ANTIARRHYTHMIC ACTIVITY OF A NOVEL AMINO-ACID-CONTAINING COMPOUND NIBENTAN

To study the antiarrhythmic activity of L-glutamyl Nibentan racemate, experiments were carried out on 120 white mice of both sexes and the weight of 18 20 g, rats of both sexes and the weight of 180 220 g, as well as on 24 mongrel cats of both sexes and the weight of 2,800-4,000 g. The substance of a structural analog of Nibentan, L Glutamate-(RS)-Nibentan, synthetized and manufactured by Russian Scientific Center for Safety of Biologically Active Compounds (manufacturer’s ID code: LHT 01 14) was studied. The acute toxicity of the compounds was studied during a single intraperitoneal administration of LHT 01 14 to white laboratory mice. The DL50 index was assessed using the probit analysis. The LHT 01 14 antiarrhythmic activity was studied on the models of aconitine arrhythmia in rats as well as early occlusion/reperfusion arrhythmia in cats. The initial dose of the study compound was determined as 5% of murine DL50 taking the interspecies dose scaling into the account. Nibentan was used as a comparator. DL50 for LHT 01 14 made up 80.8±7.2 mg/kg (CI: 70.9-90.8 mg/kg), i.e., higher than that for Nibentan (50.2±3.4 mg/kg, p=0.012) and permits one to consider the study compound as of Grade III of toxicity. LHT 01 14 effectively prevented development of atrial arrhythmia caused by administration of aconitine nitrate. The antiarrhythmic index calculated for LHT 01 14 is higher than that for Nibentan. Therefore, LHT 01 14 has a higher therapeutic safety than the comparator. This fact gives evidence of a higher safety of LHT 01 14 with the same activity. Administration of LHT 01 14 in doses of 0.6 mg/kg and 0.3 mg/kg prevented ischemic arrhythmia and ischemic/reperfusion ventricular fibrillation in 100% of experiments (statistically significant as compared with the control, p<0.05) and decreased the risk of reperfusion ventricular arrhythmia to 33%. Thus, the novel medication manufactured in Russia, Nibentan racemate compound with L-glutamyl, is less toxic than its structural predecessor, has a more considerable therapeutic window, and has a similar strength and duration of its therapeutic effect on the model of transient ischemic and reperfusion arrhythmogenesis as its structural predecessor, Nibentan.

antiarrhythmics, aconitine arrhythmia, occlusion and reperfusion arrhythmias, Nibentan compounds, acute toxicity

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