Effects of K201 on repolarization and arrhythmogenesis in anesthetized chronic atrioventricular block dogs susceptible to dofetilide-induced torsade de pointes

The novel antiarrhythmic drug K201 (4-[3-{1-(4-benzyl)piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine monohydrochloride) is currently in development for treatment of atrial fibrillation. K201 not only controls intracellular calcium release by the ryanodine receptors, but also possesses a ventricular action that might predispose to torsade de pointes arrhythmias. The anti- and proarrhythmic effects of K201 were investigated in the anesthetized canine chronic atrioventricular block model. Two doses of K201 (0.1 and 0.3mg/kg/2 min followed by 0.01 and 0.03 mg/kg/30 min i.v.) were tested in 4 serial experiments in dogs with normally conducted sinus rhythm (n=10) and in torsade de pointes-susceptible dogs with chronic atrioventricular block. Susceptibility was assessed with dofetilide (0.025 mg/kg/5 min i.v.). Beat-to-beat variability of repolarization was quantified as short-term variability of left ventricular monophasic action potential duration. In dogs with normally conducted sinus rhythm, both doses of K201 prolonged ventricular repolarization whereas only the higher dose prolonged atrial repolarization. At chronic atrioventricular block, dofetilide induced torsade de pointes in 9 of 10 dogs. K201 did neither suppress nor prevent dofetilide-induced torsade de pointes. K201 dose-dependently prolonged ventricular repolarization. In contrary to the lower dose, the higher dose did increase beat-to-beat variability of repolarization (from 1.2 ± 0.3 to 2.9 ± 0.8 ms, P<0.05) and resulted in spontaneous, repetitive torsade de pointes arrhythmias in 1 of 7 dogs; Programmed electrical stimulation resulted in torsade de pointes in 2 more dogs. In conclusion, both doses of K201 showed a class III effect. No relevant antiarrhythmic effects against dofetilide-induced torsade de pointes were seen. Only at the higher dose a proarrhythmic signal was observed.     

A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs

INTRODUCTION: Instability of QT duration is a marker to predict Torsade de Pointes (TdP) associated with both congenital and drug-induced long QT syndrome. We describe a new method for the quantification of instability of repolarization. METHODS: Female, adult beagle dogs anesthetized with a potent morphinomimetic were treated with either solvent (n=7) or dofetilide (n=7). Poincaré plots with QT(n) versus QT(n+1) were constructed to visualize the beat-to-beat variation in QT intervals from the lead II ECG. Short-term instability (STI), long-term instability (LTI) and total instability (TI) were quantified by calculating the distances of 30 consecutive data-points from the x and y-coordinate to the "centre of gravity" of the data cluster. Dofetilide at 0.0025 to 0.04 mg/kg i.v. (plasma concentrations of 4+/-0.6 to 41+/-2.7 ng/ml), dose-dependently prolonged QT and QTcV (at 0.04 mg/kg i.v.: QT: 280+/-ms versus 236+/-5 ms with solvent; p<0.05 and QTcV: 290+/-9 ms versus 252+/-4 ms with solvent; p<0.05). Concomitantly, the compound induced an increase in the instability parameters in a similar dose-dependent manner (at 0.04 mg/kg i.v.: TI: 6.8+/-0.9 ms versus 1.7+/-0.3 ms; p<0.05, LTI: 3.6+/-0.5 ms versus 1.0+/-0.2 ms; p<0.05 and STI: 4.2+/-0.6 ms versus 1.0+/-0.2 ms; p<0.05). The increases induced by dofetilide were associated with a high incidence of early afterdepolarizations (EADs) in the endocardial monophasic action potential (in 6 out of the 7 compound-treated animals versus 0 out of the 7 solvent animals; p<0.05). CONCLUSION: Quantification of beat-to-beat QT instability by our method clearly detects changes in short-term, long-term and total instability induced by dofetilide, already at pre-arrhythmic doses. Dofetilide administration to anesthetized dogs prolongs ventricular repolarization, concomitantly increases beat-to-beat QT instability and induces early after depolarizations (EADs). As such, the use of these parameters in this in vivo model shows clear potential for risk identification in cardiovascular safety assessment.     

Electropharmacologic characteristics of ventricular proarrhythmia induced by ibutilide.

The purpose of this study was to evaluate in vivo the proarrhythmic effects of ibutilide in dogs with or without ventricular hypertrophy. Fourteen dogs received repeated experiments both during the acute and chronic phases (8 weeks, with ventricular hypertrophy) of complete atrioventricular (AV) block. Twelve-lead ECG, monophasic action potentials in the left and right ventricle were recorded before and after each dose of ibutilide (0.01-0.08 mg/kg) during different ventricular rates. In these dogs, ibutilide increased QT interval, biventricular APD90, interventricular deltaAPD90 (difference between the left and right ventricular APD90), and QT dispersion, and induced early afterdepolarizations in a dose-dependent manner. The interventricular deltaAPD90, QT dispersion, and increases of QT interval were more pronounced during slower ventricular rates. There were greater QT interval, biventricular APD90 interventricular deltaAPD90, and QT dispersion values during chronic AV block than during acute AV block. Moreover, ibutilide can induce higher incidences of early afterdepolarizations and torsades de pointes [six (43%) of 14 versus 0 of 14; p < 0.05] during chronic AV block than during acute AV block. In conclusion, ibutilide can prolong ventricular repolarization and increase dispersion of ventricular repolarization in a dose-dependent and reverse rate-dependent manner. The high incidence of torsades de pointes in the dogs during chronic AV block suggests the importance of ventricular hypertrophy in the occurrence of ibutilide-induced proarrhythmia.     

Effects of clinically available drugs on the repolarization process of the heart assessed by the in vivo canine models

The proarrhythmic effects of class III antiarrhythmic agents and non-cardiovascular drugs, which have been shown to prolong QT interval, were assessed using two types of in vivo canine models. First, electrophysiological effects of dofetilide, nifekalant, amiodarone, cisapride, astemizole, sulpiride, haloperidol, and sparfloxacin were assessed using halothane-anesthetized dogs. Each drug prolonged the monophasic action potential (MAP) duration and effective refractory period (ERP) at clinically recommended daily doses. The extent of increase was greater in the refractoriness than in the repolarization only for amiodarone, indicating abbreviation of the terminal repolarization period. The reverse was true for the other drugs. Next, torsadogenic action of sematilide, nifekalant, amiodarone, cisapride, terfenadine, sulpiride, and sparfloxacin was assessed using chronic complete atrioventricular block dogs with Holter ECG monitoring in the conscious state. Oral administration of 1-10 times higher doses than the clinically relevant doses of the drugs induced polymorphic ventricular tachycardia torsades de pointes (TdP), except for amiodarone. These results indicate that the prolongation and backward shift of the terminal repolarization period may be closely related to the drug-induced TdP and suggest that these in vivo models can be used to screen proarrhythmic potential of new drugs.     

Effects of desipramine and tramadol in a chronic mild stress model in mice are altered by yohimbine but not by pindolol

There are few investigations on azimilide effects during ischemia/reperfusion. We have therefore investigated low concentrations of azimilide (0.1 and 0.5 micromol/l) versus Controls on action potential parameters and occurrence of repetitive responses during simulated ischemia and reperfusion. An in vitro model of "border zone" in guinea-pig ventricular myocardium (n=30) was used. Azimilide 0.5 micromol/l lengthened action potential duration in normoxic but not in ischemic-like conditions. Therefore an increased dispersion of action potential duration at 90% of repolarization during simulated ischemia in presence of azimilide was seen. Upon reperfusion, both normal and reperfused myocardium showed azimilide-induced action potential duration increase. There was a neutral effect on the occurrence of arrhythmias during simulated ischemia; however azimilide showed significant (P=0.033) antiarrhythmic properties following reperfusion. To mimic I(Kr) and I(Ks) blocking properties of azimilide we further used dofetilide 10 nmol/l with HMR 1556 1 nmol/l (N=9), which was accompanied by less severe shortening (P<0.05) of action potential duration at 90% of repolarization at 30 min of ischemic-like conditions (-43+/-9%), as compared with azimilide 0.5 micromol/l (-64+/-5%) but similar to what seen with azimilide 0.1 micromol/l (-53+/-5%) and Controls (-52+/-6%). During reperfusion, 2/9 (22%) preparations had sustained activities, which was less than what observed in Controls (5/10, 50%) and with azimilide 0.5 micromol/l (0/10, 0%), although not statistically different (respectively, P=0.35 and P=0.21). Lack versus homogenous class III effects of azimilide in respectively simulated ischemia and reperfusion may explain its different efficacy on arrhythmias, although prevention of reperfusion arrhythmias calls for other than just its I(Kr) and I(Ks) blocking properties.     

Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig

Beat-to-beat alternations of the cardiac monophasic action potential, known as electrical alternans, were studied at drug concentrations that have known arrhythmogenic outcomes. Electrical alternans were elicited from the heart of anesthetized guinea pigs, both in the absence and presence of drugs that inhibit the delayed rectifier K(+) channel encoded by the human ether a-go-go related-gene (HERG), and are associated with the fatal arrhythmia, Torsade de Pointes. Two other HERG inhibiting drugs not associated with Torsade de Pointes were also studied. At concentrations known to be proarrhythmic, E-4031 and bepridil increased mean alternans 10 and 40 ms at pacing frequencies 相似文献   

Azimilide

Azimilide is a potassium channel antagonist that, in contrast to existing class III antiarrhythmic agents, blocks both the rapidly (I(Kr)) and slowly (I(Ks)) activating components of the delayed rectifier potassium current. In animal and clinical studies, azimilide prolonged repolarisation by increasing the action potential duration and effective refractory period. In animal models, azimilide was effective in terminating both atrial and ventricular arrhythmias. Azimilide also demonstrated antifibrillatory efficacy in a canine model of sudden cardiac death. In patients with a history of atrial fibrillation/flutter, oral azimilide controlled arrhythmias more effectively than placebo in a 6-month randomised double-blind study. At a dosage of 125 mg once daily, azimilide significantly increased the time to first symptomatic recurrence of atrial fibrillation/flutter. However, no significant difference between placebo and azimilide was found in another study. Oral azimilide 100 mg once daily demonstrated clinically significant treatment effects in patients with paroxysmal supraventricular tachycardia. In clinical trials, azimilide was generally well tolerated and headache was the most commonly occurring adverse event. Azimilide is associated with a low incidence of proarrhythmic events, such as torsades de pointes, and few serious adverse events have been reported.     

Comparison of guinea-pig ventricular myocytes and dog Purkinje fibres for in vitro assessment of drug-induced delayed repolarization

INTRODUCTION: QT interval prolongation and Torsade de Pointes (TdP) arrhythmias are recognised as a potential risk with many drugs, most of which delay cardiac repolarization by inhibiting the rapidly activating K(+) current (I(Kr)). The objective of this study was to compare the effects of compounds on cardiac action potentials recorded from guinea-pig ventricular myocytes and dog Purkinje fibres. METHODS AND RESULTS: Effects of dofetilide, sotalol, cisapride, terfenadine, haloperidol and sparfloxacin, compounds known to cause QT prolongation (positive controls), and nifedipine and verapamil, not associated with QT prolongation (negative controls) were studied on intracellular action potentials recorded from guinea-pig isolated ventricular myocytes (VM) and dog isolated Purkinje fibres (PF). Prolongation of action potential duration (APD) by sotalol, dofetilide and sparfloxacin was concentration-dependent and of greater magnitude in dog PF compared to guinea-pig VM. The maximum prolongation of APD in guinea-pig VM at 0.5 and 1 Hz was approximately 25% and this was associated with complete inhibition of I(Kr) by dofetilide. Effects on APD of cisapride and haloperidol in both preparations, and terfenadine in guinea-pig VM, were biphasic, consistent with inhibition of multiple ion channels. There was no effect of terfenadine on APD in dog PF. Haloperidol increased APD by more than 25% in guinea-pig VM, consistent with effects on additional repolarizing currents. The negative controls shortened APD to a greater extent in guinea-pig VM compared to dog PF. In general, the positive control drugs increased action potential triangulation (APD(40-90)) to a greater extent than APD(90). CONCLUSION: Guinea-pig isolated VM may be more sensitive for detecting APD prolongation with compounds inhibiting multiple ion channels and action potential triangulation (APD(40-90)). Effects on repolarizing currents other than I(Kr) were also distinguished in guinea-pig VM.     

Effects of artilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction

The electrophysiologic and antiarrhythmic effects of artilide were evaluated in dogs 24 h after myocardial infarction. Artilide (0.1 to 3.0 mg/kg or 0.2 to 7.0 μuM/kg iv) prevented programmed stimulation induced ventricular arrhythmias in 9 out of 9 dogs that had demonstrated inducibe ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Lower doses of artilide tended to reduce the incidence of spontaneous ventricular arrhythmias but these effects were not significant. These results are consistent with the concept that spontaneous and pacing induced ventricular arrhythmias result from different mechanisms, and that class III anti-arrhythmic agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias which result from nonreentrant mechanisms. © 1993 wiley-Liss, Inc.     

Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action

BACKGROUND AND PURPOSE

The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca²⁺ channel antagonists, flunarizine and verapamil against TdP were investigated.

EXPERIMENTAL APPROACH

Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca²⁺ sparks in RyR2^R4496+/+ mouse myocytes; and (iii) peak and late I_Na in SCN5A-HEK 293 cells.

KEY RESULTS

Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I_Na. Ca²⁺ sparks were reduced with verapamil.

CONCLUSIONS AND IMPLICATIONS

Robust anti-arrhythmic efficacy was seen with both Ca²⁺ channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.     

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide greater than sotalol much greater than encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide much greater than ibutilide = sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Azimilide, a novel oral class III antiarrhythmic for both supraventricular and ventricular arrhythmias

Azimilide is an investigational Class III antiarrhythmic that has been developed for treating both supraventricular and ventricular tachyarrhythmias. Similar to other Class III antiarrhythmics, azimilide prolongs myocardial repolarization in a dose-dependent manner by increasing the action potential duration, QT interval, and effective refractory period. The most frequent reported side effect is headache, with rare serious adverse events of early reversible neutropenia and Torsades de Pointes. In long-term follow up, the patient withdrawal rate has been low. Azimilide has very predictable pharmacokinetics, is predominantly hepatically metabolized, and has no significant drug interactions with digoxin or warfarin. In animal models, azimilide has been shown to be very effective in suppressing both atrial and ventricular tachyarrhythmias, decreasing the defibrillation energy requirement, and preventing post-myocardial infarction ventricular tachycardia and fibrillation. Clinically, in a series of 4 double-blind, randomized, placebo-controlled trials, the Azimilide Supraventricular Arrhythmia Program which included over 1000 patients and approximately 70% with structural heart disease, azimilide showed a significant prolongation in the time to first recurrence of paroxysmal supraventricular tachycardia or atrial fibrillation/flutter. With respect to ventricular tachyarrhythmias, the AzimiLide post-Infarct surVival Evaluation Trial was a large randomized, multinational, prospective, placebo-controlled study in recent survivors of myocardial infarction at high risk for sudden cardiac death. After 1 year of follow-up, this study showed no statistical difference in all-cause mortality between placebo and azimilide. However, azimilide did statistically reduce the incidence of new atrial fibrillation. Further trials are necessary to evaluate the efficacy of azimilide in patients with symptomatic ventricular arrhythmias.     

Proarrhythmic effects of fluoroquinolone antibacterial agents: in vivo effects as physiologic substrate for torsades

Drug-induced prolongation of the QT interval is often associated with the onset of Torsades de Pointes (TdP) resulting in a life-threatening ventricular arrhythmia. The potential of the proarrhythmic effects of the new fluoroquinolone antibacterial agents, levofloxacin and sparfloxacin, was examined in the chronic complete atrioventricular block dogs with stable idioventricular automaticity using Holter ECG monitoring in conscious state (Experiment 1). Next, to better analyze the mechanisms of the proarrhythmic property, the cardiovascular effects of these two drugs were compared in the halothane-anesthetized dogs under the monitoring of ECG, His bundle electrogram, systemic and left ventricular pressure, monophasic action potential, cardiac output, and effective refractory period (Experiment 2). In Experiment 1, oral administration of 6 mg/kg (n = 4) as well as 60 mg/kg (n = 4) of levofloxacin did not induce any ventricular premature depolarization. On the other hand, oral administration of 60 mg/kg of sparfloxacin (n = 4) induced TdP leading to ventricular fibrillation in all animals within 24 h, while 6 mg/kg of sparfloxacin (n = 4) did not induce any ventricular premature depolarization. In Experiment 2, intravenous administration of 0.3 mg/kg as well as 3.0 mg/kg of levofloxacin slightly increased cardiac output, but no significant changes were detected in the other parameters (n = 6). On the other hand, intravenous administration of 0.3 mg/kg of sparfloxacin prolonged the effective refractory period. Additional administration of 3.0 mg/kg of sparfloxacin decreased the heart rate and prolonged the effective refractory period and ventricular repolarization phase in a similar extent, but no significant changes were detected in the other parameters (n = 6). These results suggest that backward shift of the relative repolarization period in a cardiac cycle may be the mechanism responsible for the torsadegenic effect of sparfloxacin.     

A gender-independent proarrhythmic action of 17beta-estradiol in anaesthetized rabbits

Women are at increased risk of having drug-induced arrhythmias such as torsade de pointes but less susceptible to arrhythmias associated with myocardial ischaemia. We have shown previously that 17beta-estradiol had greater antiarrhythmic activity in female rats than in male rats subject to myocardial ischaemia. The aim of this work was to investigate the effects of acute administration of 17beta-estradiol in both sexes in an established in vivo model of drug-induced arrhythmias. In alpha(1)-adrenoceptor-stimulated, pentobarbital-anaesthetized rabbits, 17beta-estradiol (100, 300 or 1000 ng/kg bolus followed by 10, 30 or 100 ng/kg/min infusion) tended to increase the incidence of torsade de pointes, induced by clofilium, in both sexes: from 50% in controls to 80%, 70% and 80% in females; from 40% in controls to 60%, 70% and 80% in males with increasing doses of 17beta-estradiol (n=10 per group). The total duration of all episodes of torsade de pointes was increased significantly by the highest dose of 17beta-estradiol compared to vehicle in both female and male rabbits: from 9+/-4 s to 93+/-26 s in females; from 26+/-14 s to 96+/-20 s in males. There were no baseline differences between the sexes in heart rate, QTc interval or epicardial monophasic action potential duration. The proarrhythmic effect of acute administration of 17beta-estradiol in the alpha(1)-adrenoceptor-stimulated anaesthetized rabbit model was independent of gender. This indicates that the underlying mechanism differs from that involved in the gender-selective reduction of ischaemia-induced arrhythmias by 17beta-estradiol.     

Oscillations of cardiac wave length and proarrhythmia

Drug-induced action potential duration (APD) prolongation was first proposed to be antiarrhythmic, but is now widely presumed to be torsadogenic. To elucidate this paradox, we tested the effect of APD upon liability for torsade de pointes. In addition, torsadogenicity is commonly associated with disturbances of repolarization, but at least in theory, it could also result from disturbances of conduction. These possibilities were tested in female rabbit hearts. Dofetilide, ATX II, and sodium channel blockers that did not prolong the action potential duration were used to modulate the APD and induce disturbances of conduction and disturbances of repolarization. Torsadogenicity could be induced by dofetilide and ATX II starting at normal APD (210 ms), reaching a peak incidence around a doubling of APD (400 to 450 ms), to then sharply decline with further APD prolongation, until torsade de pointes disappeared above 725 ms. Early afterdepolarizations (EAD) were regular triggers for torsade de pointes; while most of the EADs occurred in the plateau range, their incidence declined with repolarization but their potential for torsadogenicity increased. Sodium channel blockers that shorten the APD, even when devoid of hERG blocking properties, can yield torsade de pointes. Torsade de pointes can occur at normal, prolonged, and shortened APD, so that QT prolongation is an incomplete predictor of torsadogenicity. Torsade de pointes can result not only from disturbances of repolarization but also from disturbances of conduction.     

Transmural Dispersion of Repolarization as a Preclinical Marker of Drug-induced Proarrhythmia

ABSTRACT:: Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development.     

Torsades de pointes associated with chlorpromazine: case report and review of associated ventricular arrhythmias.

PURPOSE: To present a case of chlorpromazine-associated torsades de pointes, review established cases of ventricular arrhythmias associated with chlorpromazine, and describe the proarrhythmic characteristics of this drug. DATA SOURCES: Articles identified through a search of MEDLINE and IDIS from January 1966-November 2000 and thorough review of the article bibliographies. Patient cases also were identified from a search of the Food and Drug Administration's Adverse Event Reporting System database (November 1997-March 2001). Cases involving intentional overdoses of chlorpromazine were excluded. RESULTS: In addition to the case reported herein, 12 cases of documented, chlorpromazine-associated ventricular arrhythmias were identified; five had characteristic features of torsades de pointes. Chlorpromazine delayed repolarization and produced electrocardiographic abnormalities; although, whether chlorpromazine induced torsades de pointes through a mechanism of early afterdepolarizations is unclear. Similar to other instances of drug-induced torsades de pointes, concurrent factors such as electrolyte deficiencies may place the patient at increased risk for arrhythmia. CONCLUSIONS: Chlorpromazine can delay repolarization and produce electrocardiographic abnormalities. These can result infrequently in ventricular arrhythmias and torsades de pointes, particularly in patients with confounding factors.     

Effects of azimilide, a KV(r) and KV(s) blocker, on canine ventricular arrhythmia models.

Using canine coronary artery ligation/reperfusion and adrenaline arrhythmia models, we determined the effects of azimilide, a class III antiarrhythmic agent, E-1-[[(5-(4-chlorophenyl)-2-furanyl) methylene]-amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidi nedione dihydrochloride. The coronary ligation/reperfusion arrhythmia experiments were divided into two groups, one using low heart rate halothane-anesthetized and the other using high heart rate pentobarbital-anesthetized dogs. Azimilide (6 mg kg(-1) + 0.1 mg kg(-1) min(-1) i.v.) prolonged the corrected QT interval (QTc), decreased the heart rate and suppressed the premature ventricular complexes during ligation (35 +/- 17 beats/30 min as compared with 909 +/- 246 in the control group), and also suppressed ventricular fibrillation induced by coronary ligation/reperfusion in the two groups (1/8 halothane-anesthetized dogs as compared with 7/8 dogs in the control group and 2/8 pentobarbital-anesthetized dogs as compared with 8/8 dogs in the control group). In adrenaline arrhythmia, azimilide hastened the onset of adrenaline arrhythmias and also aggravated the arrhythmias, showing proarrhythmic effects.     

Prolongation in QT interval is not predictive of Ca2+-dependent arrhythmias: implications for drug safety

Background: Voltage-gated ion channels are the main providers of drug-induced delayed repolarization and, therefore, first line targets in cardiac safety assessments. Objectives/methods: We review mechanisms of drug-induced ventricular arrhythmias that may be associated with sudden cardiac death. We focus on Ca²⁺-dependent mechanisms with drug safety concerns. Results: Early afterdepolarizations occur during abnormally prolonged action potential repolarization. QT interval measurement is commonly used to assess the proarrhythmic risk of a drug. However, delayed afterdepolarizations are triggered by intracellular Ca²⁺ overload and/or abnormal spontaneous openings of ryanodine receptors in diastole. A drug promoting alterations of Ca²⁺ handling may be pro-arrhythmogenic without QT interval change at rest. Conclusion: Ca²⁺-dependent arrhythmia should be investigation matter in drug safety evaluation.     

粉防己碱抗氯化铯诱发家兔在体心脏早期后除极化及心律失常的作用

目的　研究粉防己碱 (Tet)抗氯化铯 (CsCl)诱发触发活动及触发性心律失常作用。方法　 14只家兔分对照组和Tet组 ,Tet组给予Tet 0 5mg·kg-1·min-1共 10min ,对照组给予生理盐水 ,然后给予CsCl1 5mmol/kg静脉注射 ,给药前后记录心电图和右室心内膜单向动作电位 (MAP)。结果　Tet组和对照组均诱发早期后除极 (EAD) ,但Tet组EAD幅度小于对照组 ,室性心律失常发生率低于对照组。结论　Tet有抗CsCl诱发EAD及室性心律失常作用。其机制可能是Tet抑制慢钙通道 ,减少内向电流