Nupafant, a PAF‐antagonist prototype for suppression of ventricular fibrillation without liability for QT prolongation?

• Published in: British journal of pharmacology Vol. 149; no. 3; pp. 269 - 276
• Main Authors: Baker, K E, Wood, L M, Whittaker, M, Curtis, M J
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-10-2006; Nature Publishing; Nature Publishing Group
• Subjects: Animals; Anti-Arrhythmia Agents - pharmacology; antiarrhythmic; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Coronary heart disease; Dose-Response Relationship, Drug; Electrocardiography - drug effects; Heart; Leucine - analogs & derivatives; Leucine - pharmacology; Male; Medical sciences; myocardial ischaemia; Myocarditis. Cardiomyopathies; nupafant; Pharmacology. Drug treatments; platelet activating factor; Platelet Activating Factor - antagonists & inhibitors; Platelet Activating Factor - physiology; Rats; Rats, Wistar; Research Papers; Sulfonamides - pharmacology; ventricular fibrillation; Ventricular Fibrillation - drug therapy; Ventricular Fibrillation - etiology; Sulfanilamide derivatives; Heart; Nupafant; Arrhythmia; myocardial ischaemia; Prolonged QT interval; antiarrhythmic; Cardiovascular disease; Myocardial ischemia; Antiarrhythmic agent; Coronary heart disease; Myocardial disease; Conduction disorder; Excitability disorder; Platelet activating factor; Ventricular fibrillation; Vascular disease; Heart block; Circulatory system; Antagonist
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706846

Background and purpose:
PAF antagonists inhibit ischaemia‐induced ventricular fibrillation (VF) in animals. However, unfavourable ancillary actions (on QT interval and coronary flow) have been reported with the PAF antagonist, BN‐50739. If these are class actions, they would preclude development of PAF antagonists as novel anti‐VF drugs. Our purpose was to examine this proposition using the hitherto untested PAF antagonist, nupafant.
Experimental approach:
Two rat heart preparations (Langendorff and ‘dual coronary’ perfusion) were used to assay nupafant's effects on ischaemia‐induced VF, coronary flow and QT interval, and to test for the site‐selectivity necessary if any effects on VF are caused by PAF antagonism.
Key results:
Global (whole‐heart) delivery of 10 μM nupafant, reduced the incidence of ischaemia‐induced VF and widened QT interval without affecting coronary flow. Importantly, lower concentrations (0.1 and 1 μM) had no effect on VF, yet widened QT almost identically to 10 μM nupafant. When nupafant was delivered selectively to (and entrapped within) the involved region it partially protected against VF (P<0.05). This occurred without change in QT interval. Selective nupafant delivery to the uninvolved region was without effect.
Conclusions and implications:
Nupafant protects against ischaemia‐induced VF primarily by site‐selective actions in the ischaemic region but, unlike BN‐50739, the effect is unrelated to its QT widening action, and is not compromised by any effect on coronary flow. This establishes proof of concept that VF suppression by PAF antagonism need not invariably be associated with QT prolongation or vasodilatation, justifying further development of this drug class.
British Journal of Pharmacology (2006) 149, 269–276. doi:10.1038/sj.bjp.0706846