Anti-arrhythmic agent
FIELD: medicine, chemistry of peptides.
SUBSTANCE: invention proposes a new anti-arrhythmic agent that represents a peptide ligand of opioid receptors deltorphine D - compound of the formula (I): Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2 (I). The effect of this agent is associated with stimulation of opioid receptors and results to reducing frequency in arising multiple ventricular extrasystoles and episodes of ventricular tachycardia.
EFFECT: valuable medicinal properties of agent.
1 tbl, 1 ex
The invention relates to the section of experimental medicine and can be used to create a new effective anti-arrhythmic drug.
Today it is known that ligands of opioid receptors possess analgesic [3] and immunomodulatory [2] actions.
Used the tool deltorphin D was synthesized in the Department of Pathology, University of Kentucky (Lexington, Kentucky, USA).
In its structure this connection peptide of the following composition:
Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2
For the first time revealed its antiarrhythmic effect.
Previously it was shown that injection of peptide agonists μ-opioid receptor is accompanied by increased tolerance of the heart to the arrhythmogenic effects of epinephrine, aconitine and CaCl2[1]. Considering the obtained results, let us assume that the drug deltorphin D which are able to bind with opioid receptors, can also have antiarrhythmic action. Therefore the research on the impact of deltorphin D on the stability of the heart to the arrhythmogenic action of transient ischemia and reperfusion.
The invention will be clear from the following description.
Experiments conducted on rats male Wistar rats weighing 200-250 g, anesthetized with ketamine (50 mg/kg intraperitoneally). Arrhythmia was modeled PR is using the occlusion of the left coronary artery (10 min) and subsequent restoration of coronary blood flow (reperfusion 10 min) [4]. During the whole experiment the animals were housed in artificial ventilation of room air, which was performed using the modernized machine RO-2 (St. Petersburg, Russia). 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 computer Pentium using the original software package. Deltorphin D was dissolved in dimethyl sulfoxide (DMSO) followed by dilution of a 45%aqueous solution of 2-hydroxypropyl-β-cyclodextrin (Sigma-RBI, Natick, MA, USA). The study drug was administered intravenously 15 minutes before coronariography at a dose of 0.3 mg/kg served as Control animals in which simulated transient ischemia and reperfusion without the introduction of drugs. The results were processed statistically using the method χ2and t-student test.
Example. Study the antiarrhythmic activity of deltorphin D was carried out according to the following scheme.
The control group was taken 15 animals, which for 15 min to simulate arrhythmias was intravenously injected with isotonic NaCl solution. B group of experimental animals was taken 14 rats over 15 MINDO of coronarography was intravenously injected a solution of the drug. Then, within each series of experiments conducted ECG recording in the second chest leads and counted the frequency of occurrence of multiple ventricular extrasystoles (MIA), episodes of ventricular tachycardia (VT) and ventricular fibrillyatsy (state), and the number of animals without cardiac arrhythmias (BIA). The results were summed up for each group and statistically were analyzed by nonparametric criterion χ2.
During ischemia, as shown in table 1, the introduction of deltorphin D (0.3 mg/kg) decreases the incidence MIA in 1.5, VT - 2.5 times. In addition, a 3 times increase in the number of rats without ventricular arrhythmias. At reperfusion reduced the likelihood of adipose tissue and MGE 3.8 and 2.4 times, respectively. In addition, 3 times increases the number of animals without cardiac rhythm.
The results indicate that models of ischemic and reperfusion arrhythmias deltorphin D has a pronounced antiarrhythmic effect during 10-minute coronariography and subsequent reperfusion.
Thus, this drug can be used as a new anti-arrhythmic drug.
| Table1 | ||||||
| Ischemia | Reperfusion | |||||
| BIA(%) | MGA(%) | Adipose tissue(%) | BIA(%) | MGA(%) | Adipose tissue(%) | |
| Control(n=15) | 2(13) | 13(87) | 11(73) | 2(13) | 12(86) | 8(53) |
| Deltorphin D | * | ** | * | *** | ||
| (0.3 mg/kg) (n=14) | 6(43) | 8(57) | 4(29) | 6(43) | 5(36) | 2(14) |
| Notes: * P<0.01; ** P<0.025; *** P<0.05 (trustworthiness in relation to control) |
LITERATURE
1. Lishmanov SHE, Maslov LN, Krylatov AV Peripheral μ-opiate receptors and regulation of the stability of the heart to the arrhythmogenic effects. BBM. 1998. 125(6): S-653.
2. Plotnikoff, N., Miller G. Enkephalins as immunomodulators. Int. J. Immunopharm. 1983. 5(5): P.437-441
3. Roemer D., H. Buescher, R. Hill et al A synthetic enkephalin with prolonged par-enteral and oral analgesic activity. Nature. 1977. No. 268. R-549.
4. Schultz J.E.J., Hsu AK, Nagase h., Gross G.J. TAN-67, δ1-opioid receptor agonist, reduces infarct dementia size via activation of Gi/oproteins and KATPchannels. Am. J. Physiol. 1998. 274: H909-H914.
The use of a ligand of the opioid receptor deltorphin D as a new antiarrhythmic agent.
FIELD: medicine.
SUBSTANCE: method involves applying the remedy comprising taurine, an ingredient containing magnesium, an ingredient having tartaric acid as base, an ingredient having L-glutamic acid as base, an ingredient having fumaric acid as base, an ingredient having succinic acid as base, an ingredient having L-aspartic acid as base. An ingredient serving as magnesium source has at least one magnesium compound with succinic, fumaric, glutamic, aspartic, malic, citric or isocitric acid and/or any compound of general formula (I): (R1)n-Mg-(R2)m, where R1 and R2 are succinic, fumaric, glutamic, aspartic, malic, citric or isocitric acid radicals, n=1-50, m=1-50. The remedy is supposed to have at least one potassium salt and at least one ammonium salt.
EFFECT: enhanced effectiveness of treatment.
8 cl, 8 tbl
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new piperidine compounds of the general formula (I) wherein A means preferably ring of the formula:
wherein R1 means hydrogen atom (H), cyano-group (CN), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group; W means (C1-C6)-alkylene that can be substituted, ordinary bond; Z means optionally substituted aromatic hydrocarbon cyclic (C6-C14)-group; l means a number from 0 to 6. Compounds show the excellent activity directed for inhibition of sodium channels and selective inhibition of potassium channels.
EFFECT: improved preparing method, improved inhibiting method, valuable medicinal properties of compounds.
26 cl, 4 tbl, 476 ex
FIELD: organic chemistry, chemical technology, medicine, pharmacy.
SUBSTANCE: invention relates to a new biologically active compound. Invention describes quaternary ammonium derivative of lidocaine of the formula:
eliciting anti-arrhythmic activity. Also, invention describes a method for preparing quaternary ammonium derivative of lidocaine of the formula (1). Method involves interaction of N-(2,6-dimethylphenylaminocarbonylmethyl)-morpholine with allyl bromide in isopropyl alcohol medium at temperature 58-62°C followed by cooling the reaction mixture to room temperature and isolation of N-allyl-(2,6-dimethylphenylaminocarbonylmethyl)-morpholinium bromide. Invention provides preparing new compound eliciting useful biological properties.
EFFECT: improved preparing method.
2 cl, 4 tbl, 4 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new derivatives of cyclic amide of the formula (I)
or its salt, or hydrate, or solvate wherein X represents (C1-C6)-alkyl, (C1-C6)-alkyl substituted with phenyl, (C2-C6)-alkenyl substituted with phenyl or halogenphenyl, (C2-C6)-alkynyl substituted with phenyl, phenyl that can be substituted with (C1-C6)-alkyl; one or more halogen atom, nitro-group, phenyl, (C1-C6)-alkoxy-group, halogen-(C1-C6)-alkyl, halogen-(C1-C6)-alkoxy-group, phenyl-(C1-C6)-alkyl, (C1-C6)-alkoxyphenyl-(C1-C6)-alkyl, amino-group, optionally substituted with (C1-C6)-alkyl, acetyl, (C1-C6)-alkoxy-group, substituted with phenyl, phenylcarbonyl, furanyl; 1- or 2-naphthyl, monocyclic (C3-C8)-cycloalkyl, amino-group substituted with one or more substitutes taken among phenyl, halogenphenyl, (C1-C6)-alkoxyphenyl, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, phenyl-(C1-C6)-alkyl; 5- or 6-membered monocyclic heterocyclic group comprising 1 or 2 heteroatoms, such as nitrogen (N), oxygen (O), sulfur (S) atom optionally substituted with halogenphenyl, halogen atom, benzyl, (C1-C6)-alkyl, phenyl; 8-10-membered bicyclic heteroaryl group comprising 1 or 2 heteroatoms taken among N, O and optionally substituted with halogen atom; 8-10-membered polycyclic cycloalkyl group; Q means -CH2-, -CO-, -O-, -S-, -CH(OR7)- or -C(=NR8)- wherein R7 means hydrogen atom (H), (C1-C6)-alkyl; R8 means OH, (C1-C)-alkoxy-group, acylamino-group, (C1-C6)-alkoxycarbonylamino-group, phenyl-(C1-C6)-alkoxy-group; n = 0-5; B represents group
or
wherein each among R3, R4, R5 and R6 represents independently substitute taken among group consisting of hydrogen atom (H), halogen atom, NO2 (nitro-group), (C1-C6)-alkoxy-group, CN (cyano-group); m = 1 or 2; ring
represents 5- or 6-membered aromatic heterocyclic ring comprising one or two heteroatoms taken among O, S, N. Compound of the formula (I) elicit activity inhibiting binding sigma-receptors that allows their using as component of medicinal agent.
EFFECT: valuable medicinal properties of compounds.
21 cl, 2 sch, 4 tbl, 183 ex
FIELD: medicine, cardiology.
SUBSTANCE: along with injecting antiarrhythmic remedy one should introduce varfarin at the dosage of 1-5 mg for 6-8 d followed by a maintenance course in 1-1.5 mo at the dosage of 2-3 mg for 6-7 d and in 2-3 mo at the dosage of 1-2 mg for 5-7 d.
EFFECT: higher efficiency of therapy.
3 ex
FIELD: pharmaceutical chemistry, medicine.
SUBSTANCE: invention relates to new compounds of formula I ,
solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,
wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.
EFFECT: new antiarrhythmic drugs.
30 cl, 12 dwg, 34 ex
FIELD: organic chemistry, pharmacology.
SUBSTANCE: invention relates to compounds of formula I ,
where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).
EFFECT: higher efficiency.
13 cl, 18 ex, 1 tbl
FIELD: organic chemistry, heterocyclic compounds, purines, medicine.
SUBSTANCE: invention relates to a method for treatment of arrhythmia in mammal. Method involves administration of agonist of adenosine A1-receptors in the therapeutically effective minimal dose of the formula:
wherein R1 represents optionally substituted heterocyclic group. The indicated dose of agonist is in the range from 0.0003 to 0.009 mg/kg. Method shows the enhanced effectiveness and doesn't result to undesirable adverse effects.
EFFECT: improved treatment method, valuable medicinal properties of substances.
11 cl, 1 dwg, 2 ex
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to synthesis of new biologically active substance, namely, to γ-hydroxypropylammonium-5-hydroxynicotinate of the formula (I): , eliciting an anti-ischemic, anti-arrhythmic and hypolipidemic activity. This compound shows low toxicity and absence of cardiodepressive effect. Compound of the formula (I) is prepared by interaction of 5-hydroxynicotinic acid with 3-amino-1-propanol in the presence of a solvent at heating.
EFFECT: valuable medicinal properties of compound.
1 cl, 7 tbl, 3 ex
where R and R1have the meanings indicated in the claims
-helix in the presence of lipids and which is characterized by the following formula: Z1-X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-Z2,or its pharmaceutically acceptable salt, values radicals cm
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FIELD: medicine, chemistry of peptides.
SUBSTANCE: invention proposes a new anti-arrhythmic agent that represents a peptide ligand of opioid receptors deltorphine D - compound of the formula (I): Tyr-D-Leu-Phe-Ala-Asp-Val-Ala-Ser-Thr-Ile-Gly-Asp-Phe-His-Ser-Ile-NH2 (I). The effect of this agent is associated with stimulation of opioid receptors and results to reducing frequency in arising multiple ventricular extrasystoles and episodes of ventricular tachycardia.
EFFECT: valuable medicinal properties of agent.
1 tbl, 1 ex
