본문 바로가기
KERD
논문KCI 등재

Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes

0

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류화학

초록

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs.

Abstract

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs.

참고문헌 (40)

  1. Savarino A, "Effects of chloroquine on viral infections: an old drug against today's diseases?", Lancet Infect Dis, 3, pp.722~727 (2003)
  2. Savarino A, "New insights into the antiviral effects of chloroquine", Lancet Infect Dis, 6, pp.67~69 (2006)
  3. Vincent MJ, "Chloroquine is a potent inhibitor of SARS coronavirus infection and spread", Virol J, 2, pp.69~ (2005)
  4. Wang M, "Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus(2019-nCoV)in vitro", Cell Res, 30, pp.269~271 (2020)
  5. Yao X, "In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2)", Clin Infect Dis, 71, pp.732~739 (2020)
  6. Gautret P, "Hydroxychloroquine and azithromycin as a treatment of COVID-19 : results of an open-label non-randomized clinical trial", Int J Antimicrob Agents, 56, pp.105949~ (2020)
  7. Colson P, "Chloroquine for the 2019 novel coronavirus SARS-CoV-2", Int J Antimicrob Agents, 55, pp.105923~ (2020)
  8. Satarker S, "Hydroxychloroquine in COVID-19 : Potential mechanism of action against SARS-CoV-2", Curr Pharmacol Rep, 6, pp.203~211 (2020)
  9. Das S, "An Updated Systematic Review of the Therapeutic Role of Hydroxychloroquine in Coronavirus Disease-19(COVID-19)", Clin Drug Investig, 40, pp.591~601 (2020)
  10. Pillat MM, "Insights in chloroquine action : perspectives and implications in Malaria and COVID-19", Cytometry A, 97, pp.872~881 (2020)
  11. Boulware DR, "A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19", N Engl J Med, 383, pp.517~525 (2020)
  12. Chatre C, "Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine : A Systematic Review of the Literature", Drug Saf, 41, pp.919~931 (2018)
  13. White NJ, "Cardiotoxicity of antimalarial drugs", Lancet Infect Dis, 7, pp.549~558 (2007)
  14. Min JY, "Macrolide therapy in respiratory viral infections", Mediators Inflamm, 2012, pp.649570~ (2012)
  15. Tran DH, "Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus internalization process", J Antibiot(Tokyo), 72, pp.759~768 (2019)
  16. Scherrmann JM, "Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19Therapy", AAPS J, 22, pp.86~ (2020)
  17. Ohe M, "Macrolide treatment for COVID-19: Will this be the way forward?", Biosci Trends, 14, pp.159~160 (2020)
  18. Chorin E, "The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin", Nat Med, 26, pp.808~809 (2020)
  19. Ramireddy A, "Experience With Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic : Implications for QT Interval Monitoring", J Am Heart Assoc, 9, pp.e017144~ (2020)
  20. Juurlink DN, "The cardiovascular safety of azithromycin", CMAJ, 186, pp.1127~1128 (2014)
  21. Mitra RL, "An algorithm for managing QT prolongation in coronavirus disease 2019(COVID-19)patients treated with either chloroquine or hydroxychloroquine in conjunction with azithromycin : Possible benefits of intravenous lidocaine", Heart Rhythm Case Rep, 6, pp.244~248 (2020)
  22. Ray WA, "Azithromycin and the risk of cardiovascular death", N Engl J Med, 366, pp.1881~1890 (2012)
  23. Juurlink DN, "Safety considerations with chloroquine, hydroxychloroquine and azithromycin in the management of SARS-CoV-2 infection", CMAJ, 192, pp.E450~E453 (2020)
  24. Gintant G, "Evolution of strategies to improve preclinical cardiac safety testing", Nat Rev Drug Discov, 15, pp.457~471 (2016)
  25. Satsuka A, "Cardiotoxicity Assessment of Drugs Using Human iPS Cell-Derived Cardiomyocytes : Toward Proarrhythmic Risk and Cardio-Oncology", Curr Pharm Biotechnol, 21, pp.765~772 (2020)
  26. Sharma A, "Use of human induced pluripotent stem cell-derived cardiomyocytes to assess drug cardiotoxicity", Nat Protoc, 13, pp.3018~3041 (2018)
  27. Thomson JA, "Embryonic stem cell lines derived from human blastocysts", Science, 282, pp.1145~1147 (1998)
  28. Cheng DK, "Nonuniform responses of transmembrane potential during electric field stimulation of single cardiac cells", Am J Physiol, 277, pp.H351~362 (1999)
  29. Rast G, "An integrated platform for simultaneous multiwell field potential recording and Fura-2-based calcium transient ratiometry in human induced pluripotent stem cell(hiPSC)-derived cardiomyocytes", J Pharmacol Toxicol Methods, 75, pp.91~100 (2015)
  30. Inciardi RM, "Cardiac Involvement in a Patient With Coronavirus Disease 2019(COVID-19)", JAMA Cardiol, 5, pp.819~824 (2020)
  31. Sala S, "Acute myocarditis presenting as a reverse Tako-Tsubo syndrome in a patient with SARS-CoV-2 respiratory infection", Eur Heart J, 41, pp.1861~1862 (2020)
  32. Tavazzi G, "Myocardial localization of coronavirus in COVID-19cardiogenic shock", Eur J Heart Fail, 22, pp.911~915 (2020)
  33. Sirenko O, "Multiparameter in vitro assessment of compound effects on cardiomyocyte physiology using iPSC cells", J Biomol Screen, 18, pp.39~53 (2013)
  34. Traebert M, "Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells", Eur J Pharmacol, 484, pp.41~48 (2004)
  35. Mubagwa K, "Cardiac effects and toxicity of chloroquine : a short update", Int J Antimicrob Agents, 56, pp.106057~ (2020)
  36. Vicente J, "Assessment of Multi-Ion Channel Block in a Phase I Randomized Study Design : Results of the CiPA Phase I ECG Biomarker Validation Study", Clin Pharmacol Ther, 105, pp.943~953 (2019)
  37. Haeusler IL, "The arrhythmogenic cardiotoxicity of the quinoline and structurally related antimalarial drugs : a systematic review", BMC Med, 16, pp.200~ (2018)
  38. Lian X, "Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt", beta-catenin signaling under fully defined conditions, 2013, pp.8, 162~175
  39. Lian X, "Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling", Proc Natl Acad Sci U S A, 109, pp.E1848~1857 (2012)
  40. Tohyama S, "Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes", Cell Stem Cell, 12, pp.127~137 (2013)

관련 논문AI추천

Comparison of Cardiac Action Potential between Human Pluripotent Stem Cell-Derived Cardiomyocytes(hPSC-CM) and CiPA (Comprehensive in vitro proarrhythmic assay)-based In Silico Simulation김기광, 김기석, 이현이한국동물실험대체법학회 · 한국동물실험대체법학회지2024 · 제18권 제2호Development and evaluation of next-generation cardiotoxicity assay based on embryonic stem cell-derived cardiomyocytes김경설, 유보경, 정영훈, 정초록, Hyung-Min Chung, Jae-Hak Park, Jin Kim, Seong Woo Choi, Seul-Gi Lee, Ukjin Kim생화학분자생물학회 · BMB Reports2020 · 제53권 제8호Tomatidine-stimulated maturation of human embryonic stem cell-derived cardiomyocytes for modeling mitochondrial dysfunction한진, 염재범, Choi Seunghak, Heo Soon Chul, Hyun Sung-Ae, Kim Dasol, Kim Deok-Ho, Kim Hyoung Kyu, Kim Jae Ho, Kim Ye Seul, Seo Jung-Wook, Yoon Jung Won생화학분자생물학회 · Experimental and Molecular Medicine2022 · 제54권 심근 세포의 전기생리학적 특징을 이용한 인공 신경망 기반 약물의 심장독성 평가유예담, 임기무, 정다운, Aroli Marcellinus대한의용생체공학회 · 의공학회지2021 · 제42권 제6호Engineered human cardiac tissues for modeling heart diseases조승우, Sungjin Min생화학분자생물학회 · BMB Reports2023 · 제56권 제1호토끼 심장에서 단상활동전위의 TRIaD 분석을 이용한 약물에 대한 심장 안전성 평가김기석, 남대환, 박순현, 한종탁한국동물실험대체법학회 · 한국동물실험대체법학회지2017 · 제11권 제1호

이 간행물의 다른 논문 (7건)