WO2004024135A1

WO2004024135A1 - Antiarrythmic agent

Info

Publication number: WO2004024135A1
Application number: PCT/UA2003/000001
Authority: WO
Inventors: Victor Pavlovich Kutnyak; Taras Nikolayevich Lipnitsky; Vadim Alekseyevich Kozlovsky
Original assignee: Victor Pavlovich Kutnyak; Taras Nikolayevich Lipnitsky; Vadim Alekseyevich Kozlovsky
Priority date: 2002-09-16
Filing date: 2003-01-04
Publication date: 2004-03-25
Also published as: AU2003228204A1; UA72317C2

Abstract

Antiarrythmic agent based on gluconic acid salts, which (with the purpose of significant acceleration in arresting paroxysms of arrythmia of various etiology and reduction in risk of aggravations in their prophylactics and therapy) includes at least one salt comprising a cation selected from the group consisting of potassium and magnesium.

Description

ANTIARRHYTHMIC AGENT Technical Field This invention relates to antiarrhythmic agents based on gluconic acid salts, and more particularly on potassium gluconate and/or magnesium gluconate. Background Art

It is generally known that paroxysmal disturbances in cardiac rhythm are one of the most important reasons for sudden death of humans. The risk of fatal outcome is especially great in case of ventricular polytopic, group or early extrasystolic arrhythmia in patients with myocardial infarction in the acute period and in persons with postmyocardial-infarction and atherosclerotic cardiosclerosis or with expressed cardiac insufficiency of arbitrary etiology (Bobrov V.A., Kupnovitskaya I.G.: "Refrakterniye Takhiaritmii" [Refractory Tachyarrhythmias]. Kiev, Zdorovya Publishing House, 1994).

Various factors or their combinations may condition cell-ionic mechanism of arrhythmia formation (Sulimov V.A.: "Sitsilianskiy Gambit': Patofiziologicheskiy Podkhod k Medikamentoznoy Antiaritmicheskoy Terapii" // Terapevticheskiy Arkhiv ['Sicilian

Gambit': Pathophysiological Approach to Pharmaceutical Antiarrhythmic Therapy II

Therapeutic Archive]. 1999, No.8, pp. 67-74.).

Actually, concentration of Na⁺ and Ca²⁺ ions inside of myocardium cells increases before the beginning of arrhythmia paroxysms while concentration of K⁺ and Mg²⁺ ions decreases with changes in electrophysiologic properties of cardiac myocytes.

However, known antiarrhythmic agents, as a rule, are narrowly oriented to the block of either ionic canals for Na⁺ (Class /) or receptor-mediated canals for Ca²⁺ (Class

//) or for K⁺ (Class ///). Calcium proper antagonist agents are reckoned among Class IV, and bradycardic agents affecting the activity of only sinoatrial node are reckoned among Class V.

Therefore, the success of arresting the paroxysms and the following therapy and prophylactics of arrhythmia depends directly on the correct choice of antiarrhythmic agents useful for certain patients in certain conditions made by the physician.

However, it is only a long examination that makes possible to determine the condition of central nervous system, hormonal and electrolytic status, acid-alkali balance and the level of the patient's body metabolism, to appraise anatomico- functional condition of cardiac myocytes and by way of complicated electrophysiological study to determine the type of ionic mechanism of paroxysmal disturbances in cardiac rhythm for reliable substantiation of the choice of antiarrhythmic agent or a set of such agents.

Unfortunately, there is usually a lack of time for that, and physicians depend on their own experience only, which causes unavoidable and frequently fatal mistakes.

Thus, efficiency of pharmaceutical arrest of paroxysmal arrhythmia does not exceed 60%-70%; the prophylactics of repeated episodes of arrhythmia are effective only in 20%-30% of patients; and arrhythmia is aggravated or transformed in other, frequently fatal, forms in 12%-15% of patients (op cit Bobrov V.A., Kupnovitskaya I.G.: "Refrakterniye Takhiaritmii" [Refractory Tachyarrhythmias]). Similar though not so complete data have been obtained in the result of vast randomised study CAST and CAST II (1. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators //New Engl. J. Med.- 1989, V.321 , pp.406-412; 2. The Cardiac Arrhythmia Suppression Trial I (CAST-II) Investigators //Ibid.- 1992, V.327, pp.227-233). It was found out that the risk of sudden death increased 2 and 3,64 times in those patients who had received Class / antiarrhythmic agents Moricizine (Moricizine Hydrochloride) and Flekainide (Flekainide Acetate), respectively, as compared to the patients of the control group not given said agents.

Said unfortunate results are conditioned by the following: not a single separately taken known antiarrhythmic agent is able to normalise ionic homeostasis for all types of ions, the surplus or deficiency of which is able to cause arrhythmia; each separately taken known antiarrhythmic agent gives side effects thus having a lot of contraindications; each separately taken known blocking agent for ionic canals of any class is able to aggravate the ionic misbalance in cardiac myocytes in certain conditions and cause proarrhythmic action whose expression varies in the above range of 12-15% despite of their designated use,

The aforesaid can be easily confirmed by reference data open to general use (see e.g. Mashkovskiy M.D.: "Lekarstvenniye Sredstva". Posobiye dlya Vrachei [Drugs. Manual for Physicians] 14^th Revised Edition in 2 volumes. V.1. Moscow. OOO "Izdatelstvo Novaya Volna", 2001 , pp.357-388).

Particularly, la Subclass drug Procainamide Hydrochloride can cause negative effects, such as hypotension, collapse, intracardiac block and asystolia, overexcitation, insomnia, headache and nausea (to vomiting) and, in case of long-term administration, lupoid syndrome. This drug is contraindicated for patients with even slightly expressed cardiac insufficiency for long-term administration.

Disopyramide (Disopyramide Hydrochloride, Rhytmilenum), another widely used agent of the same subclass, possesses anticholinergic effect and causes xerostomia, disturbance of accommodation and dysuria. It evidently inhibits myocardium contractility, and thus it is contraindicated for patients with cardiac insufficiency.

Ethmosine, still another agent of this subclass, is able to cause dizziness and even mental disorder in case of simultaneous administration with (mono)amine oxidase inhibitors. It acts a short time, so patients have to take it up to six times a day. ypo ens on, con uc on sor er an arr y mogen c e ec s are no n requen agains this background.

Lidocaine Hydrochloride (Xylocainum), the most widespread lb Subclass drug, is effective only in cases of arrhythmia conditioned by myocardial ischemia; it has low bio- accessibility when administered, and parenteral therapy can sharply reduce (up to collapse) arterial pressure and cause somnolence, anxiety, murmur in the ears, tongue numbness, dysopia, dizziness and tremor.

Mexyletine Hydrochloride, a drug of the same subclass, is well absorbed after administration but it causes the same side effects as lidocaine. It is contraindicated in cases of syndrome of weakness of sinoatrial node, renal and hepatic insufficiency.

Ic subclass drug Etacisine adversely affects the central nervous system causing dizziness and/or numbness of different parts of the body, cardiovascular system causing hypotension, restraining the heart conductive system and reducing contractility of myocardium. Aggravation of coronary cyrculation and arrhythmogenic effect are possible.

Allapinine Hydrochloride, a drug of the same subclass, adversely affects the central nervous system causing dizziness, headache, face hyperemia and diplopia, and also cardiovascular system causing hypotension, tachycardia and conduction disorder.

All the Class // drugs (β-adrenoblockers) are characterised with disturbance of function of the central nervous system (distraction, depression, debility), bronchopulmonary system (bronchospasm up to development of asthma status), cardiovascular system (hypotension, suppression of the heart conduction system and of myocardium contractility, bradycardia, Reino syndrome). These drugs cannot be prescribed in cases of pregnancy and diabetes mellitus. Amiodarone Hydrochloride, a most popular Class /// drug, sometimes causes disturbance of function of: cardiovascular system, leading to hypotension, stable bradycardia, blocks, cardiac insufficiency and, not infrequently fatal, arrhythmia related to prolongation of QT interval; central nervous system, leading to asthenia and tremor; bronchopulmonary system, leading to interstitial pneumonia/alveolitis or pneumosclerosis with frequent lethal outcome; gastrointestinal tract, leading to nausea, constipation and pharmaceutical hepatitis; thyroid gland, leading to hypothyroidism or hyperthyroidism; organs of vision and skin (with a photosensitization effect); immune system, leading to allergic reactions; sexual system of men, leading to erectile dysfunction. Amiodarone strengthens arrhythmogenic action of Class / drugs (except for Lidocaine) and changes metabolism of many pharmaceuticals.

Another Class /// drug Sotalol Hydrochloride (Gilucor) alongside with negative effects inherent in the above-mentioned group of β-adrenoblockers, can cause reduction in contractile ability of the heart, blockage, torsade de pointes tachycardia related to prolongation of QT interval and expressed bradycardia. The bronchopulmonary system can suffer of bronchospasm and bronchial asthma attacks.

Class IV drugs, antagonists of calcium in phenyl alkyl amine group Verapamil Hydrochloride (Gallopamil), adversely affect contractile ability of the myocardium, which limits their application for patients with cardiac insufficiency (especially in the acute period of myocardial infarction) and in case of pregnancy. Actually, calcium antagonists suppress function of sinoatrial and atrioventricular nodes, causing bradycardia, hypotension, peripheral oedema, increased fatigue and constipation. Therefore, they are usually prescribed in combination with Class V drugs, typical agents of which being Alinidine Hydrochloride and Phalipamil.

Salts dissociation of which in the human body increases concentration of ions of potassium and/or magnesium are quite often used as antiarrhythmic agents alongside with the described synthetic organic drugs. These ions are the basic physiological stimulators of enzyme of Na⁺-K⁺ATPase responsible for maintenance of electric potential of rest of cardiac myocytes (see, e.g.: "Aritmii Serdtsa" [Cardiac Arrhythmia]. Edited by V.D. Mandel. In 3 volumes. V.1 , Moscow, Meditsina Publishers, 1996, pp.155-188).

The K⁺ ions exert non-specific antiarrhythmic action, normalising the generation of rhythm impulses on the background of suppression of self-acting activity of ectopic pacemakers, interrupting excitement flow and levelling refractory character of cells in the myocardium. Therapeutic efficiency of potassium is substantially the same in all the patients having its low or normal concentration in the blood.

The effect of the K⁺ ions on the rhythm depends on electrical continuity of the myocardium, initial concentration of potassium in the blood and the rate of its change. The latter factor is essential because several milligram-equivalents of potassium are quite often enough to administer in order to restrain arrhythmia. In case of repetition of the arrhythmia paroxysm, potassium is administered to normalise the rhythm. Failures of such therapy are usually conditioned by continuation in administration of potassium after the restriction of arrhythmia. However, medical effect of potassium therapy is of short duration. Moreover, administration of potassium chloride as a source of K⁺ ions requires precise dose calculation in order to avoid hyperkalemia. Finally, administration of potassium chloride may cause ulceration of gastrointestinal tract and perforation of ulcers that appear. Antiarrythmic and antifibrillation action of magnesium ions is based on their antagonism to ions of calcium, and it is especially expressed in arrhythmia conditioned by erroneous administration of Class la and /// drugs and related to prolongation of QT interval. Taking part in many enzymatic reactions, Mg²⁺ ions play important role in metabolism regulation including synthesis of adenosine triphosphate (ATP). Besides, magnesium is able to modulate the work of receptors and thus control cell activity.

Same as with potassium, therapeutic efficiency of magnesium is substantially the same in patients having its low or normal concentration in the blood.

Long-term administration of magnesium improves the condition of patients with ischemic heart disease and promotes regression of atherosclerosis. Application of magnesium in patients with myocardial infarction reduces the risk of sudden death (Shilov A.M., Svyatov I.S., Kravchenko VN. et al.: "Primyenyeniye preparatov magniya dlya profilaktiki narusheniy ritma serdtsa u bolnykh ostrym infarctom miokarda" [Application of Magnesium Drugs for Prophylactics of Disturbances in Heart Rhythm in Patients with Acute Myocardial Infarction]. Rossiyskiy kardiologicheskiy zhurnal. 2002, Νo.1 , pp.16-19). Magnesium is able to control the coronary blood flow and to reduce negative inotropic action of ischemia (Chekman I.S.: "Biokhimicheskaya Farmako- dinamika" [Biochemical Pharmacodynamics]. Kiev. Zdorovya Publishers, 1991).

Unfortunately, magnesium sulphate usually used in therapy is essentially not absorbed from the gastrointestinal tract and exerts the aperient action. Therefore, it is used only in parenteral way. However, medical effect is not long with such way of application because of fast dissociation of the salt, and the associated saturation of fluid media with sulphate-anions adversely affects the human body as a whole.

They manage to eliminate this undesirable effect by application of an organic salt, namely magnesium orotate (otherwise named Magnerot). However, it is poorly dissolvable too and also exerts aperient action, and the residue of orotic acid promotes fatty degeneration of the liver with long-term application of Magnerot and thus requires pharmaceutical correction (Smirnov V.A.: "Vitaminy" [Vitamins]. Moscow, Meditsina Publishers. 1974). The same can be said about potassium orotate popular in former times.

Magnesium aspartate exerts expressed antiarrhythmic effect on the background of ischemic and reperfusion damage of the myocardium (op cit Chekman I.S.: "Biokhimicheskaya Farmakodinamika" [Biochemical Pharmacodynamics]). It should be noted that amino-acid residue included in its composition joins in metabolic processes and can be completely utilised in plastic metabolism, and thus it is generally harmless for humans.

That is probably why quite often in clinical practice, a substantially equimolar mixture of potassium and magnesium pspartates (known under the trademarks of Pananginum or Asparcam) is used (mainly in the parenteral way) in case of paroxysmal disturbances in cardiac rhythm caused by overdosage of cardiac glycosides

However obviously expressed antiarrhythmic effect is usually reached only by administration of combinations of Pananginum with other antiarrhythmic agents. Therefore, a sharp demand is felt in such antiarrhythmic drugs that would be substantially non-toxic and have no harmful side effects. It can be supposed that such drugs should be developed on the basis of chemical compounds that are initially present in the normally functioning human body as anabolic agents (same as aspartic). Gluconic acid otherwise termed 2,3,4,5,6-pentahydroxy-pentiformic acid or 2,3,4,5, 6-pentahydroxy-hexanoic acid can be selected from the multitude of such substances.

It is a substrate of pentose-phosphate pathway of glucose oxidation and, in normal oxygen metabolism conditions, serves as a donor of pyridine nucleotides that take part in plastic syntheses. The same pentose-phosphate pathway provides energy for the work of ionic pumps especially in the conductive system of the heart, and in the conditions of ischemia and/or hypoxia of myocardium, the pentose-phosphate shunt supplies substrates of glycolytic pathways of glucose oxidation, which also normalises cardiac action (Olbinskaya L.I., Litvitskiy P.F.: "Koronarnaya i Miokardialnaya Nedostatochnost" [Coronary and Myocardial Insufficiency]. Moscow, Meditsina Publishers. 1987, pp.75-76).

It is known that calcium salt of dimethyl-glycidic ester of gluconic acid (otherwise, Calcium Pangamate) activates succinate dehydrogenase with expressed antihypoxic and cardioprotective action in case of local ischemia (Anisimov V.E.: "Pangamat Kalciya" [Calcium Pangamate]. Kazan, 1965, p.7). At the same time, it was shown in experiments with cats that administration of calcium pangamate prior to artificially induced myocardial hypoxia makes the term to the beginning of paroxysm of arrhythmia approximately three times longer as compared to the control (Andreyev S.V., Dokukin AN., Chechulin Ju.S, Bukin YuN.: "Deystviye Pangamovoy Kisloty na Gipoxiyu Serdtsa i Golovnogo Mozga // Vitamin B₁₅ (Pangamovaya Kislota). Svoystva, Funktsii i Phmyenyeniye" [Action of Pangamic Acid on Cardiac and Brain Hypoxia. Vitamin B₁₅ (Pangamic Acid). Properties, Functions and Application]. Moscow, "Νauka" Publishers, 1965, pp. 80-90).

Thus, the most alike, as for the technological essence, with the antiarrhythmic agent of the invention are considered to be drugs based on calcium salts derived from glluconic acid. Nowadays calcium gluconate is the only agent of them known to be used in medical practice, and it is administered predominantly as a source of calcium for osteosynthesis in children and patients who have suffered a long-term compelled hypodynamia (see op cit Mashkovskiy M.D.: "Lekarstvenniye Sredstva" [Pharmaceuticals]. V.2, pp.144-145).

However, as it was observed above, the surplus of calcium ions induces arrhythmia.

That is the reason why nobody has considered gluconic acid derivatives as basis for practically applicable antiarrhythmic agents for more than 35 years

Disclosure of the Invention The invention is based on the problem of creation, by way of selection of chemical compounds based on glluconic acid, of a new class of substantially non-toxic antiarrhythmic agents which would exhibit a complex membrane protective action upon administration in the human body and thus essentially accelerate arresting the paroxysms of arrhythmia of various etiology and reduce the risks of aggravations in their prophylactics and therapy.

The problem is solved in that the antiarrhythmic agent on the basis of glluconic acid salts, according to the invention, includes at least one salt comprising a cation selected from the group consisting of potassium and magnesium.

Actually, as will be shown below, practical application of any of possible combinations of cations of potassium and/or magnesium with gluconate-anions allows a membrane protective action to be provided irrespective of typical reasons for disturbances in continuity of cellular membranes and at least efficiently arrest attacks of paroxysmal arrhythmia.

The first additional characteristic feature consists in that the basis for antiarrhythmic agent is potassium gluconate. Such agent is the most effective in cases of arrhythmia on the background of surplus of sodium cations and deficit of potassium cations in the patient's body. The second additional characteristic feature consists in that the basis for antiarrhythmic agent is magnesium gluconate. Such agent is the most effective in cases of arrhythmia on the background of deficit of magnesium cations in the patient's body.

The third additional characteristic feature consists in that the basis for antiarrhythmic agent is a mixture of potassium gluconate and magnesium gluconate. Drugs of this type can be used in arresting paroxysms, prophylactics and therapy of arrhythmia of arbitrary etiology.

The fourth feature, additional to the third one, consists in that not less than 1.0 mole of magnesium gluconate is taken per mole of potassium gluconate in said mixture.

Drugs of this type are preferable in prophylactics and therapy of arrhythmia when data about the deficit of specific cations of potassium or magnesium in the patient's body are taken into consideration.

The fifth feature, additional to the fourth one, consists in that 4.0 to 6.0 moles of magnesium gluconate are taken per mole of potassium gluconate in said mixture. Drugs of this type are most preferable in fast (during several seconds) arrest of attacks of paroxysmal arrhythmia by injection of a solution of said mixture directly into a blood channel.

The sixth feature, additional to the third one, consists in that said mixture additionally contains not less than 1.0 mole of Amiodarone per mole of potassium gluconate, which promotes successful arrest of arrhythmia even when the mixture is administered peros and enhances its prophylactic action.

The seventh feature, additional to the third one, consists in that said mixture additionally contains not less than 1.0 mole of inosine per mole of potassium gluconate, which is especially effective in long-term pharmaceutical prophylactics of arrhythmia of arbitrary etiology.

Best Mode for Carrying out the Invention The invention will now be explained by:

(1) Description of methods of production of experimental pharmaceutical forms; (2) Description of experiments on laboratory models of arrhythmia of various etiology and of the obtained results as compared with results of action of customarily used antiarrhythmic agents;

(3) Recommendations concerning methods of administration of drugs of the proposed class for arresting paroxysms of arrhythmia and its prophylactics and therapy. ( 1) Method of producing experimental pharmaceutical forms

Raw materials in all cases were substances of potassium gluconate and magnesium gluconate commercially available in the form of chemical reagents having the quality of not less than "chemically pure substance" and also Amiodarone and Inosinum (Riboxinum) available at the pharmaceutical market. As far as only solutions for injections were used in experiments, the method of preparing experimental specimens of antiarrhythmic agents of the invention named below included the following steps: calculating required doses by means of methods known to those skilled in the art; dosing selected dry ingredients by weight; mixing said ingredients with isotonic solution of sodium chloride or glucose to obtain 5%, 10% or 20% solutions for injections.

Solutions having appropriate molar concentrations prepared in good time were used in experiments taking into account molar ratio of K/Mg ions and additions of Amiodarone or Inosinum, said solutions being mixed prior to utilisation in the required proportions.

It must be understood to those skilled in the art that preparing solid pharmaceutical forms having required contents of the substances is of no problem either. (2) Experimental trial of drugs of the invention

Antiarrhythmic activity of the drugs of the invention, mechanism of their action, scope of possible application and advantages as compared to known antiarrhythmic agents were determined in experiments on models of cardiac arrhythmia with known pathogenesis in accordance with the procedure established by the Ministry of Public Health of Ukraine (Bobrov V.A., Gorchkova N.A., Simorot V.N. et al.: "Experimentalnoye i Klinicheskoye Izucheniye Antiaritmicheskikh Sredstv: Metodicheskiye Rekomendatsii" [Experimental and Clinical Study of Antiarrhythmic Agents: Methods Recommendations]. Kiev, Pharmacological Committee of Ukrainian Ministry of Public Health, 1995). Such models are based on administration of standard arrhythmogenic agents. The doses of all the utilised drugs will be specified in the following calculations on the basis of 1 kg of weight of the experimental animal.

Aconitine Model is based on intravenous injection of a solution of aconitine sulphate or aconitine bromide at doses of 30-40 μg/kg and is characterised by disturbances in cardiac action in the range from the atrial and ventricular extrasystole to the ventricular fibrillation, which occur in 1.3-4 minutes, continuing longer than 1 hour and leading to death of the majority of animals in the control.

This model serves for detection of disturbances in permeability of cellular membranes for Na⁺ ions, and suppression of arrhythmia induced by aconitine allows the studied drugs to be included in Class / to which Lidocaine and Ethmosine belong.

Calcium-chloride Model is based on fast intravenous injection of solution of calcium chloride at doses of 200-250 mg/kg and is characterised with ventricular fibrillation (VF) and respiratory standstill conditioned by the toxic effect of the surplus of Ca²⁺ ions. This model (taking into account expressiveness of disturbances of cardiac action and the number of survived animals) allows assessment of the preventive effect of the studied drugs upon the cardiovascular system and probability of including them in Classes / and IV. Procainamide in the dose of 20 mg/kg was used for comparison (M.R. Malinov, F.F. Battle, B. Malmud: Nervous Mechanisms in Ventricular Arrhythmias Induced by Calcium Chloride in Rats II Circ. Res. -1953, V.1 , pp. 554-559)

Barium-chloride Model is based on intravenous injection of a solution of barium chloride in the dose of 4 mg/kg (H. Brasch: Protective Effects of Na Salicilate against Digoxin- and BaCI₂- Induced Arrhythmias in Guinea-Pigs II Eur. J. Pharmacol. -1984. - V.2, pp. 297-301). This model serves for detection of disturbances in permeability of cellular membranes for K⁺ ions, and suppression of arrhythmia induced by barium chloride allows the studied drugs to be included in Class /// to which Amiodarone belongs, which is used in the dose of 5 mg/kg for comparison. Strophanthin Model is based on intravenous injection of 0.12-0.25 mg/kg solution of the mentioned cardiac glycoside which blocks NaJK⁺-ATPase causing deviation from norm of concentration of ions of potassium, sodium and calcium inside of cardiac myocytes and intoxicates central nervous system inducing bradycardia, extrasystolic arrhythmia, paroxysmal tachycardia and ventricular fibrillation, which usually leads to death of animals in the control.

Comparison with Amiodarone in the dose of 5 mg/kg allows the studied drugs to be included in Class ///.

Membrane-destructive Model (UA Patent 43207 A) is based on intravenous administration of solutions of an inducer of peroxide oxidation of lipids and free radical oxidation of proteins, such as mixture of ascorbic acid (50 mg/kg) with ferric sulphate

(10 mg/kg) and calcium chloride (100 mg/kg), which induces disturbances in conductivity and rhythm at the very first minute ending in ventricular fibrillation.

Suppression of arrhythmia on such model (as compared to Amiodarone in the dose of 5 mg/kg) points out at prophylactic efficiency of the studied drugs.

All the manipulations were carried out with experimental animals being narcotised with pentobarbital (40 mg/kg). Electrocardiograms (ECG) were recorded in II standard lead from extremities. Consideration was given during analysis to:

Number (n) of experimental animals with arrhythmia Features of cardiac arrhythmia (ventricular fibrillation being specially marked with abbreviation 'VF')

Duration of sinus rhythm (S/r) in minutes and

Number of survived animals.

The data received were statistically processed. In the tables, data concerning effectiveness of known antiarrhythmic agents recommended by the above methods by Ukrainian Ministry of Public Health as the reference for comparison with effectiveness of the drugs being tested on the appropriate laboratory model of cardiac arrhythmia (CA) are marked with inverted comas (") placed before the numbers. The asterisk (*), placed after the numbers, points out that the statistical difference p < 0.05 as compared to the control.

Antiarrhythmic effect of drugs, the scope and safety of their action (particularly in a prolonged use and giving consideration to side effects) were appraised in complex by the results of experiments, and equally effective doses were determined. Antiarrhythmic effect of separately administered potassium and magnesium gluconates was appraised in the first series of experiments. Thus, aconitine, membrane-destructive and calcium-chloride models of arrhythmia were tried on mature white mongrel rats, Strophanthin arrhythmia model was tried on guinea-pigs, and barium-chloride arrhythmia model, on rabbits (see respective Tables 1 and 2).

Table 1

Comparative data on antiarrhythmic effect of potassium and magnesium gluconates in experimental arrhythmia models with rats

Table 2

Comparative data on antiarrhythmic effect of potassium and magnesium gluconates in experimental arrhythmia models with guinea-pigs and rabbits

Cursory glance to Tables 1 and 2 may give and impression that the data on separately administered potassium and magnesium gluconates (shown in italics) illustrate only the applicability of these drugs as antiarrhythmic agents but not prove their effectiveness in comparison with the reference antiarrhythmic agents of corresponding classes.

However, consideration should be given to the fact that even separately administered potassium and magnesium gluconates, firstly, exhibit antiarrhythmic effect in all tested arrhythmia models and, secondly, they are essentially less toxic than the known drugs, and thus, taken in normal doses, they can not cause side effects of the hyperkalemia or hypermagnemia types.

To prove the second advantage, experiments were conducted on mature white mongrel rats to appraise acute toxicity with determination of LD₅₀ of potassium gluconate and magnesium gluconate and mixtures thereof.

It was observed that LD₅₀ of the pure potassium gluconate was not less than 2500 mg/kg with intraperitoneal way of administration, and in case of intravenous infusion, LD₅₀ depended on the duration of infusion of the whole dose, making up not less than 450 mg/kg for 30 c, 580 mg/kg for 1 min, and 1100 mg/kg for 3 min. In all cases of exceeding the indicated dosage of potassium gluconate, the death of not survived rats resulted from the cardiac arrest. The survived rats remained flaccid during 2 to 3 hours. Then their conditions essentially did not differ from the control.

Still higher LD₅₀ indices happened to be with pure magnesium gluconate. Thus, LD₅₀ was not less than 2800 mg/kg in intraperitoneal administration, and also depended on the time of infusion of the whole dose in intravenous infusion, making up not less than 450 mg/kg for 30 c, 600 mg/kg for 1 min, and 1400 mg/kg for 3 min.

Moreover, unlike hyperkalemia, in case of exceeding said magnesium gluconate dosage, the death of not survived rats resulted from respiratory standstill on the background of acute bradycardia. Toxic effects used to become apparent 3 or 4 min after intraperitoneal administration. The animals assumed expressly sedate, not mobile state, some fell asleep. Breathing became noisy, infrequent and deep; apnoea educed during 12-30 min. The survived animals remained in depression during 3-5 h, gradually gaining the initial conditions, and they did not differ from the control only 12-15 h later.

LD₅₀ of mixtures of potassium and magnesium gluconates tested as solutions for injection in molar ratios of 1 :4 to 1 :6 indicated in the following Table 3 did not exceed 56 ml/kg for 5% solution and 28 ml/kg for 10% solution in all cases of intraperitoneal administration generally regardless of the fact whether it had been prepared with the use of sodium chloride or glucose.

With such way of administration, the toxicity depended primarily on concentration of magnesium gluconate because the toxic effects and LD₅₀ essentially coincided with the data obtained in its individual application (without potassium gluconate).

In intravenous infusion of mixtures of potassium and magnesium gluconates, LD₅₀ depended on the duration of infusion of the whole dose, making up not less than 7 mg/kg for 30 c, 13 mg/kg for 1 min, and 26 mg/kg for 3 min in case of 5% solution.

The death of not survived animals resulted from apnoea on the background of acute bradycardia in the same way as in case of application of pure magnesium gluconate (regardless of the way of administration of mixtures of potassium and magnesium gluconates).

Thus, potassium gluconate, magnesium gluconate and their mixtures belong to Class IV toxicity, and therefore their therapeutic or prophylactic doses are essentially safe.

Actually, usual pharmacological calculations utilising the given data show that the lowest LD₅₀ of magnesium ion contained in the gluconate cannot be worse than 155 mg/kg whereas it is known from the reference data that: LD₅₀ of MgSO₄*7H₂O equals to 770,9 mg/kg, which corresponds to LD₅₀ of 75 mg/kg magnesium ions,

LD₅₀ of magnesium ions contained in MgCI₂*6H₂O equals to 83,6 mg/kg, and the best of known LD₅₀ of magnesium ions contained in drug Pananginum, which (as was pointed out above) is a mixture of potassium and magnesium aspartates, does not exceed 140,8 mg/kg.

More effective data on recovery of stable sinus rhythm in arrhythmia models were obtained thanks to utilisation of combinations of potassium and magnesium gluconates in various molar ratios (Table 3).

Table 3

Effectiveness of mixtures of potassium and magnesium gluconates in inhibition of cardiac arrhythmia (% of total number of experiments in models)

Table 3 shows that mixtures of potassium and magnesium gluconates effectively inhibit arrhythmia regardless of pathogenesis. The data typed in italics and shifted to the left underline that mixtures having molar rations of potassium and magnesium in the range of 1 :4 to 1 :6 are the most effective as antiarrhythmic agents.

Antiarrhythmic index LD₅o/ED₅o was calculated for some models and optimal mixture of potassium and magnesium gluconates having ratio of K/Mg = 1 :5. Thus, in Aconitine Model of arrhythmia, the magnitude ED₅₀ (which corresponds to short time recovery of sinus rhythm and is calculated on the basis of magnesium gluconate as a more toxic component) did not exceed 50 mg/kg, i.e. 8.3% of LD₅₀ at intravenous administration and insignificant magnitude of 1.8% of LD₅₀ at intraperitoneal administration of magnesium gluconate. Therefore, LD₅o/ED₅o is enclosed in the interval of minimum 12.0 to maximum 55.6. Similar magnitude of LD₅₀/ED₅o for intravenous magnesium sulphate (available data) does not exceed 30.8.

It follows from the above that: a mixture of potassium and magnesium gluconates in the optimum molar ratio excels pangamate of calcium and of inorganic potassium and magnesium salts in antiarrhythmic action in all the studied models of disturbances in cardiac action; effectiveness of cupping paroxysms of arrhythmia by potassium and magnesium gluconates and their mixtures excels the effectiveness of the reference antiarrhythmic agents in the Strophanthin arrhythmia model and is close to their effectiveness in Aconitine and barium-chloride arrhythmia models; preventive action of mixtures of potassium and magnesium gluconates in membrane-destructive arrhythmia model is notably higher than in known antiarrhythmic agents and is close to their action in calcium-chloride arrhythmia model.

Characteristic examples of therapeutic and preventive antiarrhythmic action of drugs of the invention are given below.

Example 1. An initial ECG was recorded in a 520 g guinea-pig narcotised with pentobarbital, said ECG testifying stable cardiac output. Then, a solution of barium chloride at a dose of 4 mg/kg was infused in the femoral vein. After 15 c polytopic ventricular extrasystolic arrhythmia of the bigeminy type was registered in ECG. A solution of mixture of potassium and magnesium gluconates at doses of 20 mg/kg and 80 mg/kg respectively was immediately infused in the same vein on the basis of 2 ml/kg. A transition to sinus rhythm was observed right after the infusion, which rhythm lasted 2.4 min, and then arrhythmia recommenced. A repeated administration of half the dose of said mixture lead to recovery of stable sinus rhythm. Example 2. An initial ECG was recorded in a 150 g rat narcotised with pentobarbital, said ECG testifying stable cardiac output. Then, a solution of the mixture of potassium and magnesium gluconates at doses of 30 mg/kg and 150 mg/kg respectively was infused in the femoral vein on the basis of 2 ml/kg, which somewhat slowed down the cardiac activity. Two minutes later, a solution of ascorbic acid at a dose of 50 mg/kg was infused in the same vein, and after an interval of 1 min a solution of ferric sulphate, prepared ex tempore, at a dose of 10 mg/kg was infused.

In 30 c, changes in ventricular complex were observed in ECG in the form of 'gigantic' teeth T indicating damage of cardiac myocytes. At this time, a solution of calcium chloride at a dose of 100 mg/kg was administered. The ECG showed solitary ventricular extrasystoles on the background of atrioventricular block. However, only 40 c later, the cardiac rhythm became quicker, and in another 30 c, the normal sinus rhythm restored. In 3.3 min, solitary ventricular extrasystoles were recorded, after which the stability of sinus rhythm was not disturbed any more (whereas such extrasystoles usually transformed into ventricular fibrillation in the control at this time, i.e. without preliminary administration of a mixture of potassium and magnesium gluconates). More effective data on therapeutic antiarrhythmic action were obtained after administration of the drugs of the invention on the background of Amiodarone.

Example 3. An initial ECG was recorded in a 560 g guinea-pig narcotised with pentobarbital, said ECG testifying stable cardiac output. Then, a solution of barium chloride at a dose of 4 mg/kg was infused in the femoral vein. After 12 c polytopic ventricular extrasystolic arrhythmia of the bigeminy type was detected in ECG. A solution of Amiodarone hydrochloride at a dose of 5 mg/kg was immediately infused in the same vein. Antiarrhythmic effect was not observed in the ECG. In 2 min, a solution of the mixture of potassium and magnesium gluconates at doses of 20 mg/kg and 80 mg/kg respectively was infused in the same vein on the basis of 2 ml/kg. Transition to stable sinus rhythm was observed right in the process of administration.

The greatest prophylactic antiarrhythmic effect was achieved after a joint simultaneous administration of the drugs of the invention and Amiodarone.

Example 4. A normal ECG was recorded in a 160 g rat narcotised with pentobarbital. Then, a solution of Amiodarone hydrochloride at a dose of 5 mg/kg and 3 ml/kg of a solution of the mixture of potassium and magnesium gluconates at respective doses of 30 mg/kg and 150 mg/kg were infused in the femoral vein. Retardation of the cardiac activity was observed.

One minute later, a solution of calcium chloride at a loading dose of 220 mg/kg was infused in the same vein. Only solitary ventricular extrasystoles on the background of atrioventricular block appeared in the ECG, and as soon as in 40 c, the cardiac rhythm became quicker, and in another 30 c, the normal sinus rhythm restored.

And at last, effectiveness of prophylactics of arrhythmia by means of drugs of the invention in combination with Inosinum (Riboxinum) was tested. Example 5. A normal ECG was recorded in a 760 g guinea-pig narcotised with pentobarbital. Then, a solution of Strophanthin at a dose of 0.25 mg/kg was infused in the femoral vein. After 3.2 min, polytopic ventricular extrasystolic arrhythmia of the bigeminy type, which transferred into ventricular tachycardia, was registered in ECG.

A solution of the mixture of potassium and magnesium gluconates and Inosinum at respective doses of 30 mg/kg, 150 mg/kg and 10 mg/kg was immediately infused in the same vein. Episodes of sinus rhythm were recorded 45 min later. A half of the initial dose of said mixture was repeatedly infused in the same vein. A transfer to sinus rhythm alternating with idioventricular rhythm was detected 30 c after administration. However, episodes of ventricular rhythm gradually shortened, and the stable sinus rhythm restored in 3 min from the moment of the latest administration of the drugs.

(3) Recommendations concerning administration of drugs of the invention based on experimentally found facts of: essential absence of cholinolytic activity of potassium and magnesium gluconates; their very low toxicity at high single doses and ability to increase antiarrhythmic action of other prophylactic drugs with reduction of the risk of appearance of arrhythmogenic effects (particularly in combination with drugs that prolong QT interval).

Therefore, potassium and magnesium gluconates taken separately and in mixtures are indicated in case of myocardial infarction for prophylactics and therapy of disturbances in cardiac rhythm.

Mixtures of potassium and magnesium gluconates are expedient to be administered:

Firstly, as agents for cupping off (preferably by way of intravenous infusion during 3-5 min or drop by drop administration): paroxysms of ectopic arrhythmia due to overdosage of cardiac glycosides and paroxysmal atrial fibrillation, ventricular extrasystolia and paroxysmal ventricular tachycardia of the 'pirouette' type (even in cases of circulation of arrhythmogenic impulses along additional tracts); and

Secondly, as agents for increasing efficiency of antiarrhythmic action of other prophylactic drugs and reducing the risk of their arrhythmogenic action (particularly with drugs prolonging QT interval). Thus, mixtures of potassium and magnesium gluconates are expedient to be prescribed simultaneously with cardiac glycosides and/or diuretics of the saluretic group for safe complex therapy of cardiac insufficiency.

Similar mixtures are indicated as agents for complex therapy of disturbances in electrolyte metabolism for correction of the level of potassium and magnesium. As for medicinal forms, preferable are solutions for injections prepared on the basis of isotonic solutions of glucose or sodium chloride and tablets or capsules (which are preferable in case of prophylactics of arrhythmia).

Industrial Applicability The invention can be readily realised on the available industrial basis involved in production of potassium and magnesium gluconates, Amiodarone and Inosinum and also standard medicinal forms in the shape of solutions for injections and tablets or capsules with generally known pharmaceutically suitable fillers.

Practical application of such medicinal forms will allow reduction in the risk of aggravation of arrhythmia in the course of cupping off its paroxysms and improvement in effectiveness of long-term therapy and prophylactics of arrhythmia of arbitrary types. Actually, the results of experimental studies prove the fact that potassium and magnesium gluconates possess wide scope of antiarrhythmic activity and exert therapeutic and prophylactic antiarrhythmic effect essentially in all utilized experimental cardiac arrhythmia models. Moreover, arresting paroxysms of arrhythmia by some drugs of the invention is achieved essentially in the moment of their administration, whereas known antiarrhythmic agents (excluding significantly less effective magnesium sulphate) exert effect only 1.3 to 1.5 min after administration.

Claims

C L A I M S 1. An antiarrhythmic agent based on salts of gluconic acid characterised in that it includes at least one salt comprising a cation selected from the group consisting of potassium and magnesium.

2. The antiarrhythmic agent of Claim 1 , characterised in that potassium gluconate is the basis thereof.

3. The antiarrhythmic agent of Claim 1 , characterised in that magnesium gluconate is the basis thereof.

4. The antiarrhythmic agent of Claim 1 , characterised in that a mixture of potassium gluconate and magnesium gluconate. is the basis thereof.

5. The antiarrhythmic agent of Claim 4, characterised in that not less than 1.0 mole of magnesium gluconate is taken per mole of potassium gluconate in said mixture.

6. The antiarrhythmic agent of Claim 5, characterised in that 4.0 to 6.0 moles of magnesium gluconate are taken per mole of potassium gluconate in said mixture.

7. The antiarrhythmic agent of Claim 4, characterised in that said mixture additionally contains not less than 1.0 mole of Amiodarone per mole of potassium gluconate.

8. The antiarrhythmic agent of Claim 4, characterised in that said mixture additionally contains not less than 1.0 mole of Inosinum per mole of potassium gluconate.