Antiarrhythmic Activity of Amino Acids Containing Nibentan Derivatives in Case of Symptoms of Occlusive and Reperfusion Arrhythmias

S. M. Napalkova, O. V. Buyuclinskaya
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Abstract

Introduction. Pharmacotherapy of cardiac arrhythmias is one of the urgent problems of modern medicine. The presence of serious side effects, in particular proarrhythmic action, limits the use of known antiarrhythmics in clinical practice. One way to reduce the toxicity of pharmacological agents is to use them as complex compounds with amino acids.Aim. Studying the effect of nibentan derivatives containing magnesium salt of L-aspartic acid and glycine as anions on the course of early occlusive and reperfusion arrhythmias.Materials and methods. Aminоacid derivatives of nibentan have been studied in models of occlusive and reperfusion arrhythmias in rats. The activity of the drugs was assessed by the incidence of ventricular extrasystoles (VEC), ventricular tachycardia (VT), ventricular fibrillation (VF), by the latent period and duration of arrhythmias, the average duration of VT, and by the number of VEC per 1 animal.Results and discussion. Nibentan derivatives in models of early occlusive and reperfusion arrhythmias were not inferior in antiarrhythmic activity to lidocaine and nibentan in their ability to prevent cardiac arrhythmias. The nibentan derivative containing the magnesium salt of L-aspartic acid (compound LHT-53-91) in the model of occlusive arrhythmias at a dose of 2 % LD50 completely prevented cardiac arrhythmias in experimental animals. A nibentan derivative containing glycine (compound LHT-20-92) at a dose of 1 % LD50 significantly reduced the number of cases of PVCs, prevented the occurrence of ventricular tachycardia and ventricular fibrillation in 100 % of cases. In the model of reperfusion arrhythmias, LHT-53-91 at a dose of 1 % LD50 prevented the development of ventricular fibrillation and paroxysms of ventricular tachycardia and reduced the risk of developing ventricular extrasystole (p < 0.05). Increasing the dose to 2 % LD50 led to an increase in the activity of the substance, which was expressed in the prevention of cardiac arrhythmias in 100 % of the animals. LHT-20-92 at a dose of 1 % LD50 in this model of cardiac arrhythmias statistically significantly reduced the occurrence of VES and VT paroxysms and completely prevented the occurrence of VF (p < 0.05).Conclusion. The inclusion of nibenthan amino acids in the structure, which shielded genotic grouping and reduced potential teratogenicity and mutagenicity, had not led to a reduction in the antiarrhythmic and antifibril-torn activity on the studied models of rhythm disorders.
含尼本坦衍生物的氨基酸对闭塞性和再灌注性心律失常症状的抗心律失常活性
介绍。心律失常的药物治疗是现代医学亟待解决的问题之一。严重副作用的存在,特别是促心律失常的作用,限制了已知抗心律失常药物在临床实践中的应用。降低药理学药物毒性的一种方法是将其作为氨基酸的复合化合物使用。以l -天冬氨酸镁盐和甘氨酸为阴离子的尼本坦衍生物对早期闭塞性和再灌注性心律失常病程的影响。材料和方法。研究了尼本坦氨基甲酸衍生物在大鼠闭塞性和再灌注性心律失常模型中的作用。以室性早搏(VEC)、室性心动过速(VT)、心室颤动(VF)发生率、心律失常潜伏期和持续时间、室性心动过速平均持续时间、每1只动物VEC数评价药物的活性。结果和讨论。尼本坦衍生物在早期闭塞性和再灌注性心律失常模型中的抗心律失常活性并不亚于利多卡因和尼本坦预防心律失常的能力。含l -天冬氨酸镁盐的尼本丹衍生物(化合物LHT-53-91)在2% LD50剂量下对闭塞性心律失常模型有完全预防作用。含有甘氨酸的尼本坦衍生物(化合物LHT-20-92)在1% LD50剂量下显著减少了室性早搏的病例数,100%的病例中防止了室性心动过速和心室颤动的发生。在再灌注型心律失常模型中,1% LD50剂量的LHT-53-91可预防室性颤动和室性心动过速发作,降低室性心动过速发作的风险(p < 0.05)。将剂量增加到2% LD50导致该物质的活性增加,在100%的动物中表现为预防心律失常。1% LD50剂量的LHT-20-92可显著降低心律失常模型VES和VT发作的发生,完全阻止VF的发生(p < 0.05)。在结构中包含nibenthan氨基酸,屏蔽了基因分组,降低了潜在的致畸性和诱变性,并没有导致抗心律失常和抗原纤维撕裂活性的降低。
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