RU2235553C1 - Anti-arrhythmic agent - Google Patents
Anti-arrhythmic agent Download PDFInfo
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- RU2235553C1 RU2235553C1 RU2003106354/15A RU2003106354A RU2235553C1 RU 2235553 C1 RU2235553 C1 RU 2235553C1 RU 2003106354/15 A RU2003106354/15 A RU 2003106354/15A RU 2003106354 A RU2003106354 A RU 2003106354A RU 2235553 C1 RU2235553 C1 RU 2235553C1
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- arrhythmic
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- arrhythmias
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- 239000003416 antiarrhythmic agent Substances 0.000 title claims abstract description 6
- 239000000556 agonist Substances 0.000 claims abstract description 3
- 230000003288 anthiarrhythmic effect Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 5
- NUNBRHVOPFWRRG-RCEFDBTISA-N Deltorphin B Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(=O)NCC(N)=O)C(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 NUNBRHVOPFWRRG-RCEFDBTISA-N 0.000 abstract description 3
- 108700040991 Ala(2)- deltorphin II Proteins 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- 230000000694 effects Effects 0.000 abstract 2
- 230000004913 activation Effects 0.000 abstract 1
- 230000007721 medicinal effect Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 206010003119 arrhythmia Diseases 0.000 description 6
- 230000006793 arrhythmia Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 3
- 208000028867 ischemia Diseases 0.000 description 3
- 230000010410 reperfusion Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010047302 ventricular tachycardia Diseases 0.000 description 3
- 208000001778 Coronary Occlusion Diseases 0.000 description 2
- 206010011086 Coronary artery occlusion Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 108700023159 delta Opioid Receptors Proteins 0.000 description 2
- 102000048124 delta Opioid Receptors Human genes 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 208000003663 ventricular fibrillation Diseases 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 108010092674 Enkephalins Proteins 0.000 description 1
- 206010015856 Extrasystoles Diseases 0.000 description 1
- 102000016924 KATP Channels Human genes 0.000 description 1
- 108010053914 KATP Channels Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 206010058156 Reperfusion arrhythmia Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 208000009729 Ventricular Premature Complexes Diseases 0.000 description 1
- 206010047289 Ventricular extrasystoles Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003502 anti-nociceptive effect Effects 0.000 description 1
- 230000003126 arrythmogenic effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 206010061592 cardiac fibrillation Diseases 0.000 description 1
- 230000005961 cardioprotection Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000002600 fibrillogenic effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000001013 sinoatrial node Anatomy 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000001515 vagal effect Effects 0.000 description 1
- 230000000980 vagolytic effect Effects 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Изобретение относится к разделу экспериментальной медицины и может быть использовано для создания нового антиаритмического средства.The invention relates to the field of experimental medicine and can be used to create a new antiarrhythmic drug.
На сегодняшний день известно, что дельторфин II оказывает антиноцицептивный [1] и ваголитический эффекты [2].To date, it is known that deltorfin II has antinociceptive [1] and vagolytic effects [2].
Использованное нами средство deltorphin II было закуплено в фирме Тоcris Cookson Ltd., UK.The deltorphin II product we used was purchased from Tocris Cookson Ltd., UK.
По своей структуре это соединение пептидной природы следующего состава:In its structure, it is a peptide compound of the following composition:
Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH 2
Нами впервые выявлено его антиаритмическое действие.We first revealed its antiarrhythmic effect.
Ранее было показано, что внутривенная инъекция агонистов дельтаопиоидных рецепторов сопровождается повышением устойчивости миокарда к аритмогенным воздействиям [3, 4]. Учитывая данные результаты, мы предположили, что агонист дельта2-ОР дельторфин II также может обладать антиаритмическим действием.It was previously shown that intravenous injection of deltaopioid receptor agonists is accompanied by increased myocardial resistance to arrhythmogenic effects [3, 4]. Given these results, we hypothesized that the delta2-OP agonist, deltorfin II, may also have antiarrhythmic effects.
Изобретение будет понятно из следующего описания:The invention will be clear from the following description:
Эксперименты проведены на крысах самцах линии Вистар массой 180-200 г. аритмии моделировали при помощи окклюзии левой коронарной артерии (10 мин) и последующим восстановлением коронарного кровотока (реперфузия 10 мин) под кетаминовым наркозом. Во время ишемии и реперфузии регистрировали ЭКГ во втором грудном отведении с определением частоты возникновения желудочковых нарушений ритма сердца (экстрасистолии, тахикардии и фибрилляции) в группе. Запись и обработку данных ЭКГ осуществляли при помощи усилителя биопотенциалов (УБФ4-03, Россия) и ПЭВМ IBM/AT/486 с использованием оригинального пакета прикладных программ. Дельторфин II растворяли в изотоническом растворе NaCl и вводили экспериментальным животным внутривенно в дозе 0,12 мг/кг за 10 мин до коронароокклюзии. Результаты обрабатывали статистически, используя метод χ2 и t-критерий Стьюдента.The experiments were carried out on rats of male Wistar strain weighing 180-200 g. Arrhythmias were simulated by 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, an ECG was recorded in the second chest lead with a determination of the frequency of occurrence of ventricular cardiac arrhythmias (extrasystoles, tachycardia and fibrillation) in the group. ECG data were recorded and processed using a biopotential amplifier (UBF4-03, Russia) and an IBM / AT / 486 PC using an original application package. Deltorfin II was dissolved in an isotonic NaCl solution and administered to experimental animals intravenously at a dose of 0.12 mg / kg 10 min before coronary occlusion. The results were statistically processed using the χ 2 method and student t-test.
Пример. Исследование антиаритмической активности дельторфина II проводилось по следующей схеме. В группу опытных животных нами было взято 14 крыс, которым за 10 мин до моделирования аритмий внутривенно вводился раствор исследуемого препарата. В качестве контрольной группы брали 15 животных, которым за 10 мин до моделирования аритмий внутривенно вводился изотонический раствор NaCl. Затем в каждой серии экспериментов мы проводили запись ЭКГ во втором грудном отведении и подсчитывали частоту встречаемости множественных желудочковых экстрасистол (МЖЭ), желудочковой тахикардии (ЖТ), желудочковой фибрилляции (ЖФ), а также количество животных без нарушений сердечного ритма (БЖА). Результаты суммировались по каждой группе и статистически обрабатывались по непараметрическому критерию χ2.Example. The study of the antiarrhythmic activity of deltorfin II was carried out according to the following scheme. In the group of experimental animals, we took 14 rats, which 10 minutes before the simulation of arrhythmias, a solution of the studied drug was injected intravenously. As a control group, 15 animals were taken, which 10 minutes before the simulation of arrhythmias was injected with an isotonic NaCl solution. Then, in each series of experiments, we recorded the ECG in the second chest assignment and calculated the frequency of occurrence of multiple ventricular extrasystoles (MJE), ventricular tachycardia (VT), ventricular fibrillation (VF), and the number of animals without heart rhythm disturbances (BVA). The results were summarized for each group and statistically processed according to the nonparametric criterion χ 2 .
При ишемии, как показано в таблице 1, введение дельторфина II (0,12 мг/кг) приводит к уменьшению частоты возникновения ЖТ в 4 раза как во время ишемии, так и в период реперфузии.With ischemia, as shown in table 1, the introduction of deltorfin II (0.12 mg / kg) leads to a decrease in the frequency of occurrence of VT by 4 times both during ischemia and during reperfusion.
Полученные нами результаты свидетельствуют о том, что на модели ишемических и реперфузионных аритмий дельторфин II обладает выраженным антиаритмическим эффектом как во время 10-минутной коронароокклюзии, так и при последующем восстановлении коронарного кровотока. Таким образом, данный опиоид может быть использован в качестве нового антиаритмического средства.Our results indicate that in the model of ischemic and reperfusion arrhythmias, deltorfin II has a pronounced antiarrhythmic effect both during 10-minute coronary occlusion and in the subsequent restoration of coronary blood flow. Thus, this opioid can be used as a new antiarrhythmic agent.
ЛитератураLiterature
1. The δ-opioid receptor: Molecular Pharmacology, Signal Transduction, and the determination of drug efficacy /R.M.Quock, Т.Н.Burkey, E.Varga et al. //Pharmacol. Rew. - 1999. - Vol.51, №9. - P. 503-532.1. The δ-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 {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. 9.2. Farias I.M. Cardiac Enkephalins Interrupt Vagal Brady Cardia Via {delta} -2-Opioid Receptors in the Sinoatrial Node. / I.M. Faris, 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. Exp. Ther. - 2000. - Vol.294. - P. 451-457.3. 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. Exp. Ther. - 2000. - Vol. 294. - P. 451-457.
4. Роль δ-опиатных рецепторов в механизме развития ишемических аритмий сердца /С.Д.Михайлова, Н.А.Бебякова, Г.И.Сторажаков, Т.М.Семушкина //Бюл. эксперим. биологии и медицины. - 1999. - Т. 127, №2. - С. 164-166.4. The role of δ-opiate receptors in the mechanism of development of ischemic arrhythmias of the heart / S.D. Mikhailov, N. A. Bebyakova, G. I. Storazhakov, T. M. Semushkina // Bull. an experiment. biology and medicine. - 1999. - T. 127, No. 2. - S. 164-166.
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| Application Number | Priority Date | Filing Date | Title |
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| RU2003106354/15A RU2235553C1 (en) | 2003-03-05 | 2003-03-05 | Anti-arrhythmic agent |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2260442C1 (en) * | 2004-02-03 | 2005-09-20 | ГУ Научно-исследовательский институт кардиологии Томского научного центра СО РАМН | Anti-arrhythmic agent |
| RU2320342C2 (en) * | 2005-07-27 | 2008-03-27 | ГУ Научно-исследовательский институт кардиологии Томского научного центра Сибирского отделения Российской академии медицинских наук, ГУ НИИ кардиологии ТНЦ СО РАМН | Anti-arrhythmic agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294519B1 (en) * | 1998-05-01 | 2001-09-25 | University Of Kentucky Research Foundation | Method for treating ischemia |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6294519B1 (en) * | 1998-05-01 | 2001-09-25 | University Of Kentucky Research Foundation | Method for treating ischemia |
Non-Patent Citations (2)
| Title |
|---|
| Дощицин В.Л. Лечение аритмий сердца. - М.: Медицина, 1993, с.38. * |
| Реферат из АБД Medline: Gustafsson H. et al. Morphine-induced in vivo release of spinal cholecystokinin is mediated by delta-opioid receptors-effect of peripheral axotomy. J. Neurochem. 2001 Jul; 78(1): 55-63. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2260442C1 (en) * | 2004-02-03 | 2005-09-20 | ГУ Научно-исследовательский институт кардиологии Томского научного центра СО РАМН | Anti-arrhythmic agent |
| RU2320342C2 (en) * | 2005-07-27 | 2008-03-27 | ГУ Научно-исследовательский институт кардиологии Томского научного центра Сибирского отделения Российской академии медицинских наук, ГУ НИИ кардиологии ТНЦ СО РАМН | Anti-arrhythmic agent |
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