrogen carbonate on the cardiotoxic effect of the preparation according to the invention was investigated.

It was found that the dropwise intravenous infusion of sodium bicarbonate in the form of a 4% solution in an amount of 100 to 200 ml was the strongly pronounced electrocardiographic changes caused by administration of toxic doses of the preparation according to the invention, 15 to 30 minutes after the start of the infusion compensates. The reduction in arterial pressure observed when the drug was overdosed is compensated for in the infusion of sodium bicarbonate solution in parallel with the compensation of the ECG values. The joint use of sodium bicarbonate infusion together with adrenaline resulted in a faster compensation of the hemodynamics and the ECG changes in the animals.

The clinical examination of the preparation according to the invention was carried out on 200 patients suffering from various diseases which were accompanied by various cardiac arrhythmias (ischemic heart disease, various types of cardiomyopathy, etc.). The preparation was administered intravenously in an amount of 1 or 2 ampoules (each ampoule contains 2 ml of a 0.5% solution of the active ingredient) and orally in an amount of 50 mg (2 to 3 tablets per day for the first two days and 1 up to 2 tablets on the following days). The ECG values, the arterial pressure, the pulse rate and various parameters of the hemodynamics were registered.

The examinations were carried out both in acute cases and during course treatment. The preparation was found to have a pronounced antiarrhythmic effect on patients with a stable form of various types of ventricular and supraventricular extrasystole. No side effects (hypotension, heart rate, pulse rate, respiratory rate) were observed. The preparation is effective in course treatment in the form of tablets.

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The preparation according to the invention can be administered in various dosage forms, preferably in the form of injection solutions and tablets.

The dosage forms can be prepared by customary methods.

The active substance of the preparation according to the invention, the alkaloid lappakonitin hydrobromide, can be obtained as follows by a known method:

The unearthly part and the root (tubers) of the Aconitum leucostomum plant are crushed. The crushed air-dry raw material is wetted with a 3% solution of sodium carbonate and poured over after 1 hour with chloroform. After 12 hours, the chloroform is poured off and the plant is poured with a fresh portion of chloroform. A total of 8 castings are obtained, which are combined and evaporated to a small volume under vacuum. The alkaloids are separated from the concentrated chloroform extract with 2% sulfuric acid. The combined acidic extracts are washed with chloroform, alkalized with soda and the alkaloids are extracted with chloroform. The chloroform extract is evaporated and technical lappakonitin is obtained from the residue by treatment with acetone, which is recrystallized from methanol. The methanolic solutions of lappaco-nitin and hydrobromic acid are mixed. The precipitated lap-pakonitin hydrogen bromide is recrystallized from methanol. White or yellowish-white crystals with a bitter taste are obtained which are soluble in water, alcohol and more soluble in methanol. The melting point is: 216-220 ° C; [a] 24D = + 27 (alcohol). C3208N2-HBr. Molecular weight = 664.9.

The preparation according to the invention can be administered orally, intramuscularly. or administered intravenously. The preparation is preferably administered in the form of 0.05 g tablets 2 to 3 times a day or in the form of injections in an amount of 1 ml of the 0.5% solution 2 to 3 times a day. The preparation is conveniently taken orally before meals. The duration of the treatment course is generally 10 days.

Side effects: In some cases the feeling of weakness or dizziness can be observed, but this disappears after 10 to 15 minutes.

No contraindications to the use of the preparation were found.

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Claims (5)

661 208 PATENT CLAIMS 1. Medicinal product with an antiarrhythmic effect, characterized in that, in addition to a pharmaceutically acceptable carrier as active ingredient, the hydrobromic acid salt of the alkaloid lappakonitin of the formula H-CO - OCH OH O . HBr C = 0 NHCOCH contains. 2. Medicament preparation according to claim 1, characterized in that it is in the form of tablets and that 0.05 of the active ingredient of the formula I is contained per tablet. 3. Medicament preparation according to claim 1 and 2, characterized in that the pharmaceutically acceptable carrier is sucrose and starch. 4. Medicament preparation according to claim 1, characterized in that it is in the form of an injection solution which contains 0.5% by weight of the active ingredient of the formula I. 5. Medicament preparation according to claim 1 and 4, characterized in that the pharmaceutically acceptable carrier is a solvent, namely distilled water.