Combination of dofetilide and mexiletine for the prevention and treatment of atrial fibrillation

Abstract

Effective and safe pharmaceutical composition and method for treating atrial fibrillation are described. The combined use of dofetilide and mexiletine resulted in an enhanced efficacy in the prevention and treatment of atrial fibrillation with markedly reduced risk of the life-threatening ventricular arrhythmia TdP.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is entitled to priority pursuant to 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 222,973, filed Sep. 24, 2015, the disclosure of which is hereby incorporated by reference herein in its entirety.BACKGROUND OF THE INVENTION[0002]Atrial fibrillation is the most common abnormal heart rhythm affecting approximately 5.2 million people in United States, more than 10 million in China1,2 and 33 million world-wide.3 Despite improvements in primary and secondary prevention of coronary artery disease, and effective treatment of hypertension and other heart diseases, the prevalence of atrial fibrillation continues to rise. The rise in atrial fibrillation may, at least in part, be due to the longer average life span of humans. It is projected that atrial fibrillation prevalence will increase to 12.1 million cases in 2030 in the US.4 Atrial fibrillation predisposes patients, particularly elders, to a higher risk for s...

AI Technical Summary

Benefits of technology

[0007]It is now discovered that mexiletine not only is an effective suppressor of TdP via inhibition of the late sodium current, but also acts synergistically with dofetilide, an antiarrhythmic drug for the treatment of atrial fibrillation, to result in a major improvement in the treatment of atrial fibrillation, with a decreased risk of ventricular arrhythmias. Combined use of dofetilide and mexiletine can expand the dose range of dofetilide bidirectionally (i.e. a smaller minimal effective dose to a higher safe dose) in the treatment of atrial fibrillation because of the synergistic effect of both drugs in suppression of atrial fibrillation and reduction of risks of ventricular proarrhythmias. This will greatly enhance capability of clinicians to treat atrial fibrillation in a conservative way rather than via invasive procedures like radiofrequency ablation because both efficacy and safety profiles of the combined use of dofetilide and mexiletine are markedly improved.

[0009]In another general aspect, embodiments of the invention relate to a method of treating and / or preventing atrial fibrillation or a symptom associated therewith in a subject in need thereof, comprising administering to the subject an effective amount of dofetilide and an effective amount of mexiletine. The effective amount of mexiletine can be administered together with the effective amount of dofetilide in the same pharmaceutical composition such as that according to an embodiment of the invention. The effective amount of mexiletine can also be administered separately from the effective amount of dofetilide in a different pharmaceutical composition, so long as the dosing schedules of dofetilide and mexiletine overlap, such that the administered mexiletine is effective to reduce the risk of adverse effects associated with the administered dofetilide and / or to enhance the efficacy of the administered dofetilide.

[0010]In a preferred embodiment of the invention, a method of the invention results in more efficacious treatment of atrial fibrillation or a symptom associated therewith with reduced adverse effects in a subject in need thereof than the conventional treatment with dofetilide alone. For example, according to an embodiment of the invention, a method of the invention significantly increases atrial effective refractory period (ERP) in comparison to that achieved by the administration of the effective amount of dofetilide alone, and reduces at least one of early after depolarization (EAD), EAD-dependent R-on-Textrasystoles, and Torsades de Pointes (TdP) induced by the administration of the effective amount of dofetilide, in a subject in need thereof.

Problems solved by technology

Both approaches have advantages and disadvantages, and both are insufficient to eliminate atrial fibrillation.

There is a higher reoccurrence rate of atrial fibrillation when patients are treated with drug therapy than radiofrequency ablation due to relatively poor efficacy and incidence of adverse effects of drugs for the management of atrial fibrillation.

Images