BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents

• Published in: British journal of pharmacology 1986-06, Vol.88 (2), p.333-343
• Main Authors: Allan, G., Donoghue, S., Follenfant, M.J., Sawyer, D.A.
• Format: Article
• Language: English
• Subjects: Aconitine - pharmacology; Action Potentials - drug effects; Anesthesia; Animals; Anti-Arrhythmia Agents - pharmacology; Antiarythmic agents; Applied sciences; Arrhythmias, Cardiac - drug therapy; Arrhythmias, Cardiac - etiology; Biological and medical sciences; Cardiovascular system; Dogs; Electrocardiography; Exact sciences and technology; Female; Guinea Pigs; In Vitro Techniques; Male; Medical sciences; Membrane Potentials - drug effects; Other techniques and industries; Pharmacology. Drug treatments; Rats; Rats, Inbred Strains; Time Factors; Triazines - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1986.tb10209.x

1 BW A256C (5(3)‐amino‐6‐(2,3‐dichlorophenyl)‐2,3(2,5)‐dihydro‐3(5)‐imino‐2‐isopropyl‐1,2,4‐triazine) is a novel class 1 antiarrhythmic agent designed to combine the features of potency with reduced central nervous system penetration. 2 BW A256C reduced the maximum rate of depolarization of guinea‐pig ventricle and dog Purkinje fibres in vitro (EC50, 2.2 × 10−6 M and 1.8 × 10−6 M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine‐induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses. 3 In anaesthetized dogs, intravenous administration of BW A256C (0.25‐1 mg kg−1) caused a dose‐dependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery. 4 In conscious dogs, intravenous infusion (total dose, 1.5 mg kg−1) or oral administration of BW A256C (1.25‐5 mg kg−1) caused dose‐dependent suppression of the ventricular ectopic activity that occurred following 20–24 h of permanent coronary artery ligation. 5 In the conscious dog, BW A256C was approximately 7 times more potent and was also longer acting than flecainide. 6 Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3–4 times greater than the antiarrhythmic levels were associated with a pro‐arrhythmic activity.