Antiarrhythmic agent
(57) Abstract:
The invention relates to the section of experimental medicine and can be used to create a new antiarrhythmic drug. The application of the agonist Delta-opioid receptor deltorphin II as an anti-arrhythmic drug. Action means associated with activation Delta-opioid receptor. The invention expands the Arsenal of the declared destination. table 1.
The invention relates to the section of experimental medicine and can be used to create a new antiarrhythmic agent.
Today we know that deltorphin II exerts antinociceptive [1] and wagoliticeski effects [2].
We used the tool deltorphin II was purchased in the firm cris Cookson Ltd., UK.
In its structure this connection peptide of the following structure:
Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2
We first identified its antiarrhythmic effect.
Previously it was shown that intravenous injection of agonists deltapine receptors is accompanied by increased resistance of the myocardium to the arrhythmogenic effects [3, 4]. Given these results, we hypothesized that children understood from the following description:
Experiments conducted on rats male Wistar rats weighing 180-200 g arrhythmia modeled by means of occlusion of the left coronary artery (10 min) and subsequent restoration of coronary blood flow (reperfusion 10 min) under ketamine anesthesia. During ischemia and reperfusion were recorded ECG in the second chest leads to determining the frequency of occurrence of ventricular heart rhythm disturbance (arrhythmia, tachycardia and fibrillation) in the group. Recording and processing of ECG data was carried out with the help of the biopotential amplifier (UBF-03, Russia) and IBM PC/AT/486 using the original software package. Deltorphin II was dissolved in isotonic NaCl and injected experimental animals intravenously at a dose of 0.12 mg/kg for 10 min to coronarography. The results were processed statistically using the method2and t-student test.
Example. Study the antiarrhythmic activity of deltorphin II was carried out according to the following scheme. In the group of experimental animals we have taken 14 rats, which for 10 min to simulate arrhythmias was intravenously injected a solution of the drug. As a control group took 15 animals, which for 10 min to simulate arrhythmias of nutrion odnom lead and counted the frequency of occurrence of multiple ventricular extrasystoles (MIA), ventricular tachycardia (VT), ventricular fibrillation (state), and the number of animals without cardiac arrhythmias (BIA). The results were summed up for each group and statistically were analyzed by nonparametric criterion2.
During ischemia, as shown in table 1, the introduction of deltorphin II (0,12 mg/kg) decreases the incidence of VT in 4 times during ischemia and during reperfusion.
Our results show that in models of ischemic and reperfusion arrhythmias deltorphin II has a pronounced antiarrhythmic effect during 10-minute coronariography and subsequent restoration of coronary blood flow. Thus, this drug can be used as a new antiarrhythmic agent.
Literature
1. The-opioid receptor: Molecular Pharmacology, Signal Transduction, and the determination of drug efficacy /R. M. Quock, T. N. Burkey, E. Varga et al. //Pharmacol. Rew. - 1999. - Vol.51, No. 9. - P. 503-532.
2. Farias I. M. Cardiac Enkephalins Interrupt Vagal Brady Cardia Via the {delta}-2-Opioid Receptors in the Sinoatrial Node. /I. M. Farias, K. E. Jackson, D. Yoshishige, J. L. Caffrey //Am. J. Physiol. Heart. Circ. Physiol. - 2003. - Vol. 9.
3. Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive potassium channels /R. M. Fryer, A. K. Hsu, H. Nagase, G. J. Gross //J. Pharmac. ExC.D. Mikhailova, N. A. Babakova, ,And. Storageco, T. M. Semushkina //Bul. the experimental. biology and medicine. - 1999. - T. 127, No. 2. - S. 164-166.
The use of agonist Delta-opioid receptor deltorphin II as a new antiarrhythmic agent.
where R1and R2each independently represent a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, a C1-6-alkoxygroup or a hydroxyl group; R3represents a hydroxyl group or a C1-6-alkylcarboxylic; R4represents a hydrogen atom, or R3and R4together form a bond, m is an integer from 0 to 4, n represents an integer from 0 to 4, Y is absent or represents CR11R12where R11and R12each independently represents a hydrogen atom or a C1-6is an alkyl group, R5represents an aryl group or heteroaryl group, such as thienyl, pyridyl or indolyl, where this aryl group may be optionally substituted
(R10), where R10represents a halogen atom, a hydroxyl group, a C1-6-alkyl group, where this alkyl group may be optionally substituted by atom galactography, di-C1-6-alkylamino, C1-6-alkoxycarbonyl group, carboxyl group, q is an integer from 1 to 3, and each R10may be the same or different when q is 2 or 3, R6represents a hydrogen atom or a C1-6is an alkyl group, R10represents a hydrogen atom or a C1-6is an alkyl group, X is absent or represents C=O or SO2; R8represents a hydrogen atom, a C1-6-alkyl group, where this alkyl group may be optionally substituted by a halogen atom, or WITH3-6-cycloalkyl group, and R9represents a halogen atom, a nitro-group, or cyano; or their pharmaceutically acceptable salts, as well as a drug on the basis of these compounds with anti-arrhythmic activity
where VI, R=-H, VIa R=-C(O)H, VIIŠ± R=-C(O)CH3, VIIIa R=-CH3, VIIIŠ± R=-C2H5and their pharmaceutically acceptable salts of dicarboxylic acids, which have anti-arrhythmic and anti-ischemic activity and intensity of effect exceeds applicable in the clinic verapamil, amiodarone and lidocaine
-hydroxyethyl)tsitizina formula (I) exhibiting high antiarrhythmic activity and low toxicity
where R(1) denotes CF3; one of the substituents R(2) and R(3) represents hydrogen; and the other of the substituents R(2) or R(3) represents-CH(CH3)-CH2OH; R(4) denotes methyl, and their pharmaceutically acceptable salts
FIELD: medicine, cardiology.
SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.
EFFECT: higher efficiency of therapy.
3 ex
