Assessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA concept

Thomet, Urs; Amuzescu, Bogdan; Knott, Thomas; Mann, Stefan A.; Mubagwa, Kanigula; Radu, Beatrice Mihaela

doi:10.1016/j.ejphar.2021.174632

Cited by 17 publications

(31 citation statements)

References 97 publications

(169 reference statements)

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“…in all the lines), a large decrease in the upstroke velocity and a decrease in the plateau amplitude (p < 0.05 in all the lines) that overall could be linked to the decreased FP quality observed in Figure 3. These effects are consistent with patch clamp data in heterologous systems indicating HCQ as a blocker of multiple ion currents (Thomet et al, 2021). Some of the cells in all groups did not tolerate the acute exposure to 10 µM HCQ (Supplementary Figure 1), with a larger effects on cells from JLNS and CALM-LQTS groups; this confirms that isolated hiPSC-CMs have higher sensitivity to drugs than those included in monolayers, and that data from these two models may be interpreted and considered differently in terms of translational relevance (Sala et al, 2016).…”

Section: A Genotype-specific Response To Hydroxychloroquine Can Be Re...supporting

confidence: 90%

Use of hiPSC-Derived Cardiomyocytes to Rule Out Proarrhythmic Effects of Drugs: The Case of Hydroxychloroquine in COVID-19

et al. 2022

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In the early phases of the COVID-19 pandemic, drug repurposing was widely used to identify compounds that could improve the prognosis of symptomatic patients infected by SARS-CoV-2. Hydroxychloroquine (HCQ) was one of the first drugs used to treat COVID-19 due to its supposed capacity of inhibiting SARS-CoV-2 infection and replication in vitro. While its efficacy is debated, HCQ has been associated with QT interval prolongation and potentially Torsades de Pointes, especially in patients predisposed to developing drug-induced Long QT Syndrome (LQTS) as silent carriers of variants associated with congenital LQTS. If confirmed, these effects represent a limitation to the at-home use of HCQ for COVID-19 infection as adequate ECG monitoring is challenging. We investigated the proarrhythmic profile of HCQ with Multi-Electrode Arrays after exposure of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from two healthy donors, one asymptomatic and two symptomatic LQTS patients. We demonstrated that: I) HCQ induced a concentration-dependent Field Potential Duration (FPD) prolongation and halted the beating at high concentration due to the combined effect of HCQ on multiple ion currents. II) hiPSC-CMs from healthy or asymptomatic carriers tolerated higher concentrations of HCQ and showed lower susceptibility to HCQ-induced electrical abnormalities regardless of baseline FPD. These findings agree with the clinical safety records of HCQ and demonstrated that hiPSC-CMs potentially discriminates symptomatic vs. asymptomatic mutation carriers through pharmacological interventions. Disease-specific cohorts of hiPSC-CMs may be a valid preliminary addition to assess drug safety in vulnerable populations, offering rapid preclinical results with valuable translational relevance for precision medicine.

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Section: A Genotype-specific Response To Hydroxychloroquine Can Be Re...supporting

confidence: 90%

Use of hiPSC-Derived Cardiomyocytes to Rule Out Proarrhythmic Effects of Drugs: The Case of Hydroxychloroquine in COVID-19

et al. 2022

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“… 52 In contrast, Thomet et al stated that on ATX-II-induced non-inactivating persistent currents of Nav1.5, inhibition by CQ and HCQ gave IC 50 values of 159 μM and 96 μM respectively. 21 The IC 50 values for the rapid component of the delayed rectifier potassium current mediated by hERG K + channels are considerably lower (2–8 μM for CQ and 3–10 μM for HCQ). 21 , 52 , 61 , 62 However, the sole validity of IC 50 values for predicting proarrhythmic risks due to inhibition of hERG K + channels have been challenged, noting that they do not account for dynamic time- and state-dependent drug–channel interactions.…”

Section: Discussionmentioning

confidence: 99%

“… 41 , 42 Class I agents inhibit both peak and late sodium currents by blocking Nav1.5, a feature previously described for CQ and HCQ. 21 , 43 , 44 Blockade of Nav1.5 is associated with an intracardiac conduction delay and thus, depending on the extent of the propagation delay, with an elongation of the QRS complex in the electrocardiogram. 45 , 46 Drug-induced QRS prolongation due to Nav1.5 inhibition which slows the rate of cardiac depolarization enables life-threatening ventricular arrhythmias and even sudden cardiac death, thus contributing to morbidity and mortality associated with Nav1.5 blockers.…”

Section: Discussionmentioning

confidence: 99%

“… 18 , 19 In addition, both substances have also been demonstrated to inhibit further cardiac ion channels, such as the inwardly rectifying potassium channel, L-type calcium and sodium channels. 20 , 21 The opioids methadone or buprenorphine, which can also trigger LQTS, inhibit the cardiac-specific isoform of voltage-gated sodium channels, Nav1.5. 19 , 22 , 23 Vice versa, LAs like bupivacaine, ropivacaine and mepivacaine inhibit hERG K + channels, suggesting that this may contribute to their cardiotoxic potential.…”

Section: Introductionmentioning

confidence: 99%

“…63,64 Both CQ and HCQ also inhibit L-type calcium currents with IC 50 values of 3-30 μM and 8-90 μM, respectively. 21,52 Kir2.1, generating the rectifying potassium current, is also blocked by both agents with IC 50 values of 6 μM for CQ and 30 μM for HCQ. 21 Taken together, different studies confirm that both CQ and HCQ inhibit several cardiac ion channels with potential significance for cardiac arrhythmias.…”

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confidence: 96%

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Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

Hage¹,

Vries²,

Leffler³

et al. 2022

JEP

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Introduction: Chloroquine (CQ) and its derivate hydroxychloroquine (HCQ) are successfully deployed for different diseases beyond the prophylaxis and treatment of malaria. Both substances exhibit antiviral properties and have been proposed for prophylaxis and treatment of COVID-19 caused by SARS-CoV-2. CQ and HCQ cause similar adverse events including life-threatening cardiac arrhythmia generally based on QT-prolongation, which is one of the most reported adverse events for both agents associated with the treatment of COVID-19. Various drugs known to induce QT-prolongation have been proven to exert local anesthetic (LA)-like properties regarding their impact on the cardiac Na + channel Nav1.5. Inhibition of Nav1.5 is considered as the primary mechanism of cardiotoxicity caused by LAs. However, the mechanism of the arrhythmogenic effects of CQ and HCQ related to Nav1.5 has not yet been fully investigated. Therefore, the exact mechanism of how CQ and HCQ affect the sodium currents generated by Nav1.5 need to be further elucidated. Objective: This in vitro study aims to investigate the effects of CQ and HCQ on Nav1.5-generated sodium currents to identify possible LA-like mechanisms that might contribute to their arrhythmogenic properties. Methods: The effects of CQ and HCQ on Nav1.5-generated sodium currents by HEK-293 cells expressing either wild-type human Nav1.5 or mutant Nav1.5 F1760A are measured using the whole-cell patch-clamp technique. Results: Both agents induce a state-dependent inhibition of Nav1.5. Furthermore, CQ and HCQ produce a use-dependent block of Nav1.5 and a shift of fast and slow inactivation. Results of experiments investigating the effect on the LA-insensitive mutant Nav1.5-F1760A indicate that both agents at least in part employ the proposed LA-binding site of Nav1.5 to induce inhibition. Conclusion:This study demonstrated that CQ and HCQ exert LA-typical effects on Nav1.5 involving the proposed LA binding site, thus contributing to their arrhythmogenic properties.

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HPC Framework for Performing in Silico Trials Using a 3D Virtual Human Cardiac Population as Means to Assess Drug-Induced Arrhythmic Risk

Aguado-Sierra,

Brigham,

Baron

et al. 2023

Methods in Molecular Biology

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Assessment of proarrhythmogenic risk for chloroquine and hydroxychloroquine using the CiPA concept

Cited by 17 publications

References 97 publications

Use of hiPSC-Derived Cardiomyocytes to Rule Out Proarrhythmic Effects of Drugs: The Case of Hydroxychloroquine in COVID-19

Use of hiPSC-Derived Cardiomyocytes to Rule Out Proarrhythmic Effects of Drugs: The Case of Hydroxychloroquine in COVID-19

Local Anesthetic Like Inhibition of the Cardiac Na+ Channel Nav1.5 by Chloroquine and Hydroxychloroquine

HPC Framework for Performing in Silico Trials Using a 3D Virtual Human Cardiac Population as Means to Assess Drug-Induced Arrhythmic Risk

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