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Antiarrhythmic plasma concentrations of NIK-244 on canine ventricular arrhythmias
K Hashimoto1, T Matsuzaki, A Haruno
1Department of Pharmacology, Yamanashi Medical College, Japan.
Abstract:
Using two-stage coronary ligation-, digitalis-, and epinephrine (EPI)-induced canine ventricular arrhythmias, we examined antiarrhythmic effects of NIK-244 and determined the minimum effective plasma concentration for each arrhythmia model. NIK-244 suppressed coronary ligation- and digitalis-induced arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24-h and 48-h coronary ligation and digitalis were 0.41 +/- 0.10 (by 1 mg/kg i.v.), 0.70 +/- 0.13 (by 1 mg/kg i.v.), and 0.21 +/- 0.08 (by 0.5 mg/kg i.v.) microgram/ml, respectively (mean +/- SD of the mean, n = 6). The concentration for digitalis-induced arrhythmia was significantly lower than those for coronary ligation arrhythmias. NIK-244 was not effective on EPI arrhythmia, and 1 mg/kg worsened the arrhythmia to ventricular fibrillation in three of six dogs. This pharmacologic profile is similar to those of disopyramide, procainamide, and SUN 1165. Since NIK-244 had no deleterious effects on blood pressure and sinus node activity, its clinical usefulness is expected.
Insights
NIK-244 effectively suppressed canine ventricular arrhythmias induced by coronary ligation and digitalis. Its antiarrhythmic effects were observed at specific plasma concentrations, with no adverse impact on blood pressure or sinus node activity.
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
Background:
- Ventricular arrhythmias pose a significant clinical challenge.
- Developing novel antiarrhythmic agents with favorable safety profiles is crucial.
Purpose of the Study:
- To evaluate the antiarrhythmic efficacy of NIK-244 in canine models of ventricular arrhythmias.
- To determine the minimum effective plasma concentration of NIK-244 for different arrhythmia types.
Main Methods:
- Ventricular arrhythmias were induced using two-stage coronary ligation, digitalis, and epinephrine (EPI) in canine models.
- Antiarrhythmic effects and minimum effective plasma concentrations of NIK-244 were assessed.
- Hemodynamic parameters, including blood pressure and sinus node activity, were monitored.
Main Results:
- NIK-244 demonstrated significant suppression of coronary ligation- and digitalis-induced arrhythmias.
- Minimum effective plasma concentrations were determined: 0.41 ± 0.10 µg/ml (24-h ligation), 0.70 ± 0.13 µg/ml (48-h ligation), and 0.21 ± 0.08 µg/ml (digitalis).
- NIK-244 was ineffective against EPI-induced arrhythmias and, at 1 mg/kg, exacerbated them to ventricular fibrillation in 50% of subjects.
Conclusions:
- NIK-244 exhibits potent antiarrhythmic activity against specific models of ventricular arrhythmias.
- The drug's favorable safety profile, with no adverse effects on blood pressure or sinus node function, suggests potential clinical utility.
- The observed pharmacologic profile resembles that of established antiarrhythmic drugs like disopyramide and procainamide.