High Risk of QT Interval Prolongation and Torsades de Pointes Associated with Intravenous Quinidine Used for Treatment of Resistant Malaria or Babesiosis

Wroblewski, Heather A.; Kovacs, Richard J.; Kingery, Joanna R.; Overholser, Brian R.; Tisdale, James E.

doi:10.1128/aac.06396-11

Cited by 21 publications

(11 citation statements)

References 26 publications

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“…In addition, iPSC-CM arrhythmias developed at or near clinical concentrations (Fig. 6), consistent with the known torsade de pointes risk of dofetilide and quini-dine (Kolb et al , 2008; Nagra et al , 2005; Reiffel, 2005; Wroblewski et al , 2012). …”

Section: Discussionsupporting

confidence: 74%

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias

et al. 2016

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Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.

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Section: Discussionsupporting

confidence: 74%

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias

et al. 2016

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“…Although artemisinin is used as a substitute for other antimalarials as the first-line drug in the treatment of malaria, quinine and/or quinidine are still widely used for treating severe malaria because of the lack of availability of intravenous artesunate [3,23,24]. However, cardiotoxicity has become a major adverse effect during treatment with quinidine and quinine [4,5]. The cardiotoxicity of these drugs mainly focuses on delayed ventricular repolarization which increases the risk of LQTS and TdP.…”

Section: Discussionmentioning

confidence: 99%

“…Quinine is important for treatment of severe malaria as an antimalarial drug [3]. However, cardiotoxicity is the common serious adverse effect during treatment with both drugs [4,5]. Stereospecific electrophysiologic effects of quinidine and quinine have been reported previously in the heart.…”

Section: Introductionmentioning

confidence: 99%

“…A separate report discovered that quinidine and quinine prolonged the QaT (apex of T wave) interval in a dose-dependent manner measured by the isolated perfused guinea pig heart, with quinine more potent than quinidine [8]. In patients with malaria, quinidine has been reported can cause QT (duration from the start of QRS-wave to the end of T-wave) interval prolongation and torsade de pointes (TdP) [5]. In contrast, quinine induces a slight lengthening of the QTc interval [9].…”

Section: Introductionmentioning

confidence: 99%

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Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

Meng

Fan

Shi

et al. 2016

IJMS

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Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency.

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“…Similar adverse effects on intracellular Ca 2+ handling are exerted by the Tyrosine Kinase Inhibitors (TKIs) nilotinib and vandetanib, which have a low cardiac safety index and were previously labeled with an FDA black box cardiotoxicity warning due to associated QT prolongation and arrhythmias [ 63 ]. QT prolongation is also induced by common antiarrhythmic drugs such as quinidine, dofetilide and sotalol, which cause TdP in 1–5% of treated subjects [ 29 , 64 , 65 , 66 ].…”

Section: Drug Development Adverse Drug Reactions Mechanisms Of Cmentioning

confidence: 99%

Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening

Ovics

Regev

Baskin

et al. 2020

IJMS

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Over the years, numerous groups have employed human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) as a superb human-compatible model for investigating the function and dysfunction of cardiomyocytes, drug screening and toxicity, disease modeling and for the development of novel drugs for heart diseases. In this review, we discuss the broad use of iPSC-CMs for drug development and disease modeling, in two related themes. In the first theme—drug development, adverse drug reactions, mechanisms of cardiotoxicity and the need for efficient drug screening protocols—we discuss the critical need to screen old and new drugs, the process of drug development, marketing and Adverse Drug reactions (ADRs), drug-induced cardiotoxicity, safety screening during drug development, drug development and patient-specific effect and different mechanisms of ADRs. In the second theme—using iPSC-CMs for disease modeling and developing novel drugs for heart diseases—we discuss the rationale for using iPSC-CMs and modeling acquired and inherited heart diseases with iPSC-CMs.

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High Risk of QT Interval Prolongation and Torsades de Pointes Associated with Intravenous Quinidine Used for Treatment of Resistant Malaria or Babesiosis

Cited by 21 publications

References 26 publications

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias

Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

Drug Development and the Use of Induced Pluripotent Stem Cell-Derived Cardiomyocytes for Disease Modeling and Drug Toxicity Screening

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