F 373280, (D)-panthenol mono-ester of DHA: a novel antiarrhythmic compound for the treatment of atrial fibrillation.

E Dupont-Passelaigue, R Létienne, C Pignier, B Le Grand. Laboratoire Pierre Fabre, Castres 81106, France

F 373280 (mono-ester of panthotenic alcohol and DHA) is a novel DHA derivative which, as a safe pro-drug of DHA, exerts antiarrhythmic properties by interacting with the electrical and structural remodelling of the atria. Experimental investigations were conducted in HEK293 cell line transfected with hKv1.5 channel using the whole cell patch clamp technique to evaluate whether DHA (acid form) and F 373280 could block the sustained component of IKv1.5. Pure DHA reduces sustained IKv1.5 in a concentration-dependent manner with corresponding IC50 of 6.6 µM. F 373280 (10 µM) also reduces sustained IKv1.5 by 56.1% whereas the other derivatives including EPA remain less potent. IC50 for F373280 could only be estimated for late IKv1.5 with value of 13.7 µM. The effects of F373280 on atrial effective refractory period (AERP) were investigated in anaesthetized pig using a conventional pacing protocol through epicardial electrodes placed on the left atrium. F373280 administered as a bolus and an infusion (10 mg/kg) significantly increased AERP (23.8 ± 2.2 ms versus -7.3 ± 11.5 ms in the presence of vehicle, P<0.05). Similarly, the variation in atrial ERP reached 27 ± 4 ms in the presence of F373280 (40 mg/kg). In addition, F373280 was devoid of significant effect on the hemodynamic and the ECG intervals. F 373280 therefore represents a novel therapeutic opportunity for the intravenous and oral treatment of atrial fibrillation. Finally, F 373280 through the release of DHA will provide a safer anti-arrhythmic activity on atria than available currently used compounds in clinical practice.