Emerging antiarrhythmic agents: a personal view from the Far East.

INTRODUCTION: Arrhythmia treatments today take three different approaches. One uses electronic devices, such as electronic pacemakers or defibrillators, and this is regarded as life-saving in cases of bradyarrhythmias and ventricular fibrillation. Another is the ablation technique which eliminates abnormal pacemakers and/or conductive pathways by applying thermal or cryo-injury to pathological portions of the heart. The most classical one is the antiarrhythmic drugs, but are they effective and safe? AREAS COVERED: Recent development of the understanding of arrhythmias, cardiac ionic channels and antiarrhythmic drugs covered by papers mostly published after 2000 are discussed. EXPERT OPINION: The market size of the antiarrhythmic drugs is small, but various multichannel acting drugs may become candidates as antiarrhythmic drugs. As the cardiac ionic channels have become recognized as proteins, the molecular target for antiarrhythmic drugs has become apparent, but at the same time accurate data on clinical effectiveness and safety are required for drug approval; thus, few atrium selective drugs, such as IKur, IKACh and IKAde blocking drugs and amiodarone-like multichannel acting drugs are being developed.

Torsades de pointes liability inter-model comparisons: the experience of the QT PRODACT initiative.

Safety pharmacologists from the Japanese pharmaceutical industries and contract laboratories made a database to evaluate drug effects on the QT interval in 2005. This QT PRODACT project was a prospective study of 12 QT-prolonging (positive) drugs and 10 non-prolonging (negative) drugs to evaluate the specificity and sensitivity of several in vivo and in vitro animal models: in vitro guinea pig papillary muscle action potential recordings and in vivo ECG recordings in unanesthetized or anesthetized beagle dogs, cynomolgus monkeys and miniature pigs. In guinea pig papillary muscle action potential recordings, positive drugs showed lengthening of the action potential duration (APD). By using a new measure to detect triangulation of the action potential configuration, an IKr blocking activity of drugs with Ca channel blocking action was detected. All in vivo studies showed a QT-prolonging effect of greater than 10% for the positive drugs. These in vivo models were useful to distinguish positive from negative drugs. The QT PRODACT project showed reliability and sensitivity of the experiments to detect positive drugs. The proarrhythmic effects of these positive drugs could not be detected even though, in some animal models (e.g., unanesthetized monkey), torsades de pointes (TdP)-type arrhythmias were shown by terfenadine. We compared in vivo arrhythmia models for proarrhythmia. The halothane-anesthetized open chest coronary occlusion-reperfusion canine model, the halothane-adrenaline arrhythmia model and the chronic AV block dog models seemed to be useful to detect the arrhythmogenic potential of QT-prolonging drugs.

Analysis of proarrhythmic potential of antipsychotics risperidone and olanzapine in anesthetized dogs.

In vitro electrophysiological studies have shown that second-generation antipsychotic drugs risperidone and olanzapine inhibit rapidly activating delayed rectifier K(+) currents and prolong action potential duration of the isolated ventricular myocardium. In this study, we analyzed in vivo cardiohemodynamic and electrophysiological profiles of risperidone and olanzapine using the halothane-anesthetized canine model to clarify their proarrhythmic potential. A clinically relevant dose of risperidone (0.03 mg/kg, i.v.) did not affect the ventricular repolarization process, whereas the supra-therapeutic doses (0.3 and 3 mg/kg, i.v.) prolonged the duration of monophasic action potential of the ventricle. Furthermore, the terminal repolarization period, an index of extent of electrical vulnerability, was prolonged after the supra-therapeutic doses. In contrast, therapeutic to supra-therapeutic doses of olanzapine (0.03-3 mg/kg, i.v.) hardly affected the ventricular repolarization process. Therefore, more caution has to be paid on the use of risperidone than olanzapine for patients with risks of the elevated plasma concentration.

Cardiovascular profile of the canine torsades de pointes arrhythmia model assessed by echocardiographic and haemodynamic methods.

Chronic atrioventricular block dogs have been established as an in vivo model of drug-induced torsades de pointes arrhythmias. We compared the cardiovascular profile of the canine model with that of sham-operated animals using echocardiographic and haemodynamic methods. In the echocardiographic study, the larger diameters of the left atria, inferior vena cava and left ventricle in end-diastole in addition to greater fractional shortening, end-diastolic volume, stroke volume and ejection fraction were more often detected in the chronic atrioventricular block dogs than in the sham-operated animals. During haemodynamic examination, lower cardiac output and higher pulmonary capillary wedge pressure were detected in chronic atrioventricular block dogs more than in sham-operated animals; however, these changes were within the physiological limits, and the results suggest that the chronic atrioventricular block dogs have a pathophysiological profile of chronic compensated heart failure.

Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias.

Although a second-generation histamine H(1) blocker terfenadine induced torsades de pointes (TdP) arrhythmias in patients via the blockade of a rapid component of delayed rectifier K(+) current (I(Kr)), such action of terfenadine has not been detected in previous animal models. We analysed the potential of the canine persistent atrioventricular block heart, a new in vivo proarrhythmia model, to detect a torsadogenic effect of terfenadine of an oral dose of 3 or 30 mg kg(-1). The doses can provide therapeutic to supra-therapeutic plasma concentrations as an anti-histamine. In 2 weeks of bradycardiac heart model, there were no significant changes in any of the electrocardiogram parameters after the administration of both doses of terfenadine. In 4-6 weeks of bradycardiac heart model, the low dose of terfenadine hardly affected any of the electrocardiogram parameters except that it induced TdP in one out of six animals. The high dose significantly decreased the atrial rate and ventricular rate, prolonged the QT interval, and induced TdP in five out of six animals. Moreover, temporal variability of repolarization increased after the high-dose administration. These results suggest that long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect terfenadine-induced TdP.

Reduction of repolarization reserve by halothane anaesthesia sensitizes the guinea-pig heart for drug-induced QT interval prolongation.

The utility of halothane-anaesthetized guinea-pigs as an in vivo model for predicting the clinical potential of a drug to induce QT interval prolongation was assessed using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of D-sotalol (0.3 mg kg(-1)) and terfenadine (0.3 mg kg(-1)), blockers of a rapid component of delayed rectifier potassium currents, prolonged the QT interval by 32+/-7 and 23+/-6 ms, respectively, whereas chromanol 293B (1 mg kg(-1)), a blocker of a slow component of delayed rectifier potassium currents, lengthened it by 33+/-8 ms. The extent of the QT interval prolongation by these drugs was greater than those in previous reports using pentobarbital-anaesthetized guinea-pigs. The MAP duration at the control was shortened by decreasing the pacing cycle length from 400 to 200 ms, but the MAP duration at each cycle length was prolonged by D-sotalol. The formulas of Van de Water, Matsunaga, Fridericia and Bazett showed good correlation of the repolarization period when compared with the MAP duration at a pacing cycle length of 400 ms. The halothane-anaesthetized guinea-pig model may possess enough sensitivity to detect drug-induced QT interval prolongation, indicating that halothane anaesthesia can reduce the repolarization reserve of the heart in vivo.

Halothane sensitizes the canine heart to pharmacological IKr blockade.

The effects of halothane and pentobarbital on the cardiovascular system were compared using the in vivo canine models. The ventricular repolarization process was longer under the halothane-anesthesia than pentobarbital-anesthesia. Intravenous administration of a selective blocker of rapidly activating delayed rectifier K+ currents (I(Kr)) sematilide prolonged the ventricular repolarization period without affecting the intraventricular conduction under both anesthesia; however, the potency was about 1.5-folds greater under the halothane-anesthesia than pentobarbital-anesthesia. These results suggest that halothane can more effectively sensitize the heart to pharmacological I(Kr) blockade, resulting in the excessive QT interval prolongation. Thus, the halothane-anesthetized canine model can be useful for predicting the in vivo I(Kr) blocking property of new drugs.

Effects of SEA0400, a Na+/Ca2+ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs.

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective inhibitor of Na+/Ca2+ exchanger, was investigated for its possible antiarrhythmic effects on arrhythmias of Ca2+ overload induced by coronary ligation/reperfusion and by digitalis in the dog. SEA0400 (1.0 mg/kg) did not change the hemodynamics but slightly prolonged the QRS duration (P<0.05). Pre-ischemic administration (10 min before coronary occlusion) of SEA0400 (1.0 mg/kg) and post-ischemic administration (1 min before reperfusion) of SEA0400 (0.3, 1.0 and 3.0 mg/kg) had no effects on the incidence of ventricular fibrillation induced by coronary ligation/reperfusion. On the other hand, SEA0400 (3.0 mg/kg) decreased the arrhythmic ratio in the digitalis arrhythmias (P<0.01). However, atrioventricular block and cardiac standstill were induced in two digitalized dogs. In conclusion, SEA0400 has no significant antiarrhythmic effect on arrhythmias induced by coronary ligation/reperfusion, but has an obvious suppressing effect on tachyarrhythmias induced by digitalis in in vivo canine models.

Effectiveness of oral magnesium in a patient with ventricular tachycardia due to hypomagnesemia.

A 12-year-old girl with occasional symptoms of chest discomfort was diagnosed with ventricular tachycardia on cardiac evaluation. No evidence of organic heart disease was apparent, but a laboratory evaluation revealed hypomagnesemia. Ventricular tachycardia disappeared after treatment with 200 mg/day of oral magnesium hydroxide, and no further chest discomfort was reported. In addition to routine cardiac evaluation for arrhythmia, serum magnesium levels should be checked in patients with suspected idiopathic benign ventricular tachycardia. Treatment with oral magnesium is a physiologic therapy and should be considered for patients with ventricular tachycardia due to hypomagnesemia.

Practical application of guinea pig telemetry system for QT evaluation.

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Comparison of sensitivity of surrogate markers of drug-induced torsades de pointes in canine hearts.

Given a limited information regarding the difference of the sensitivity of surrogate markers of drug-induced torsades de pointes, including early afterdepolarization, ectopic beats, phase 3 repolarization and dispersion of ventricular repolarization, we simultaneously analyzed them in the halothane-anesthetized canine model (n=5). A non-specific IKr channel blocker sparfloxacin, which has been known to induce torsades de pointes in animals and clinical patients, prolonged the repolarization process in a dose-related and reverse use-dependent manner. No significant change was detected in any of the proarrhythmic markers except for the backward parallel shift of phase 3 repolarization in the cardiac cycle with the QT interval prolongation, which would be the most sensitive marker in predicting the potential arrhythmogenic property of sparfloxacin in the "non-remodeled" normal heart.

Effects of mexiletine on the canine model of sparfloxacin-induced long QT syndrome.

Potential utility of mexiletine for the treatment of sparfloxacin-induced long QT syndrome was assessed using the in vivo halothane-anesthetized canine model. At 30 min after the administration of a supratherapeutic dose of sparfloxacin (30 mg/kg, i.v.), the mean blood pressure and heart rate decreased, whereas repolarization process and effective refractory period of the ventricular muscle were significantly prolonged. Additional administration of a clinically recommended dose of mexiletine (3 mg/kg, i.v.) at this time point increased the mean blood pressure, suppressed ventricular contraction, delayed atrioventricular as well as intraventricular conduction, and shortened repolarization process and effective refractory period. The extent of abbreviation of the repolarization was more prominent than that of the refractoriness, indicating that mexiletine could decrease the electrical vulnerability of the heart during sparfloxacin overdose. Thus, mexiletine may become a promising pharmacological strategy against the drug-induced long QT syndrome.

Cardiovascular effects of Y-27632, a selective Rho-associated kinase inhibitor, assessed in the halothane-anesthetized canine model.

Y-27632, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate, is a selective Rho-associated kinase inhibitor, which has been suggested to possess multiple clinical applications based on the in vitro observations. Since information regarding in vivo cardiovascular effects of Y-27632 is still limited, we assessed them using the halothane-anesthetized, closed-chest canine model. Administration of Y-27632 in a dose of 0.01 mg/kg, i.v. significantly decreased total peripheral vascular resistance together with an increase of cardiac output without affecting other cardiovascular parameters. Moreover, additional administration of Y-27632 in a dose of 0.1 mg/kg, i.v. significantly decreased blood pressure and left ventricular end-diastolic pressure, increased the heart rate and cardiac contractility, enhanced atrioventricular conduction and shortened the repolarization process as well as the effective refractory period. These results indicate that Y-27632 exerts a potent arterio-venodilator action with cardiostimulatory effects possibly through the sympathetic reflex in the in vivo canine model.

In vivo experimental approach for the risk assessment of fluoroquinolone antibacterial agents-induced long QT syndrome.

The proarrhythmic effects of fluoroquinolone antibacterial agents, sitafloxacin, gatifloxacin and moxifloxacin, were compared using three in vivo models. In the halothane-anesthetized dogs (n=5), intravenous 10-min infusion of gatifloxacin and moxifloxacin (1-3 mg/kg) prolonged the ventricular effective refractory period and the repolarization period to a similar extent, whereas sitafloxacin (1-3 mg/kg) prolonged the former only. No significant change was detected in other cardiovascular parameters. In the chronic complete atrioventricular block dogs (n=4), oral administration of 100 mg/kg of gatifloxacin (2 of 4) and moxifloxacin (3 of 4) induced torsades de pointes, which was not observed by sitafloxacin. In the alpha-chloralose-anesthetized rabbits (n=5), intravenous 20-min infusion of 60 mg/kg of gatifloxacin induced torsades de pointes (1 of 5) in the presence of methoxamine infusion, which was not observed by sitafloxacin or moxifloxacin. Thus, the halothane-anesthetized model is suitable for assessing QT prolongation, whereas the chronic complete atrioventricular block model is sensitive for detecting torsadogenic action of drugs. The alpha-chloralose-anesthetized model is the simplest and least expensive method, but its sensitivity to detect proarrhythmic action may be less great.

Does Cl-/HCO3- exchange play an important role in reperfusion arrhythmias in rats?

The protective effects of Cl(-)/HCO(3)(-) exchange inhibitors, 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS) and 4-acetamido-4'isothiocyanato-stilbene-2,2'-disulfonic acid (SITS), against reperfusion-induced arrhythmias were investigated in anesthetized rats. Rats were subjected to 5-min occlusion of the left coronary artery followed by 10-min reperfusion. All drugs were intravenously administered 5 min before the onset of occlusion. DIDS (75 mg/kg) reduced the incidence of ventricular fibrillation and mortality to 0%, whereas SITS (75 mg/kg) only decreased these parameters to 60%. DIDS simultaneously decreased the mean blood pressure and heart rate, and prolonged PQ and QRS intervals, whereas SITS produced a weaker effect on these parameters and no change in QRS interval. Mexiletine (5 mg/kg), which had been demonstrated to suppress the arrhythmias and reduce the heart rate and mean blood pressure in this model, was shown to prolong PQ and QRS intervals. Verapamil (0.5 mg/kg) or diltiazem (0.4 mg/kg) suppressed the arrhythmias, simultaneously decreasing the heart rate and mean blood pressure and prolonging PQ interval. The results indicate that the protective effect of DIDS on reperfusion arrhythmias in the anesthetized rats is unlikely to be attributed to the inhibitory action on Cl(-)/HCO(3)(-) exchange, but possibly mediated by its blocking effects on cardiac ion channels, such as Na(+) or Ca(2+) channels.

Famotidine does not induce long QT syndrome: experimental evidence from in vitro and in vivo test systems.

The effects of famotidine on the cardiac repolarization process were assessed using four different levels of test systems described in the draft stage guideline ICH S7B. A supratherapeutic concentration of famotidine (10(-5) M), which is >8 times higher than C(max) obtained after its therapeutic dose, neither inhibited human ether-a-go-go-related gene (HERG) K(+) current expressed in human embryonic kidney 293 (HEK293) cells nor affected any of the action potential parameters of guinea pig papillary muscles. Therapeutic (0.3 mg/kg, i.v.) to supratherapeutic doses (3-10 mg/kg, i.v.) of famotidine did not affect the repolarization process of the halothane-anesthetized canine model, while only supratherapeutic doses exerted the positive chronotropic, inotropic and dromotropic effects without affecting the mean blood pressure. Moreover, supratherapeutic doses of famotidine (1-10 mg/kg, i.v.) neither induced torsades de pointes nor prolonged QT interval in the canine chronic atrioventricular conduction block model. These results suggest that famotidine possesses no cardiovascular effects at a therapeutic dose, while it may exert cardiostimulatory actions after drug overdoses that might potentiate the proarrhythmic potential of co-administered cardiotonic agents by increasing the intracellular Ca(2+) concentration.

Differences in the subcellular localization of alpha1-adrenoceptor subtypes can affect the subtype selectivity of drugs in a study with the fluorescent ligand BODIPY FL-prazosin.

G protein-coupled receptor (GPCR) subtypes are differentially distributed in the cell; however, it remains unclear how this affects the subtype selectivity of particular drugs. In the present study, we used flow cytometry analysis with the fluorescent ligand, BODIPY FL-prazosin, to study the relationship between the subcellular distribution of subtype receptors and the subtype-selective character of ligands using alpha1a and alpha1b-adrenoceptors (ARs). Alpha1a-ARs predominantly localize inside the cell, while alpha1b-ARs on the cell surface. Flow cytometry analysis and confocal laser-scanning micrographs of living cells showed that BODIPY FL-prazosin can label not only alpha1-ARs on the cell surface, but also those localized inside the cell. Furthermore, flow cytometry analysis of alpha1A-AR-selective drug, KMD-3213, and alpha1B-AR-selective drug, CEC, revealed that the major determinant of the subtype selectivity of each drug is different. The alpha1A-AR selectivity of KMD-3213 can be explained by its much higher affinity for alpha1a-AR than alpha1b-AR (affinity-dependent selectivity), while the alpha1B-AR selectivity of the hydrophilic alkylating agent CEC is due to preferential inactivation of alpha1-ARs on the cell surface (receptor localization-dependent selectivity). This study illustrates that factors in addition to the affinity of the drug for the receptor, such as subcellular localization of the receptor, should be taken into account in assessing the subtype selectivity of a drug.

Development of telemetry system in the common marmoset--cardiovascular effects of astemizole and nicardipine.

The purpose of this study was to evaluate a telemetry system for examining the cardiovascular system in the conscious common marmoset. Parameters obtained were blood pressure, heart rate, respiratory rate, ECG, body temperature and locomotor activity, and these were continuously recorded on a data recorder via the telemetry system and then processed by a computerized system. Diurnal rhythms of blood pressure, heart rate, body temperature and locomotor activity were observed in this system. We studied the effects of astemizole (antihistamine) and nicardipine (Ca2+ channel blocker) on cardiovascular parameters. Astemizole at 30 mg/kg (p.o.) and at 1 to 3 mg/kg (i.v.), prolonged QT interval and induced ventricular extrasystole. Torsades de pointes occurred in one of three cases at 3 mg/kg (i.v.) and 30 mg/kg (p.o.), while it did not affect the blood pressure, respiratory rate and body temperature. Nicardipine at 30 mg/kg (p.o.) caused sustained hypotension and tachycardia. These results demonstrate the usefulness of the telemetry system using the common marmoset for evaluating the cardiovascular effects of drugs under physiological conditions.

Arrhythmia models for drug research: classification of antiarrhythmic drugs.

The aim of this study was to classify antiarrhythmic drugs based on their effectiveness on 6 in vivo arrhythmia models, mainly using dogs. The models were produced by two-stage coronary ligation, digitalis, halothane-adrenaline, programmed electrical stimulation in old myocardial infarction dogs, coronary artery occlusion/reperfusion, or chronic atrioventricular block. Na(+)-channel-blocking drugs suppressed two-stage coronary ligation and digitalis arrhythmias. Ca(2+)-channel blockers and beta-blockers suppressed halothane-adrenaline arrhythmia. Positive inotropic drugs aggravated halothane-adrenaline arrhythmia, but did not aggravate digitalis arrhythmia. K(+)-channel blockers suppressed programmed electrical stimulation induced arrhythmia, but induced torsades de pointes type arrhythmia in chronic atrioventricular block dogs and aggravated halothane-adrenaline arrhythmia. Na(+)/H(+)-exchange blockers suppressed coronary artery occlusion/reperfusion arrhythmias. This classification may be useful for predicting the clinical effectiveness in the preclinical stage of drug development.

Pravastatin inhibits arrhythmias induced by coronary artery ischemia in anesthetized rats.

We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2 mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P<0.05) decreased MPO activities, but only pravastatin decreased the incidence of ischemia-induced lethal VF. Both statins had no significant effects on body weight, blood pressure, heart rate, and QT interval as we reported earlier. Our results prove further that pravastatin has benefits to decrease cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in prevention of arrhythmias. A decrease in the neutrophil infiltration may be partly involved in the inhibitory effect of pravastatin on the ischemia-induced VF.