UA74982C2 - Antiarrhythmic drug - Google Patents

Abstract

The invention relates to the medicine, in particular to the pharmacotherapy, namely to the antiarrhythmic drugs, in particular their dosage forms representing tablets, dragees, suppositories, solutions, etc. According to the invention, the drug contains the mixture of Thiotriasolin and Amiodaron, preferably at a 1:2 ratio (mass of dry substance) and the excipients. The invention provides for increasing efficacy in treating the disorders of heart rhythm allowing for decreasing doses of the active ingredients.

Description

Description of the invention

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

One of the most serious complications of cardiovascular diseases is a violation of the rhythm of cardiac activity. The course of myocardial infarction is complicated by arrhythmias in up to 90-95 cases.

The well-known drug thiotriazoline has a wide range of pharmacological effects: antioxidant, membrane-stabilizing, anti-ischemic, anti-inflammatory, immunomodulatory, cholate-stimulating, stimulating 70 cell regeneration, cardioprotective, hepatoprotective, antiarrhythmic and other types of activity.

Thiotriazoline is produced in the form of solutions for injections, tablets, ointments, suppositories, eye drops and is widely used in medical practice, including in the treatment of cardiovascular diseases. However, it is still not used enough to treat heart rhythm disorders.

Among antiarrhythmic drugs, amiodarone - a highly effective drug based on a 12-based modified benzofuran derivative - amiodarone hydrochloride, attracts special attention. It belongs to the first-line means for stopping paroxysmal flickering and fluttering of the atria, prevents and reduces the frequency of sudden death due to asymptomatic complex ventricular arrhythmias (Pashneva R.O., Kazarinov M.O. and others.

Development and research of the domestic antiarrhythmic drug - "Amiodarone" tablets// Pharm. magazine 1999, Mo. 3- p. 93-96).

We take this drug as the prototype, as it is the closest in terms of purpose and effectiveness.

The disadvantages of the prototype are the narrow spectrum of pharmacological action of amiodarone and its increased consumption to ensure the pharmacological effect of heart rhythm treatment, which may be the cause of disruption of the normal functioning of other organs. When using amiodarone tablets, numerous side effects may occur from various body systems: nausea, feeling of heaviness in the epigastrium, loss of appetite, hepatitis, cough, suffocation, wheezing in the chest, ataxia, tremor, muscle weakness, bradycardia, hypotension, Ge) slowing of atrioventricular conduction, reduction of visual acuity, photosensitization and allergic reactions

IMashkovskyi M.D. Medicines. Handbook for doctors, 2002.-11.-S.371-374).

The basis of the invention is the task of developing an antiarrhythmic drug that increases the effectiveness of biological action while reducing the dose and cost of the drug for the course of treatment of active ingredients. high school

The solution to the task is provided by an antiarrhythmic drug that contains the active ingredient amiodarone due to the introduction of the drug thiotriazoline in a ratio of thiotriazoline to amiodarone of 1:2. The specified medicinal product is applied in the form of a solid, dosed form of "Tiodarone". Me.

The pharmacological advantages of the medicinal product according to the invention are due to the mutually potentiating effect of thiotriazoline, which has antioxidant, membrane-stabilizing, cerebroprotective and other effects, and amiodarone, which has a high antiarrhythmic activity. At the same time, the consumption of a mixture of amiodarone with thiotriazoline ("Thiodarone") to eliminate heart arrhythmia is 2095 less than the consumption of amiodarone for the same purpose.

The essence of the invention is explained by the following description and examples of preclinical experiments of the drug "Thiodarone" according to the invention and the prototype - "Amiodarone" and drawings, where in Fig. 1 - the effectiveness of amiodarone in calcium chloride arrhythmia, in Fig. 2 - the effectiveness of amiodarone in aconitine arrhythmia, in Fig. 4 - From 50, the effectiveness of tiodarone in aconitine arrhythmia. c Amiodarone and tiodarone tablets were used for the experiments.

From" The composition of the ingredients for one tablet of tiodarone in terms of 10095 dry matter: - amiodarone - 0.20g - thiotriazoline - 010g - - auxiliary substances up to 0.50g "" Weight of the finished tablet - 0.B0g is), That is, a tablet (solid form) medicinal product) contains 6095 active ingredients in a total weight of 50% of the mixture at a ratio of thiotriazoline to amiodarone of 1:2 and 4095 excipients.

For experiments, tiodarone tablets were produced by the Central Laboratory of Galichpharm JSC. For

IR) comparison of their effectiveness used factory-produced amiodarone tablets.

The antiarrhythmic activity of the drugs was evaluated according to the indicators of the therapeutic index (TI) using the average lethal (LD 5o: amiodarone - 4810 mg/kg and tiodarone - 5310 mg/kg, respectively) and average therapeutic (EDvo) doses. TI - LDvo to EDvo. The therapeutic index was determined on the models of calcium chloride and aconitine arrhythmia during course administration of the comparator drugs.

Example 1. Study of the antiarrhythmic properties of the drug tiodarone on the calcium chloride model with de course administration.

Ventricular arrhythmias were induced by intravenous administration of calcium chloride at a dose of 250 mg/kg of body weight in 60 animals. The occurrence of arrhythmias is associated with an increase in the concentration of intracellular calcium, with the subsequent release of hormones, an increase in the activity of adenylate cyclase and TsAMP. Heart rhythm disturbances are detected within 10 seconds after the introduction of calcium chloride in the form of ventricular flutter (about 9095 cases), or systole followed by ventricular fibrillation (about 1095 cases). Within 120 seconds, all animals die.

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

The research was conducted on 66 Uuiviag rats of both sexes weighing 170-200g. Experimental animals were divided into 11 groups (6 animals in each). Rats of groups 1-5 during the 7th day before the beginning of pathology modeling were injected once a day intragastrically (inside) in fractions with the drug tiodarone in the dose range of 30-50 mg/kg (based on the active ingredients - thiotriazoline and amiodarone), and rats 6 - 10 groups - a comparison drug - amiodarone (arrhythmil, BHFZ) in the dose range of 40-60 mg/kg. For the preparation of the drug solution, appropriate factory-made amiodarone tablets and tiodarone tablets manufactured in the central laboratory of JSC "Halychpharm" for preclinical studies were used.

Administration of calcium chloride was carried out 1 hour after the last administration of drugs. 7/0 The eleventh group was a control for the development of pathology.

Results of observations

Arrhythmia caused by calcium chloride in rats of the control group appeared within 2-5 seconds in the form of flickering and fluttering of the ventricles, followed by asystole and the death of 10,095 animals 30 seconds after the introduction of the arrhythmogen. The absence of heart rhythm disturbances within 5 minutes after the infusion of calcium chloride was 7/5 evidence of the effectiveness of the previous administration of the antiarrhythmic agent.

Both drugs, which weakened the toxic effect of calcium chloride on the heart, contributed to an easier course of arrhythmia (Tables 1, 2; Figs. 1, 2).

The average effective doses of tiodarone tablets and the comparison drug were 53.1, 41.7 and 42.0-3 mg/kg of animal weight, respectively, and the therapeutic index was 90.6 and 129.5, respectively. with chloride calcium arrhythmia

The number of animals in Tv vn se zaptulogaye) 54310. about education) 123 55.

The tendency of tiodarone to increase antiarrhythmic activity and survival of animals can obviously be explained by the expansion of the effect of the drug tiodarone on the pathogenic zones of calcium chloride arrhythmia due to the action (ee) of the active ingredient - thiotriazoline on metabolic processes in the myocardium.

Administration 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 10,090 F cases) the development of calcium chloride arrhythmia. "And" them with chloride-calcium arrhythmia "1 zaptulotue 54810 Z s viktofo) 102355. g

Example 2. Study of the antiarrhythmic properties of the drug tiodarone on the aconitine model - Arrhythmia of the mixed atrioventricular type was reproduced in anesthetized white rats (etaminal sodium at a dose of 30 mg/kg was injected into the abdominal cavity) with the help of intravenous administration of aconitine at a dose of 40 μg/kg. Aconitine causes heart rhythm disturbances after 2.5 minutes. at 4095, and after 7 min. in is) 10,095 animals, accompanied by extrasystole, paroxysmal tachycardia, atrial flutter and about 50 ventricles, conduction disturbances. Through bOkhv. there is a gradual recovery of the rhythm of heart contractions or the animals die. About 7,095 animals died within 24 hours. Aconitine leads to the appearance

IR) of numerous pacemakers. When aconitine acts on the myocardium, fast sodium and slow calcium flows directed into the cells are activated against the background of unchanged potassium output, which shifts the membrane potential to the level of the regenerative response. 22 The antiarrhythmic effect of the comparator drugs was assessed by the number of animals that survived, as well as by duration

Gee! and severity of heart rhythm disorders. An electrocardiogram was used to monitor cardiac activity, which was recorded at the beginning of the experiment and every 2.5 minutes after aconitine administration. where Research was conducted on 66 rats of the UMiziag line of both sexes weighing 180 - 210 g. Experimental animals were divided into 11 groups (6 animals in each). Rats of groups 1-5 were injected intragastrically with the drug tiodarone in a dose range of 20-4Omg/kg for 7 days before the beginning of pathology modeling once 60 times a day, and rats of groups 6-10 - a comparison drug - amiodarone in a dose range of 30-50 mg / kg. Appropriate factory and laboratory-made tablets were used to prepare a solution of medicinal products.

Administration of aconitine was carried out one hour after the last administration of the study drug.

The eleventh group was a control for the development of pathology. 65 Results of observations

Administration of aconitine to anesthetized rats at a dose of 4 Ω/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), 66.69% of rats died within 3 hours after the onset of heart rhythm disturbances.

Absence of heart rhythm disturbances within 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 aconicotin arrhythmia, accelerated the recovery of the frequency of heart contractions, intragastric conduction and atrial excitability.

Based on the data of antiarrhythmic action (Table 3, 4; Figs. 3, 4) in aconitine arrhythmia and indicators of acute toxicity of the studied drugs (LDh5o), the average effective dose (EDrvo) of amiodarone and the drug 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.

Prior administration of amiodarone at a dose of 5 mg/kg and tiodarone at a dose of 40 mg/kg per day completely eliminated the development of aconitine arrhythmia in 100 90 cases. zaptuloyuye) 54210. vyyuloyye) 1002455. sch (8) with aconitine arrhythmia zo so zapeulotyue 5005350 viktofo) 00103015 F live 01001655 vo 8332) 100 « with m

Generalizations and conclusions

The antiarrhythmic activity of amiodarone and tiodarone drugs was studied during course (7 days) administration in "conditions of heart rhythm disorders, different in nature and mechanism of development."

At the same time, the average effective doses of drugs were -50.1--1.7mg/kg for amiodarone and 41.0-3.1mg/kg - s - for the drug tiodarone in chloride calcium arrhythmia and, accordingly, 37.6 -3.bmg /kg and 29.2--3.3mg/kg of animal weight "" in aconitine arrhythmia. The therapeutic index was - 96.0 for amiodarone and 129.5 - for the drug tiodarone in chloride calcium arrhythmia and, accordingly, 128.0 and 182.0 in aconitine arrhythmia, with lower values of LDvo in tiodarone -5310 mg/kg, against 4810 mg/kg in amiodarone. - After taking tiodarone, the therapeutic effect of eliminating arrhythmias is achieved at a significantly lower concentration of their amiodarone than after monotherapy with amiodarone (1.8 times with chlorcalcium arrhythmia and 1.7 times with anicotin arrhythmia). This is due to the potentiating effect of thiotriazoline, due to the stabilization of cell membranes, 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 the conditions of simulation of calcium chloride and aconitine arrhythmia, it can be concluded that the drug tiodarone (amiodarone - 200 mg G thiotriazoline - 100 mg) is more effective and less toxic than the reference drug - amiodarone (tablets of 200 mg) and is promising for further use in clinical conditions. (F,

Claims (3)

The formula of the invention is) 1. An antiarrhythmic drug containing amiodarone, which differs in that it additionally contains 60 thiotriazoline. 2. Antiarrhythmic drug according to claim 1, which differs in that it contains thiotriazoline in the ratio of amiodarone - 1:2 dry substance. 3. Antiarrhythmic drug according to claim 2, which differs in that it is produced in the form of a solid dosage form, for example, a tablet containing 60-5 95 of a mixture of amiodarone with thiotriazoline and the rest - auxiliary substances.