Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models

Khobragade, S. B.; Gupta, Pankaj; Gurav, Prashant; Chaudhari, Girish Hari; Gatne, M. M.; Shingatgeri, Vyas M

doi:10.4103/0976-500x.110892

Cited by 16 publications

(7 citation statements)

References 24 publications

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“…As an aminoquinolone, CQ, and its derivative, HCQ, are proarrhythmic [78]. Arrythmias arise from an imbalance of the normal physiological variables influencing the activation and inactivation kinetics of the cardiac ion channels that permit the transmembrane currents forming the foundation of the cardiac action potential.…”

Section: Discussionmentioning

confidence: 99%

Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety: Systematic review of (hydroxy)chloroquine efficacy and safety

Takla

Jeevaratnam

2020

Preprint

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Background: The COVID-19 pandemic has required clinicians to urgently identify new treatment options or the repurposing of existing drugs. Several drugs are now being repurposed with the aim of identifying if these drugs provide some level of disease resolution. Of particular interest are chloroquine (CQ) and hydroxychloroquine (HCQ), first developed as an antimalarial therapy. There is increasing concern with regards to the efficacy and safety of these agents. The aims of this review are to systematically identify and collate studies describing the use of CQ and HCQ in human clinical trials and provide a detailed synthesis of evidence of its efficacy and safety. Methods and Findings: Searches for (COVID AND chloroquine [title/abstract] AND outcomes[full text]) and two (COVID AND hydroxychloroquine[title/abstract] AND outcomes[full text]) yielded 272 unique articles. Unique articles were manually checked for inclusion and exclusion criteria and also subjected to a quality appraisal assessment. A total of 19 articles were included in the systematic review. Seventy-five percent of observational studies employing an endpoint specific to efficacy recorded no significant difference in the attainment of outcomes, between COVID-19 patients given a range of CQ and/or HCQ doses, and the control groups. All clinical trials and 82% of observational studies examining an indicator unique to drug safety discovered a higher probability of adverse events in those treated patients suspected of, and diagnosed with, COVID-19. Seventy-five percent of the total papers focusing on cardiac side-effects found a greater incidence among patients administered a wide range of CQ and/or HCQ doses, with QTc prolongation the most common finding, in addition to its consequences of VT and cardiac arrest. Of the total studies using mortality rate as an end-point, 60% reported no significant change in the risk of death, while 30% showed an elevation, and 10% a depression, in treated relative to control patients. Conclusion: The strongest available evidence suggests that, relative to standard in-hospital management of symptoms, the use of CQ and HCQ to treat hospitalised COVID-19 patients has likely been unsafe. At the very least, the poor quality of data failing to find any significant changes in the risk of VT should preclude definitive judgment on drug safety until the completion of high-quality randomised clinical trials.

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Section: Discussionmentioning

confidence: 99%

Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety: Systematic review of (hydroxy)chloroquine efficacy and safety

Takla

Jeevaratnam

2020

Preprint

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“…Adverse events, such as prolonged QRS, prolonged QT interval, TdP, and ventricular arrhythmia, have been observed in individuals receiving HCQ due to autoimmune diseases [ 20 , 21 ]. Chloroquine causes prolonged QT by increasing the ventricular myocardial action potential, by affecting Na + and Ca 2+ channels involved in depolarization, IKr channels involved in repolarization and, especially, inward rectifier K + current (IK1 current), which stabilizes the resting membrane potential [ 15 , 22 ]. The value of the QT interval for predicting TdP risk is low, but risk is known to be greater when QT > 550 ms [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Short-Term Hydroxychloroquine Plus Moxifloxacin Therapy on Corrected QT Interval and Tp-e Interval in Patients With COVID-19

2020

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Background Limited data are available regarding hydroxychloroquine (HCQ) and moxifloxacin (MOX) in patients with possible coronavirus disease 2019, (COVID-19). Both drugs may increase risk of malignant ventricular arrhythmias associated with prolongation of QT interval. Methods A total of 76 subjects with chest tomography findings compatible with COVID-19 pneumonia were enrolled in the study. Standard 12-lead electrocardiogram (ECG) was repeated on days 2 and 5 in patients receiving a combination of HCQ + MOX. Heart rate, QT interval, Tp-e interval, and Tp-e/QT ratio were measured. Results The mean age of the patients was 61.7 ± 14.8 years and 54% had hypertension. Compared to day 2, ECG on day 5 showed significant increases in QT interval (370.8 ± 32.5 vs. 381.0 ± 29.3, respectively, P = 0.001), corrected QT (QTc) interval (424 (403 - 436) vs. 442 (420 - 468), respectively, P < 0.001), Tp-e interval (60 (55 - 70) vs. 65 (57 - 75), respectively, P < 0.001), cTp-e interval (72.2 ± 12.9 vs. 75.4 ± 12.7, respectively, P < 0.001). Moreover, a slight decrease in Tp-e/QT ratio was observed (0.17 ± 0.03 vs. 0.17 ± 0.02, P = 0.030). QTc was > 500 ms in 5% of the patients, and 8% of patients had an increase in QTc interval > 60 ms. Tp-e/QT ratio was > 0.23 in 4% of patients. Five patients died due to pulmonary failure without evidence of ventricular arrhythmia. No ventricular arrhythmia events, including torsades de pointes (TdP), were observed. Conclusions HCQ + MOX combination therapy led to increases in QTc interval, Tp-e interval, and cTp-e interval. However, this therapy did not cause ventricular arrhythmia in the short-term observation.

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“…Additionally, heart rate-corrected QT (QTc) calculation was obtained by using Carlson’s formula as follows: QTc = (QT−0.175) × (RR interval−300). 21 …”

Section: Methodsmentioning

confidence: 99%

Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model

et al. 2020

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Background Cardiac contractility modulation (CCM) is non-excitatory electrical stimulation for improving cardiac function. This study aimed to evaluate the effects of CCM on structural and electrical remodeling in a rabbit model of chronic heart failure (CHF). Methods Thirty rabbits were randomly divided into the sham, CHF, and CCM groups. The CHF model was induced 12 weeks after trans-aortic constriction by pressure unloading and CCM was delivered to the myocardium for 4 weeks. Corrected QT intervals, the ventricular effective refractory period, and inducibility of ventricular tachycardia were measured by an electrophysiological examination. Connective tissue growth factor, galectin-3, Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were measured by western blotting. Results The CHF group had a significantly prolonged corrected QT interval and ventricular effective refractory period, and increased inducibility of ventricular tachycardia. Prominent myocardial fibrosis and increased hydroxyproline content were observed in the CHF group, but these were suppressed in the CCM group. Kv4.3, KCNQ1, KCNH2, and connexin 43 protein levels were significantly lower in the CHF group, but treatment with CCM partially restored their levels. Conclusions CCM attenuates myocardial structural and electrical remodeling during CHF. These findings provide evidence for clinical use of CCM in treating CHF.

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Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models

Cited by 16 publications

References 24 publications

Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety: Systematic review of (hydroxy)chloroquine efficacy and safety

Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety: Systematic review of (hydroxy)chloroquine efficacy and safety

Effects of Short-Term Hydroxychloroquine Plus Moxifloxacin Therapy on Corrected QT Interval and Tp-e Interval in Patients With COVID-19

Cardiac contractility modulation attenuates structural and electrical remodeling in a chronic heart failure rabbit model

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