Torsades de Pointes Ventricular Tachycardia Associated With Overdose of Astemizole

Rao, Krishna; Adlakha, Arun; Verma-Ansil, Bikram; Meloy, Thomas D.; Stanton, Marshall S.

doi:10.1016/s0025-6196(12)62252-6

Cited by 42 publications

(9 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Astemizole has been a second-generation selective histamine1 (H1) receptor antagonist prescribed for symptomatic relief of allergic rhinitis (Niemegeers et al, 1986;Krstenansky and Cluxton, 1987;Barnett and Kreutner, 1991). It has been reported that an overdose of astemizole is associated with prolongation of the QT interval, causing torsades de pointes (Clark and Love, 1991;Saviuc et al, 1993;Rao et al, 1994). In this study, we found that astemizole caused severe prolongation of QT interval, resulting in torsades de pointes-type ventricular tachycardia in conscious, freely moving marmosets.…”

Section: Discussionmentioning

confidence: 70%

Development of Telemetry System in the Common Marmoset - Cardiovascular Effects of Astemizole and Nicardipine -

et al. 2002

View full text Add to dashboard Cite

-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 (Ca 2+ channel blocker) on cardiovascular parameters. Astemizole at 30 mg/kg (po) and at 1 to 3 mg/kg (iv), prolonged QT interval and induced ventricular extrasystole. Torsades de pointes occurred in one of three cases at 3 mg/kg (iv) and 30 mg/kg (po), while it did not affect the blood pressure, respiratory rate and body temperature. Nicardipine at 30 mg/kg (po) 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.

show abstract

Section: Discussionmentioning

confidence: 70%

Development of Telemetry System in the Common Marmoset - Cardiovascular Effects of Astemizole and Nicardipine -

et al. 2002

View full text Add to dashboard Cite

show abstract

“…Cytochrome P450 enzymes are responsible for the metabolism of many drugs, including the nonsedating antihistamines loratadine, terfenadine, and astemizole. Several clinically important drug interactions involve coadministration of terfenadine and astemizole with drugs that inhibit their metabolism by cytochrome P450 enzymes [1–9]. For example, coadministration of ketoconazole with terfenadine has been associated with altered cardiac repolarization leading to QTc interval prolongation and torsades de pointes [2, 7].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Kosoglou¹,

Salfi²,

Lim³

et al. 2000

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. Methods Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. Results Concomitant administration of loratadine and ketoconazole signi®cantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine signi®cantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically signi®cant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety pro®le of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. Conclusions Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a signi®cant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.

show abstract

“…Astemizole is a non‐sedating antihistamine whose proarrhythmic potency has been reviewed recently [6, 7]. In man, astemizole‐induced dysrhythmias occurred mostly during overdose, with plasma concentrations higher than 20 ng/mL, while the ‘normal’ therapeutic range is 0.1–1.4 ng/mL [8].…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological effects of cetirizine, astemizole and d‐sotalol in a canine model of long QT syndrome

Weissenburger

Noyer

Cheymol

et al. 1999

Clin Experimental Allergy

View full text Add to dashboard Cite

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

show abstract

Torsades de Pointes Ventricular Tachycardia Associated With Overdose of Astemizole

Cited by 42 publications

References 22 publications

Development of Telemetry System in the Common Marmoset - Cardiovascular Effects of Astemizole and Nicardipine -

Development of Telemetry System in the Common Marmoset - Cardiovascular Effects of Astemizole and Nicardipine -

Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine

Electrophysiological effects of cetirizine, astemizole and d‐sotalol in a canine model of long QT syndrome

Contact Info

Product

Resources

About