RU2292885C2 - Anti-arrhythmic medicament "tiodaron" - Google Patents

Abstract

FIELD: medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to an anti-arrhythmic medicament in combination with amiodarone that comprises thiotriazoline in the ratio to amiodarone = 1:2 by dry matter. Proposed medicament possesses the more expressed anti-arrhythmic effect as compared with prototype (preparation amiodarone).

EFFECT: enhanced and valuable medicinal property of agent.

2 cl, 4 tbl, 4 dwg, 2 ex

Description

The invention relates to medicine, in particular to pharmacotherapy, namely to antiarrhythmic drugs in the form of tablets, dragees, suppositories, solutions for injection, etc. with a combined base of active ingredients.

One of the most serious complications of cardiovascular disease is a disturbance in the rhythm of cardiac activity. Up to 90% of cases of myocardial infarction are complicated by arrhythmias.

The known drug thiotriazolin has a wide range of pharmacological effects: antioxidant, membrane-stabilizing, anti-ischemic, anti-inflammatory, immunomodulating, cholostimulating, stimulating cell regeneration, cardioprotective, hepatoprotective, antiarrhythmic and other types of activity.

Thiotriazolin is available in the form of injectable solutions, tablets, ointments, suppositories, eye drops and is widely used in medical practice, including in the treatment of cardiovascular diseases. However, it is not used enough to treat cardiac arrhythmias.

Among antiarrhythmic drugs, amiodarone, a highly effective drug based on a modified benzofuran derivative, amiodarone hydrochloride, draws special attention. It belongs to first-line drugs for stopping paroxysmal flickering and atrial flutter, prevents and reduces the frequency of sudden death as a result of asymptomatic complex ventricular arrhythmias (Pashneva R.A., Kozarinov M.A. et al. Development and study of a domestic antiarrhythmic drug - tablets "Amiodarone" // Pharmaceutical journal. 1999, No. 3 - S.93-96).

This drug as the closest in purpose and effectiveness we take as a prototype.

The disadvantages of the prototype is a narrow spectrum of the pharmacological action of amiodarone and its increased consumption to achieve the pharmacological effect of the treatment of heart rhythm, which can cause a violation of the normal functioning of other organs. When using amidoron tablets, numerous side effects can occur from various body systems: nausea, a feeling of heaviness in the epigastrium, loss of appetite, hepatitis, coughing, suffocation, wheezing, ataxia, tremor, muscle weakness, bradycardia, hypotension, slowing of atrio-veticular conduction, decreased visual acuity, photosensitization and allergic reactions (Mashkovsky M.D. Medicines. Moscow, 2002. - T1. - S.371-374).

The basis of the invention is the task of developing an antiarrhythmic drug that increases the effectiveness of the biological effect while reducing the dose and consumption of the drug for the treatment of active ingredients. The solution of this task provides an antiarrhythmic drug that contains the active ingredient amiodarone due to the fact that it additionally contains the active ingredient thiotriazoline in the ratio of thiotriazoline and amiodarone - 1: 2. The proposed drug is used in the form of a solid dosage form "Tiodaron".

The pharmacological advantages of the drug according to the invention are due to the mutually potentiating action of thiotriazolin, which has antioxidant, antiarrhythmic, membrane-stabilizing, cerebroprotective effects, and amiodarone, which has a strong antiarrhythmic effect. At the same time, the consumption of a mixture of amiodarone with thiotriazolin ("Tiodaron") to eliminate cardiac arrhythmias is 20% less than the consumption of amiodarone for the same purpose.

In the optimal pharmacological variant, the dose of amiodarone introduced in the mixture is almost half (44-46%) of its use in its pure form (excipients are not taken into account), accordingly, its negative effect on the body is eliminated as much as possible and foreign exchange costs for acquiring the substance are reduced amiodarone.

The essence of the invention is explained by the following description, with examples of preclinical trials of the antiarrhythmic drug "Tiodaron" according to the invention and the prototype - amiodarone and drawings, where: Fig. 1 graphically shows the effectiveness of amiodarone in calcium chloride arrhythmia, in Fig. 2 - the effectiveness of thiodarone in calcium chloride arrhythmia, figure 3 - the effectiveness of amiodarone with aconitine arrhythmia, figure 4 - the effectiveness of tiodarone with aconitine arrhythmia. For experiments, amiodarone and tiodarone tablets were used. The composition of the ingredients per tablet of tiodarone in terms of 100% dry matter:

- amiodarone - 0.20 g;

- thiotriazoline - 0.10 g;

- excipients - up to 0.50 g;

- the weight of the finished tablet is 0.50 g.

That is, a tablet (solid form of the drug) contains 60% of the active ingredients in the total weight of the mixture with a ratio of thiotriazoline to amiodarone of 1: 2 and 40% of auxiliary ingredients.

For experiments, tiodarone tablets were manufactured by the Central Laboratory of JSC Halichfarm. Factory-made amiodarone tablets were used to compare their effectiveness.

The antiarrhythmic activity of drugs was evaluated according to the therapeutic index (TI) using the average lethal (LD ₅₀ : amiodarone - 4810 mg / kg and tiodarone - 5310 mg / kg, respectively) and the average therapeutic (ED ₅₀ ) dose. TI = LD ₅₀ to ED ₅₀ . The therapeutic index was determined on the models of calcium chloride and aconitine arrhythmias with the course introduction of comparison drugs.

Example I.

The study of antiarrhythmic properties of the drug tiodarone on calcium chloride model with a course introduction

Ventricular arrhythmias were caused by intravenous administration of calcium chloride at a dose of 250 mg / kg of animal weight. The occurrence of arrhythmias is associated with an increase in the concentration of intracellular calcium with the following release of hormones, an increase in the activity of adenylate cyclase and cAMP. Heart rhythm disturbances occur within 10 seconds after the administration of calcium chloride in the form of ventricular flutter (about 90% of cases) or systole followed by ventricular fibrillation (about 10% of cases). Within 120 seconds, all animals die.

The antiarrhythmic effect of the drugs was evaluated by the survival of the animals, as well as by the nature, duration and severity of heart rhythm disturbances - by the electrocardiogram indices, which were recorded in the 2nd standard lead at the beginning of the experiment and every 10 seconds after the administration of calcium chloride.

The studies were conducted on 66 Wistar rats of both sexes weighing 170-200 g. Experimental animals were divided into 11 groups (6 animals each). Rats of 1-5 groups for 7 days to the beginning of pathology modeling once a day intragastrically (inside) were fractionally injected with tiodarone in a dose range of 30-50 mg / kg (in terms of the active ingredients - thiotriazolin and amiodarone), and in rats 6-10 groups - comparison drug - amiodarone (arrhythmil, BCP) in the dose range of 40-60 mg / kg. To prepare a solution of drugs, appropriate factory-made amiodarone tablets and tiodarone tablets manufactured in the central laboratory of Galichfarm JSC for preclinical studies were used.

The introduction of calcium chloride was carried out 1 hour after the last injection of drugs. The eleventh group was a control for the development of pathology.

Observation results

The arrhythmia caused by calcium chloride in rats of the control group manifested itself for 2-5 seconds in the form of flickering and trembling of the ventricles with the following asystole and death of 100% of the animals 30 seconds after the introduction of the arrhythmogen. The absence of cardiac arrhythmias for 5 minutes after the infusion of calcium chloride was evidence of the effectiveness of the previous administration of the antiarrhythmic agent.

Both drugs weakened the toxic effect of calcium chloride on the heart, contributed to a milder course of arrhythmia (table 1, 2; figure 1, 2).

The average effective doses of thiodoron tablets and the comparison drug were 53.1 ± 1.7 and 42.0 ± 3.1 mg / kg of animal weight, respectively, and the therapeutic index was 90.6 and 129.5, respectively.

Table 1.
The effectiveness of amiodarone in calcium chloride arrhythmia Number of animals Dose mg / kg 40 45 fifty 55 60 perished (abs.) 5 four 3 one 0 survived (abs.) one 2 3 5 6 Live (%) 16.66 33.33 fifty 83.32 one hundred

The tendency of tiodarone to increase antiarrhythmic activity and animal survival can be explained by the expansion of the effect of the drug tiodarone on the pathogenic zones of calcium chloride arrhythmia due to the action of the active ingredient thiotriazolin on metabolic processes in the myocardium.

The introduction of amiodarone at a dose of 60 mg / kg and the drug tiodarone at a dose of 50 mg / kg per day completely eliminated (in 100% of cases) the development of calcium chloride arrhythmia.

Table 2.
The effectiveness of tiodarone in calcium chloride arrhythmia Number of animals Dose mg / kg 30 (20) 35 (23) 40 (26.7) 45 (30) 50 (33.3) perished (abs.) 5 four 3 one 0 survived (abs.) one 2 3 5 6 live (%) 16.66 33.33 fifty 83.32 one hundred Note: in parentheses is the dose of amiodarone in the mixture.

Example II

The study of antiarrhythmic properties of the drug tiodarone on aconitine model

Mixed arrhythmias of the atrioventricular type were reproduced in anesthetized white rats (ethinal sodium at a dose of 30 mg / kg was injected into the abdominal cavity) using intravenous administration of aconitine at a dose of 40 μg / kg. Aconitin causes a violation of the heart rhythm after 2.5 minutes in 40%, and after 7 minutes in 100% of the animals, which is accompanied by extrasystole, paroxysmal tachycardia, atrial and ventricular flutter, and conduction disturbance. After 60 minutes, a gradual resumption of the rhythm of the heartbeat occurs or the animals die. Over 24 hours, the death of about 70% of the animals. Aconitine leads to the appearance of numerous pacemakers. Under the action of aconitine on the myocardium, fast sodium and slow calcium flows directed towards the cells are activated against the background of unchanged potassium output, which excites the membrane potential to the level of the regenerative response.

The antiarrhythmic effect of the comparison drugs was evaluated by the number of animals that survived, as well as by the duration and severity of heart rhythm disturbances. To control cardiac activity, an electrocardiogram was used, which was recorded at the beginning of the experiment and every 2.5 minutes after administration of aconitine.

Studies were performed on 66 Wistar rats of both sexes weighing 180-210 g. Experimental animals were divided into 11 groups (6 animals each). Rats of 1-5 groups for 7 days to the beginning of the simulation of pathology once a day were administered intragastrically the drug tiodarone in the dose range of 20-40 mg / kg, and to rats of 6-10 groups - the comparison drug - amiodarone in the dose range of 30-50 mg / kg To prepare a solution of drugs, appropriate tablets of factory and laboratory manufacture were used.

The introduction of aconitine was carried out one hour after the last injection of the drug, which was studied. The eleventh group was a control for the development of pathology.

Observation results

The administration of aconitine to anesthetized rats at a dose of 40 mg / kg for several minutes led to the development of polytopic extrasystole, paroxysmal tachycardia, atrial fibrillation, decreased motor activity, and impaired respiratory function.

Without the use of drugs (in the control group of animals), 66.6% of rats died within 3 hours after the onset of cardiac arrhythmias.

The absence of cardiac arrhythmias for 40 minutes after the infusion of aconitine indicated the effectiveness of the previous administration of the antiarrhythmic agent.

The results of the study showed that the prophylactic administration of the studied drugs reduced the frequency or completely prevented the development of aconitine arrhythmia, increased the heart rate, intraventricular conduction and atrial excitability.

Based on the data of antiarrhythmic action (Tables 3, 4; Figs. 3, 4) with aconitine arrhythmia and acute toxicity indicators of drugs (LD ₅₀ ), which were studied, the average effective dose (ED ₅₀ ) of amiodarone and tiodarone was calculated. They were 37.6 ± 3.6 and 29.2 ± 3.3 mg / kg of animal weight, respectively, and the therapeutic index (TI) was 128.0 and 182.0, respectively.

Table 3.
The effectiveness of amiodarone in aconitine arrhythmia Number of animals Dose mg / kg thirty 35 40 45 fifty perished (abs.) 5 four 2 one 0 survived (abs.) one 2 four 5 6 live (%) 16.66 33.33 66.65 83.32 one hundred

Table 4.
The effectiveness of the drug tiodarone with aconitine arrhythmia Number of animals Dose mg / kg 20 (13.3) 25 (16.7) 30 (20) 35 (23) 40 (26.7) perished (abs.) 6 5 3 one 0 survived (abs.) 0 one 3 5 6 live (%) 0 16.66 fifty 83.32 one hundred Note: in parentheses is the dose of amiodarone in the mixture.

Preliminary administration of amiodarone at a dose of 50 mg / kg and thiodarone at a dose of 40 mg / kg per day completely eliminated the development of aconitine arrhythmia in 100% of cases.

Generalization and conclusions

The antiarrhythmic activity of the drugs amiodarone and tiodarone was studied with a course (7 days) administration under conditions of cardiac arrhythmias, different in nature and mechanism of development.

In this case, the average effective doses of drugs were: 50.1 ± 1.7 mg / kg for amiodarone and 41.0 ± 3.1 mg / kg for the drug tiodarone with calcium chloride arrhythmias and, respectively, 37.6 ± 3.6 mg / kg and 29.2 ± 3.3 mg / kg of animal weight with aconitine arrhythmia.

The therapeutic index was 96.0 for amiodarone and 129.5 for tiodarone for calcium chloride arrhythmias and 128.0 and 182.0 for aconitine arrhythmias, respectively, at lower LD ₅₀ values in tiodarone - 5310 mg / kg compared to 4810 mg / kg in amiodarone.

After taking tiodarone, the therapeutic effect of eliminating arrhythmias is achieved at a much lower concentration of amiodarone than after monotherapy with amiodarone (1.8 times with potassium chloride arrhythmia and 1.7 times with aconitine arrhythmia). This is due to the potentiating action of thiotriazolin due to stabilization of the membranes of cardiomyocytes, which contributes to a more complete manifestation of the antiarrhythmic properties of amiodarone in lower concentrations and reduces its toxicity.

Thus, based on the data on antiarrhythmic activity obtained under modeling calcium chloride and aconitine arrhythmias, we can conclude that the drug tiodarone (amiodarone - 200 mg + thiotriazolin - 100 mg) is more effective and less toxic than the reference drug - amiodarone (tablets 200 mg) and is promising for subsequent application in a clinical setting.

Information sources

1. Beregovaya EG, Dunaev VV, Mazur I.A., Knysh EG, Kovalenko S.I., Stets A.V., Dueva O.V., Bobrov V.A. Antiarrhythmic activity of triazole derivatives and quinazoline. // Sat scientific Proceedings of Zaporozhye. honey. in-that. - Zaporozhye, 1991 .-- S.312-314.

2. Vizir A.D., Dunaev V.V., Mazur I.A., Voloshin N.A., Stets V.R. Thiotriazolinum. - Zaporozhye: NPO Farmatron. - 1996. - 27 p.

3. Mashkovsky M.D. Medicines A manual for doctors, 2002. - T1. - S. 371-374.

4. Pashneva P.O., Kazarinov M.O. that in. Rozrobka and the achievement of a significant preparation for antiarrhythmic dii - Amiodaron tablets // Pharm. Journal. 1999, No. 3 - S.93-96.

5. Sichov O.S. Prevention and treatment of slut arrhythmias: Facts of evidence-based medicine. // Proof of medicine and looking for consensus in the ills of twigs of organs of blood circulation: Vibrani lectures of the Ukrainian cardiology school. M.D. Strazheska. - K .: Maksimov, 2003 .-- S.93-124.

6. Reference Vidal. Medicines in Russia. M .: AstraPharmService, 1995.- P.259.

7. Amiodarone Trial Meta-Analysis Ivestigators: Effect of prophylactic amiodarone on mortality after acute myocardial infarction and m congestive heart failure: meta-analysis of individual data from 6500 patients in randomized trials. // Lancet, 1997 .-- Vol. 350. - P.1417-1424.

Claims (2)

1. Antiarrhythmic drug with amiodarone, characterized in that it contains thiotriazolin in the ratio to amiodarone - 1: 2 dry matter. 2. The antiarrhythmic drug according to claim 1, characterized in that it is made in the form of a solid dosage form, for example, a tablet containing 60% of a mixture of amiodarone with thiotriazoline, the rest is excipients.

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