The quest for an anti-arrhythmic drug against atrial fibrillation that combines efficacy with safety.

There is a long history at AstraZeneca to succeed in developing an anti-arrhythmic agent that can safely and effectively restore and maintain sinus rhythm in atrial fibrillation (AF) patients. –7 For that purpose, the company developed agents that shared the property to suppress the rapid component of the delayed rectifier current (IKr, Table 1). These drugs prolong repolarization quantified as QT times in vivo or as duration of the action potential (APD) in vitro and are classified as Class III anti-arrhythmics. This strategy is effective against AF, but carries the risk of ventricular pro-arrhythmia, meaning that the drugs may be unsafe. With time proceeding, IKr block was accompanied in the properties of the drug by inhibiting effects on other ion currents, especially the L-type calcium current (ICaL) and both the peak and the late sodium current (INa and INa late, respectively). This combined ion channel block, by preventing the occurrence of early afterdepolarizations (EADs) and spatial dispersion of repolarization, would lead to protection against Torsade de Pointes (TdP) pro-arrhythmia, while maintaining the high efficacy against AF. These pro-arrhythmic activities are often evoked by the short– long– short sequence explaining why Andersson et al. included dynamic adaptation of APD using cycle length changes mimicking the short–long–short sequence in their paper published. But let me tell the story. It started off with almokalant, a rather specific blocker of IKr. Because this agent induced TdP in a number of patients enrolled in early clinical trials, the drug was withdrawn from further clinical development. However, research at AstraZeneca to identify novel agents as well as exploring mechanisms underlying drug-induced repolarization-related pro-arrhythmia continued. Nice examples are the relevance of the infusion rate for almokalant-induced TdP and investigations in which different antiarrhythmic drugs were combined with almokalant to reduce its potential to induce EADs and TdP. In the previous study, triggered by a clinical case of TdP in a patient unintentionally administered almokalant at twice the intended rate, it was demonstrated that slow infusion, albeit causing greater increases in QT in time, considerably reduced pro-arrhythmia (1/8 vs. 9/10) in the methoxamine-sensitized rabbit model. This indicated the relevance of the speed of drug administration for TdP development. In the second category, drugs such as: (i) lidocaine, a drug that blocks INa and, more recently, was described to also block INa late in a ratio of 1:3, (ii) the ICaL blockers nisoldipine and flunarizine, and (iii) ryanodine, a blocker of the sarcoplasmic reticulum Ca2+ release channel were combined with almokalant to prevent pro-arrhythmia. Recently, it has been shown that the ICaL blocker flunarizine also blocks IKr and INa late without affecting the peak INa current. Lidocaine administered at low and high doses was demonstrated to dose-dependently reduce almokalant-induced TdP with a total TdP prevention with the high dose (0/8) in the methoxaminesensitized rabbit model of TdP. This protective effect of lidocaine did not reflect in the QT-time, which still increased considerably with almokalant. Similar results were seen with the other agents investigated that interfere with Ca-handling. Logically, the first new anti-arrhythmic drug of AstraZeneca to be tested was a multiple ion channel blocker (Table 1): H345/52 that added ICaL-blocking properties to the regular IKr antagonism. 4 On the basis of non-clinical findings in Purkinje fibres and ventricular myocytes, Langendorff perfused hearts, and in the methoxamine-sensitized rabbit, an agent markedly delaying myocardial repolarization without inducing repolarization-related pro-arrhythmia seemed to be found. However, although no cases of TdP were reported in 350 AF patients exposed to H345/52, poor bioavailability and a low efficacy in restoring sinus rhythm halted further clinical development.