Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus

Ponti, Fabrizio De; Poluzzi, Elisabetta; Motola, Domenico

doi:10.1007/s002280100290

Cited by 162 publications

(110 citation statements)

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“…14 These differences in the electrophysiological profiles of these drugs might explain their clinically described antiarrhythmic and proarrhythmic effects. 1,2,12,13 …”

Section: Effects On the Terminal Repolarization Phasementioning

confidence: 99%

Effects of Disopyramide and Mexiletine on the Terminal Repolarization Process of the In Situ Heart Assessed Using the Halothane-Anesthetized In Vivo Canine Model.

Yoshida

Sugiyama²,

Satoh³

et al. 2002

Circ J

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rug-induced long QT syndrome is currently a hot topic of concern for the pharmaceutical companies as well as for clinicians. 1,2 We have previusly assessed the effects of class II, III and IV antiarrhythmic agents and some non-cardiovascular drugs on the repolarization process using the halothane-anesthetized canine in vivo model, and found that the effects of the drugs on phase 3 repolarization in this model are quite useful for predicting drug-induced QT prolongation that might trigger torsades de pointes in clinical practice. [3][4][5][6][7][8][9][10][11] Class I drugs are known to affect the QT interval, 12,13 but information regarding the effects of class I antiarrhythmic drugs in this type of model is still limited. [14][15][16][17] In this study, we simultaneously assessed the in vivo electrophysiological and cardiohemodynamic effects of typical class I antiarrhythmic drugs, disopyramide and mexiletine, using the halothane-anesthetized canine model. To better analyze the electrophysiological effects on the depolarization/repolarization process, we recorded His bundle electrograms and monophasic action potentials (MAPs), respectively, in addition to the standard lead II surface ECG. Moreover, a MAP recording/pacing combination catheter was used to Circulation Journal Vol.66, September 2002 simultaneously measure both MAP and effective refractory period (ERP) at the same site to assess the drug effects on the terminal repolarization period (phase 3) of the action potential. [3][4][5][6][7][8][9][10][11][14][15][16][17] MethodsAll experiments were performed in accordance with the Guidelines for Animal Experiments, Yamanashi Medical University. Experiments were carried out using beagle dogs weighing approximately 10 kg. Animals were obtained through the Animal Laboratory for Research of Yamanashi Medical University. Dogs were anesthetized initially with thiopental sodium (30 mg/kg, iv) and after intubation with a cuffed endotracheal tube, 1.0% halothane vaporized with 100% oxygen was inhaled with a volume-limited ventilator (SN-480-3; Shinano, Tokyo, Japan). Tidal volume and respiratory rate were set at 20 ml/kg and 15 stroke/min, respectively. To prevent blood clotting, heparin calcium (100 units/kg, iv) was administered. Cardiohemodynamic and Electrophysiological ParametersThe surface lead II ECG was obtained from the limb electrodes and the corrected QT interval (QTc) was calculated using Bazett's formula. 18 The systemic blood pressure (BP) was measured at the left femoral artery, and a pig-tail catheter was positioned at the left ventricle through the left femoral artery to measure the left ventricular pressure. The maximum upstroke velocity of the left ventricular pressure (LVdP/dtmax) and the left ventricular end-diastolic pressure (LVEDP) were obtained to estimate the contractility and This study was designed to assess the effects of typical class I drugs on the terminal repolarization process of the in situ heart, which is a useful marker of the potential of drug-induced long QT syndrome. Disopyr...

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“…14 These differences in the electrophysiological profiles of these drugs might explain their clinically described antiarrhythmic and proarrhythmic effects. 1,2,12,13 …”

Section: Effects On the Terminal Repolarization Phasementioning

confidence: 99%

Effects of Disopyramide and Mexiletine on the Terminal Repolarization Process of the In Situ Heart Assessed Using the Halothane-Anesthetized In Vivo Canine Model.

Yoshida

Sugiyama²,

Satoh³

et al. 2002

Circ J

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“…Considerable evidence has accrued that a variety of noncardiac drugs may prolong the QT interval of the surface electrocardiogram, which represents ventricular depolarization and repolarization, imparting an increased risk of developing a potentially fatal cardiac arrhythmia known as torades de pointes (TdP) (De Ponti et al, 2001). This has stimulated intense discussions and focused attention on methodological issues involved in the cardiac risk-benefit assessment of noncardiac pharmaceuticals, including antimicrobial agents, which has resulted in withdrawals of approved antibiotics such as grepafloxacin.…”

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confidence: 99%

Blockade of Human Cardiac Potassium Channel Human Ether-a-go-go-Related Gene (HERG) by Macrolide Antibiotics

Volberg¹,

Koci²,

Su³

et al. 2002

J Pharmacol Exp Ther

150

101

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Several macrolides have been reported to cause QT prolongation and ventricular arrhythmias such as torsades de pointes. To clarify the underlying ionic mechanisms, we examined the effects of six macrolides on the human ether-a-go-go-related gene (HERG)-encoded potassium current stably expressed in human embryonic kidney-293 cells. All six drugs showed a concentration-dependent inhibition of the current with the following IC 50 values: clarithromycin, 32.9 M; roxithromycin, 36.5 M; erythromycin, 72.2 M; josamycin, 102.4 M; erythromycylamine, 273.9 M; and oleandomycin, 339.6 M. A metabolite of erythromycin, des-methyl erythromycin, was also found to inhibit HERG current with an IC 50 of 147.1 M. These findings imply that the blockade of HERG may be a common feature of macrolides and may contribute to the QT prolongation observed clinically with some of these compounds. Mechanistic studies showed that inhibition of HERG current by clarithromycin did not require activation of the channel and was both voltage-and time-dependent. The blocking time course could be described by a first-order reaction between the drug and the channel. Both binding and unbinding processes appeared to speed up as the membrane was more depolarized, indicating that the drug-channel interaction may be affected by electrostatic responses.

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“…The reason for this was that a correction formula that adequately corrected QT intervals was used in the current study. Drug-induced QT prolongation is relatively common in clinical practice (De Ponti et al, 2001;Redfern et al, 2003;Ozkanlar et al, 2005b). It has been reported that sparfloxacin and grepafloxacin can prolong the QT interval to cause lethal ventricular arrhythmias (Bertino and Fish, 2000;Frothingham, 2001;Owens, 2001).…”

Section: Discussionmentioning

confidence: 99%

Cardiotoxic effects of enrofloxacin on electrophysiological activity, cardiac markers, oxidative stress, and haematological findings in rabbits

Durgut¹,

Öztürk²,

Nacar³

et al. 2016

Turk J Zool

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IntroductionProlongation of the QT interval is commonly used as a surrogate marker of torsades de pointes (TdP), which is a known clinical risk factor for the development of severe, life-threatening, ventricular arrhythmias (Abi-Gerges et al., 2004). Noncardiovascular drug-induced prolongation of the QT interval is often associated with the onset of TdP (Haverkamp et al., 2000;De Ponti et al., 2001). Fluoroquinolones are among the drugs of choice for the treatment of common bacterial infections due to their wide spectrum against respiratory, gastrointestinal, and genitourinary pathogens (Elmas et al., 2006). QT interval prolongation is also a class effect of fluoroquinolones but there are great differences between the various members of this group (Camm, 2005). Thus, there are significant differences in the potency to prolong QT interval among the fluoroquinolones and the risk of arrhythmia varies between drugs and with co-risk factors (Frothingham, 2001;Owens and Ambrose, 2002). Because a QT prolongation and potentially fatal ventricular arrhythmias associated with quinolones such as grepafloxacin due to several cases of sudden death and TdP have been encountered retrospectively, enrofloxacin needs to be further investigated in detail. Therefore, the purpose of this study was to investigate the effect of normal and high doses of enrofloxacin on basal electrocardiographic parameters including heart rate (HR), P, QRS, QT, and RR intervals and corrected QT (QTc) values as well as biochemical and haematological findings in healthy conscious rabbits. Materials and methods ApprovalsThis study was approved by the Institutional Laboratory Animal Care and Use Committee of Mustafa Kemal University (2011 -01 -09). ChemicalsAll chemicals were obtained from Sigma Chemical Co, and solutions were prepared fresh daily from concentrated stock solutions. Animal preparationAfter 1 week of quarantine and acclimatisation, a total of 21 healthy New Zealand rabbits of both sexes, 12-18 months old, and of 2-4 kg body weight were used. The rabbits were housed individually in stainless-steel wire mesh cages and provided with food and water ad libitum. All rabbits were

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Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus

Cited by 162 publications

References 0 publications

Effects of Disopyramide and Mexiletine on the Terminal Repolarization Process of the In Situ Heart Assessed Using the Halothane-Anesthetized In Vivo Canine Model.

Effects of Disopyramide and Mexiletine on the Terminal Repolarization Process of the In Situ Heart Assessed Using the Halothane-Anesthetized In Vivo Canine Model.

Blockade of Human Cardiac Potassium Channel Human Ether-a-go-go-Related Gene (HERG) by Macrolide Antibiotics

Cardiotoxic effects of enrofloxacin on electrophysiological activity, cardiac markers, oxidative stress, and haematological findings in rabbits

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