The quest for an anti-arrhythmic drug against atrial fibrillation that combines efficacy with safety
This editorial refers to 'The combined ion channel blocker AZD1305 attenuates late Na current and I Kr -induced action potential prolongation and repolarization instability' B. Andersson et al., on page 1003 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. 1 -7 For that purpose, the company developed agents that shared the property to suppress the rapid
... component of the delayed rectifier current (I Kr , 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, I Kr block was accompanied in the properties of the drug by inhibiting effects on other ion currents, especially the L-type calcium current (I CaL ) and both the peak and the late sodium current (I Na and I Na 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-longshort sequence explaining why Andersson et al. 1 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, 2,3,8 a rather specific blocker of I Kr . Because this agent induced TdP in a number of patients enrolled in early clinical trials, the drug was withdrawn from further clinical development. 9 However, research at AstraZeneca to identify novel agents as well as exploring mechanisms underlying drug-induced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. 2, 3 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. 2 This indicated the relevance of the speed of drug administration for TdP development. In the second category, drugs such as: (i) lidocaine, 3 a drug that blocks I Na and, more recently, was described to also block I Na late in a ratio of 1:3, (ii) the I CaL blockers nisoldipine and flunarizine, and (iii) ryanodine, a blocker of the sarcoplasmic reticulum Ca 2+ release channel were combined with almokalant to prevent pro-arrhythmia. Recently, it has been shown that the I CaL blocker flunarizine also blocks I Kr and I Na late without affecting the peak I Na current. 10 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. 3 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 I CaL -blocking properties to the regular I Kr 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.