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Hemmati AA, Mojiri-Forushani H. Off-label Use of Medicines in COVID-19: A Lesson For Future. CORONAVIRUSES 2024; 5. [DOI: 10.2174/0126667975271719231107052426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 01/03/2025]
Abstract
Abstract:
The COVID-19 infection is rapidly spreading worldwide. Treating this new viral infection
is a great challenge worldwide. There is no specific and approved medication for its treatment,
so some medications are considered off-label. Antivirals, corticosteroids, antimalarial agents, and
antibiotics are proposed in different countries to treat COVID-19. This narrative review discussed the
off-label use of medications for COVID-19 and the beneficial and adverse effects of them. Evidence
was collected and sorted from the literature ranging from 2019 to 2022 on scientific databases such
as Web of Science, PubMed, and Scopus with suitable keywords. All papers, namely systematic
reviews, case studies, and clinical guidelines, were evaluated. Antimalarial agents, antivirals, antibiotics,
corticosteroids, NSAIDs, biological medicines, Ivermectin, and melatonin were reviewed in
this study. Some medications have direct antiviral effects, and many can reduce infection symptoms
and hospitalization. In some clinical trial trials, even some of them, such as corticosteroids, can lower
death rates, particularly during the cytokine storm period. However, the effectiveness of some
medications has not been understood. Besides, the side effects of off-label use of these medications
must be considered a serious concern. There are no proven medications for COVID-19 yet. Off-label
use of medications is a double-edged sword that can have advantages outweighing its disadvantages.
The COVID-19 crisis taught us many lessons about dealing with health-related crises and their
treatment management. One of the most important lessons is paying more attention to the discovery
and development of novel drugs and vaccines based on modern technology.
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Affiliation(s)
- Ali Asghar Hemmati
- Department of Pharmacology, Marine Pharmaceutical Science Research Center, School of Pharmacy, Ahvaz
Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hoda Mojiri-Forushani
- Department of Pharmacology, School of Medicine, Abadan
University of Medical Sciences, Abadan, Iran
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2
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Jeeyavudeen MS, Chaudhari R, Pappachan JM, Fouda S. Clinical implications of COVID-19 in patients with metabolic-associated fatty liver disease. World J Gastroenterol 2023; 29:487-502. [PMID: 36688018 PMCID: PMC9850935 DOI: 10.3748/wjg.v29.i3.487] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 11/20/2022] [Accepted: 12/27/2022] [Indexed: 01/12/2023] Open
Abstract
People across the world are affected by the "coronavirus disease 2019 (COVID-19)", brought on by the "SARS-CoV type-2 coronavirus". Due to its high incidence in individuals with diabetes, metabolic syndrome, and metabolic-associated fatty liver disease (MAFLD), COVID-19 has gained much attention. The metabolic syndrome's hepatic manifestation, MAFLD, carries a significant risk of type-2-diabetes. The link between the above two conditions has also drawn increasing consideration since MAFLD is intricately linked to the obesity epidemic. Independent of the metabolic syndrome, MAFLD may impact the severity of the viral infections, including COVID-19 or may even be a risk factor. An important question is whether the present COVID-19 pandemic has been fueled by the obesity and MAFLD epidemics. Many liver markers are seen elevated in COVID-19. MAFLD patients with associated comorbid conditions like obesity, cardiovascular disease, renal disease, malignancy, hypertension, and old age are prone to develop severe disease. There is an urgent need for more studies to determine the link between the two conditions and whether it might account for racial differences in the mortality and morbidity rates linked to COVID-19. The role of innate and adaptive immunity alterations in MAFLD patients may influence the severity of COVID-19. This review investigates the implications of COVID-19 on liver injury and disease severity and vice-versa. We also addressed the severity of COVID-19 in patients with prior MAFLD and its potential implications and therapeutic administration in the clinical setting.
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Affiliation(s)
- Mohammad Sadiq Jeeyavudeen
- Department of Endocrinology and Metabolism, University Hospitals of Edinburgh, Edinburgh EH4 2XU, United Kingdom
| | - Rahul Chaudhari
- Department of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA 23298, United States
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
| | - Sherouk Fouda
- School of Health and Biomedical Sciences, RMIT University, Melbourne VIC, Australia
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Duarte-García A, Graef ER, Liew JW, Konig MF, Kim AH, Sparks JA. Response to: 'Correspondence on ' Festina lente: hydroxychloroquine, COVID-19and the role of the rheumatologist' by Graef et al' by Lo et al. Ann Rheum Dis 2022; 81:e164. [PMID: 32769149 PMCID: PMC8075104 DOI: 10.1136/annrheumdis-2020-218680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 07/31/2020] [Indexed: 01/20/2023]
Affiliation(s)
| | | | - Jean W Liew
- Divison of Rheumatology, Boston University, Boston, Massachusetts, USA
| | - Maximilian F Konig
- Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alfred Hyoungju Kim
- Medicine/Rheumatology, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
| | - Jeffrey A Sparks
- Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Baigent C, Windecker S, Andreini D, Arbelo E, Barbato E, Bartorelli AL, Baumbach A, Behr ER, Berti S, Bueno H, Capodanno D, Cappato R, Chieffo A, Collet JP, Cuisset T, de Simone G, Delgado V, Dendale P, Dudek D, Edvardsen T, Elvan A, González-Juanatey JR, Gori M, Grobbee D, Guzik TJ, Halvorsen S, Haude M, Heidbuchel H, Hindricks G, Ibanez B, Karam N, Katus H, Klok FA, Konstantinides SV, Landmesser U, Leclercq C, Leonardi S, Lettino M, Marenzi G, Mauri J, Metra M, Morici N, Mueller C, Petronio AS, Polovina MM, Potpara T, Praz F, Prendergast B, Prescott E, Price S, Pruszczyk P, Rodríguez-Leor O, Roffi M, Romaguera R, Rosenkranz S, Sarkozy A, Scherrenberg M, Seferovic P, Senni M, Spera FR, Stefanini G, Thiele H, Tomasoni D, Torracca L, Touyz RM, Wilde AA, Williams B. ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2-care pathways, treatment, and follow-up. Cardiovasc Res 2022; 118:1618-1666. [PMID: 34864876 PMCID: PMC8690236 DOI: 10.1093/cvr/cvab343] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
AIMS Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe. The aim of this two part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular (CV) disease in association with COVID-19. METHODS AND RESULTS A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts. The first, which was reported previously, focused on the epidemiology, pathophysiology, and diagnosis of CV conditions that may be manifest in patients with COVID-19. This second part addresses the topics of: care pathways and triage systems and management and treatment pathways, both of the most commonly encountered CV conditions and of COVID-19; and information that may be considered useful to help patients with CV disease (CVD) to avoid exposure to COVID-19. CONCLUSION This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.
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Banai A, Szekely Y, Lupu L, Borohovitz A, Levi E, Ghantous E, Taieb P, Hochstadt A, Banai S, Topilsky Y, Chorin E. QT Interval Prolongation Is a Novel Predictor of 1-Year Mortality in Patients With COVID-19 Infection. Front Cardiovasc Med 2022; 9:869089. [PMID: 35757338 PMCID: PMC9223350 DOI: 10.3389/fcvm.2022.869089] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 05/11/2022] [Indexed: 01/08/2023] Open
Abstract
Background QT interval prolongation is common in critically ill patients and is associated with increased mortality. However, the predictive value of a prolonged corrected QT interval (QTc) for myocardial injury and long-term mortality among patients hospitalized with COVID-19 infection is not well known. Purpose To evaluate the association of prolonged QTc with myocardial injury and with 1-year mortality among patients hospitalized with COVID-19 infection. Materials and Methods A total of 335 consecutive patients hospitalized with COVID-19 infection were prospectively studied. All patients underwent a comprehensive echocardiographic evaluation within 48 h from admission. Using the Bazett formula, the QTc interval was calculated from the first ECG tracing recorded at the ER. QTc ≥ 440 ms in males and ≥450 ms in females was considered prolonged. Patients with elevated cardiac biomarkers and/or echocardiographic signs of myocardial dysfunction were considered to have myocardial injury. The predictive value of QTc prolongation for myocardial injury was calculated using a multivariate binary regression model. One-year mortality rate of patients with and without QTc prolongation was compared using the log-rank test, and a multivariate Cox regression model adjusting for multiple covariates was performed to evaluate the 1-year mortality risk. Results One-hundred and nine (32.5%) patients had a prolonged QTc. Compared to patients without QTc prolongation, patients with prolonged QTc were older (70 ± 14.4 vs. 62.7 ± 16.6, p < 0.001), had more comorbidities, and presented with a more severe disease. Prolonged QTc was an independent predictor for severe or critical disease (adjusted HR 2.14, 95% CI 1.3-3.5; p = 0.002) and myocardial injury (adjusted HR 2.07, 95% CI 1.22-3.5; p = 0.007). One-year mortality of patients with prolonged QTc was higher than those with no QTc prolongation (40.4% vs. 15.5; p < 0.001). Following adjustment to multiple covariates including myocardial injury and disease severity, QTc prolongation was found to be associated with increased 1-year mortality risk (HR 1.69, 95% CI 1.06-2.68, p = 0.027). Conclusion Prolonged QTc is associated with disease severity, myocardial injury and 1-year mortality among patients hospitalized with COVID-19 infection.
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Affiliation(s)
- Ariel Banai
- Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Safety of Short-Term Treatments with Oral Chloroquine and Hydroxychloroquine in Patients with and without COVID-19: A Systematic Review. Pharmaceuticals (Basel) 2022; 15:ph15050634. [PMID: 35631460 PMCID: PMC9144263 DOI: 10.3390/ph15050634] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/27/2022] [Accepted: 05/13/2022] [Indexed: 01/09/2023] Open
Abstract
Chloroquine (CQ) and hydroxychloroquine (HCQ) have recently become the focus of global attention as possible treatments for Coronavirus Disease 2019 (COVID-19). The current systematic review aims to assess their safety in short treatments (≤14 days), whether used alone or in combination with other drugs. Following the PRISMA and SWiM recommendations, a search was conducted using four health databases for all relevant English-, Chinese-, and Spanish-language studies from inception through 30 July 2021. Patients treated for any condition and with any comparator were included. The outcomes of interest were early drug adverse effects and their frequency. A total of 254 articles met the inclusion criteria, including case and case-control reports as well as cross-sectional, cohort, and randomised studies. The results were summarised either qualitatively in table or narrative form or, when possible (99 studies), quantitatively in terms of adverse event frequencies. Quality evaluation was conducted using the CARE, STROBE, and JADAD tools. This systematic review showed that safety depended on drug indication. In COVID-19 patients, cardiac adverse effects, such as corrected QT interval prolongation, were relatively frequent (0–27.3% and up to 33% if combined with azithromycin), though the risk of torsade de pointes was low. Compared to non-COVID-19 patients, COVID-19 patients experienced a higher frequency of cardiac adverse effects regardless of the regimen used. Dermatological adverse effects affected 0–10% of patients with autoimmune diseases and COVID-19. A broad spectrum of neuropsychiatric adverse effects affected patients treated with CQ for malaria with variable frequencies and some cases were reported in COVID-19 patients. Gastrointestinal adverse effects occurred regardless of drug indication affecting 0–50% of patients. In conclusion, CQ and HCQ are two safe drugs widely used in the treatment of malaria and autoimmune diseases. However, recent findings on their cardiac and neuropsychiatric adverse effects should be considered if these drugs were to be proposed as antivirals again.
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Chiu MN, Bhardwaj M, Sah SP. Safety profile of COVID-19 drugs in a real clinical setting. Eur J Clin Pharmacol 2022; 78:733-753. [PMID: 35088108 PMCID: PMC8794611 DOI: 10.1007/s00228-021-03270-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/18/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has affected millions all over the world and has been declared pandemic, as of 11 March 2020. In addition to the ongoing research and development of vaccines, there is still a dire need for safe and effective drugs for the control and treatment against the SARS-CoV-2 virus infection. Numerous repurposed drugs are under clinical investigations whose reported adverse events can raise worries about their safety. The aim of this review is to illuminate the associated adverse events related to the drugs used in a real COVID-19 setting along with their relevant mechanism(s). METHOD Through a literature search conducted on PubMed and Google Scholar database, various adverse events suspected to be induced by eight drugs, including dexamethasone, hydroxychloroquine, chloroquine, remdesivir, favipiravir, lopinavir/ritonavir, ivermectin, and tocilizumab, administered in COVID-19 patients in clinical practice and studies were identified in 30 case reports, 3 case series, and 10 randomized clinical trials. RESULTS Mild, moderate, or severe adverse events of numerous repurposed and investigational drugs caused by various factors and mechanisms were observed. Gastrointestinal side effects such as nausea, abdominal cramps, diarrhea, and vomiting were the most frequently followed by cardiovascular, cutaneous, and hepatic adverse events. Few other rare adverse drug reactions were also observed. CONCLUSION In light of their ineffectiveness against COVID-19 as evident in large clinical studies, drugs including hydroxychloroquine, lopinavir/ritonavir, and ivermectin should neither be used routinely nor in clinical studies. While lack of sufficient data, it creates doubt regarding the reliability of chloroquine and favipiravir use in COVID-19 patients. Hence, these two drugs can only be used in clinical studies. In contrast, ample well-conducted studies have approved the use of remdesivir, tocilizumab, and dexamethasone under certain conditions in COVID-19 patients. Consequently, it is significant to establish a strong surveillance system in order to monitor the proper safety and toxicity profile of the potential anti-COVID-19 drugs with good clinical outcomes.
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Affiliation(s)
- Mei Nee Chiu
- University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India
| | - Maitry Bhardwaj
- University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India
| | - Sangeeta Pilkhwal Sah
- University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
- University Institute of Pharmaceutical Sciences UGC Centre of Advanced Study (UGC-CAS), Panjab University, Chandigarh, 160014, India.
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Baigent C, Windecker S, Andreini D, Arbelo E, Barbato E, Bartorelli AL, Baumbach A, Behr ER, Berti S, Bueno H, Capodanno D, Cappato R, Chieffo A, Collet JP, Cuisset T, de Simone G, Delgado V, Dendale P, Dudek D, Edvardsen T, Elvan A, González-Juanatey JR, Gori M, Grobbee D, Guzik TJ, Halvorsen S, Haude M, Heidbuchel H, Hindricks G, Ibanez B, Karam N, Katus H, Klok FA, Konstantinides SV, Landmesser U, Leclercq C, Leonardi S, Lettino M, Marenzi G, Mauri J, Metra M, Morici N, Mueller C, Petronio AS, Polovina MM, Potpara T, Praz F, Prendergast B, Prescott E, Price S, Pruszczyk P, Rodríguez-Leor O, Roffi M, Romaguera R, Rosenkranz S, Sarkozy A, Scherrenberg M, Seferovic P, Senni M, Spera FR, Stefanini G, Thiele H, Tomasoni D, Torracca L, Touyz RM, Wilde AA, Williams B. ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2-care pathways, treatment, and follow-up. Eur Heart J 2022; 43:1059-1103. [PMID: 34791154 PMCID: PMC8690006 DOI: 10.1093/eurheartj/ehab697] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/08/2021] [Accepted: 09/13/2021] [Indexed: 02/07/2023] Open
Abstract
AIMS Since its emergence in early 2020, the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019 (COVID-19) has reached pandemic levels, and there have been repeated outbreaks across the globe. The aim of this two part series is to provide practical knowledge and guidance to aid clinicians in the diagnosis and management of cardiovascular (CV) disease in association with COVID-19. METHODS AND RESULTS A narrative literature review of the available evidence has been performed, and the resulting information has been organized into two parts. The first, which was reported previously, focused on the epidemiology, pathophysiology, and diagnosis of CV conditions that may be manifest in patients with COVID-19. This second part addresses the topics of: care pathways and triage systems and management and treatment pathways, both of the most commonly encountered CV conditions and of COVID-19; and information that may be considered useful to help patients with CV disease (CVD) to avoid exposure to COVID-19. CONCLUSION This comprehensive review is not a formal guideline but rather a document that provides a summary of current knowledge and guidance to practicing clinicians managing patients with CVD and COVID-19. The recommendations are mainly the result of observations and personal experience from healthcare providers. Therefore, the information provided here may be subject to change with increasing knowledge, evidence from prospective studies, and changes in the pandemic. Likewise, the guidance provided in the document should not interfere with recommendations provided by local and national healthcare authorities.
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Zheng Z, Cai D, Fu Y, Wang Y, Song Y, Lian J. Chronic Administration of COVID-19 Drugs Fluvoxamine and Lopinavir Shortens Action Potential Duration by Inhibiting the Human Ether-à-go-go-Related Gene and Cav1.2. Front Pharmacol 2022; 13:889713. [PMID: 35873575 PMCID: PMC9301601 DOI: 10.3389/fphar.2022.889713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/07/2022] [Indexed: 02/05/2023] Open
Abstract
Background: Old drugs for new indications in the novel coronavirus disease of 2019 (COVID-19) pandemic have raised concerns regarding cardiotoxicity, especially the development of drug-induced QT prolongation. The acute blocking of the cardiac hERG potassium channel is conventionally thought to be the primary mechanism of QT prolongation induced by COVID-19 drugs fluvoxamine (FLV) and lopinavir (LPV). The chronic impact of these medications on the hERG expression has yet to be determined. Methods: To investigate the effect of long-term incubation of FLV and LPV on the hERG channel, we used electrophysiological assays and molecular experiments, such as Western blot, RT-qPCR, and immunofluorescence, in HEK-293 cells stably expressing hERG and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Results: Compared to the acute effects, chronic incubation for FLV and LPV generated much lower half-maximal inhibitory concentration (IC50) values, along with a left-shifted activation curve and retarded channel activation. Inconsistent with the reduction in current, we unexpectedly found that the chronic effects of drugs promoted the maturation of hERG proteins, accompanied by the high expression of Hsp70 and low expression of Hsp90. Targeting Hsp70 using siRNA was able to reverse the effects of these drugs on hERG proteins. In addition, FLV and LPV resulted in a significant reduction of APD90 and triggered the early after-depolarizations (EADs), as well as inhibited the protein level of the L-type voltage-operated calcium channel (L-VOCC) in hiPSC-CMs. Conclusion: Chronic incubation with FLV and LPV produced more severe channel-blocking effects and contributed to altered channel gating and shortened action potential duration by inhibiting hERG and Cav1.2.
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Affiliation(s)
- Zequn Zheng
- Department of Cardiovascular, Lihuili Hospital Facilitated to Ningbo University, Ningbo University, Ningbo, China
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
- Department of Cardiovascular Medicine, First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Dihui Cai
- Department of Cardiovascular, Lihuili Hospital Facilitated to Ningbo University, Ningbo University, Ningbo, China
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
| | - Yin Fu
- Department of Cardiovascular, Lihuili Hospital Facilitated to Ningbo University, Ningbo University, Ningbo, China
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
| | - Ying Wang
- Department of Cardiovascular, Lihuili Hospital Facilitated to Ningbo University, Ningbo University, Ningbo, China
| | - Yongfei Song
- Department of Cardiovascular, Lihuili Hospital Facilitated to Ningbo University, Ningbo University, Ningbo, China
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
- *Correspondence: Yongfei Song , ; Jiangfang Lian,
| | - Jiangfang Lian
- Department of Cardiovascular, Lihuili Hospital Facilitated to Ningbo University, Ningbo University, Ningbo, China
- Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China
- *Correspondence: Yongfei Song , ; Jiangfang Lian,
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TeBay C, McArthur JR, Mangala M, Kerr N, Heitmann S, Perry MD, Windley MJ, Vandenberg JI, Hill AP. Pathophysiological metabolic changes associated with disease modify the proarrhythmic risk profile of drugs with potential to prolong repolarisation. Br J Pharmacol 2021; 179:2631-2646. [PMID: 34837219 DOI: 10.1111/bph.15757] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 11/16/2021] [Accepted: 11/18/2021] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND AND PURPOSE Hydroxychloroquine, chloroquine and azithromycin are three drugs that were proposed to treat COVID-19. While concern already existed around their proarrhythmic potential there is little data regarding how altered physiological states encountered in patients such as febrile state, electrolyte imbalances or acidosis might change their risk profiles. EXPERIMENTAL APPROACH Potency of hERG block was measured using high-throughput electrophysiology in the presence of variable environmental factors. These potencies informed simulations to predict population risk profiles. Effects on cardiac repolarisation were verified in human induced pluripotent stem cell-derived cardiomyocytes from multiple individuals. KEY RESULTS Chloroquine and hydroxychloroquine blocked hERG with IC50 of 1.47±0.07 μM and 3.78±0.17 μM respectively, indicating proarrhythmic risk at concentrations effective against SARS-CoV-2 in vitro. Hypokalaemia and hypermagnesemia increased potency of chloroquine and hydroxychloroquine, indicating increased proarrhythmic risk. Acidosis significantly reduced potency of all drugs, whereas increased temperature decreased potency of chloroquine and hydroxychloroquine against hERG but increased potency for azithromycin. In silico simulations demonstrated that proarrhythmic risk was increased by female sex, hypokalaemia and heart failure, and identified specific genetic backgrounds associated with emergence of arrhythmia. CONCLUSION AND IMPLICATIONS Our study demonstrates how proarrhythmic risk can be exacerbated by metabolic changes and pre-existing disease. More broadly, the study acts as a blueprint for how high-throughput in vitro screening, combined with in silico simulations can help guide both preclinical screening and clinical management of patients in relation to drugs with potential to prolong repolarisation.
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Affiliation(s)
- Clifford TeBay
- Victor Chang Cardiac Research Institute, Sydney, Australia
| | - Jeffrey R McArthur
- Victor Chang Cardiac Research Institute, Sydney, Australia.,Illawarra Health and Medical Research Institute, University of Wollongong, Australia
| | - Melissa Mangala
- Victor Chang Cardiac Research Institute, Sydney, Australia.,St. Vincent's Clinical school, UNSW Sydney, Sydney, Australia
| | - Nicholas Kerr
- Victor Chang Cardiac Research Institute, Sydney, Australia.,St. Vincent's Clinical school, UNSW Sydney, Sydney, Australia
| | | | - Matthew D Perry
- Victor Chang Cardiac Research Institute, Sydney, Australia.,School of Medical Sciences, UNSW Sydney, Sydney, Australia
| | - Monique J Windley
- Victor Chang Cardiac Research Institute, Sydney, Australia.,St. Vincent's Clinical school, UNSW Sydney, Sydney, Australia
| | - Jamie I Vandenberg
- Victor Chang Cardiac Research Institute, Sydney, Australia.,St. Vincent's Clinical school, UNSW Sydney, Sydney, Australia
| | - Adam P Hill
- Victor Chang Cardiac Research Institute, Sydney, Australia.,St. Vincent's Clinical school, UNSW Sydney, Sydney, Australia
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11
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Smith MK, Bikmetov R, Al Rihani SB, Deodhar M, Hafermann M, Dow P, Turgeon J, Michaud V. Adverse drug event risk assessment by the virtual addition of COVID-19 repurposed drugs to Medicare and commercially insured patients' drug regimens: A drug safety simulation study. Clin Transl Sci 2021; 14:1799-1809. [PMID: 33786990 PMCID: PMC8251090 DOI: 10.1111/cts.13025] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 01/16/2023] Open
Abstract
Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID-19) treatment in a large-scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients' drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub-payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug-induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two-to-seven points, p < 0.001). The increase in ADE risk was mainly driven by an increase in CYP450 drug interaction risk score and by drug-induced LQTS risk score. The Medicare group presented a greater risk overall compared to the commercial group. All repurposed drugs were associated with an increased risk of ADEs. Our simulation strategy could be used as a blueprint to preemptively assess safety associated with future repurposed or new drugs.
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Affiliation(s)
- Matt K Smith
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, Florida, USA
| | - Ravil Bikmetov
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, Florida, USA
| | - Sweilem B Al Rihani
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, Florida, USA
| | - Malavika Deodhar
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, Florida, USA
| | - Matthew Hafermann
- Cambia Health Solutions - Case Management at Regence BlueShield, Tacoma, Washington, USA
| | - Pamela Dow
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, Florida, USA
| | - Jacques Turgeon
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, Florida, USA
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
| | - Veronique Michaud
- Precision Pharmacotherapy Research & Development Institute, Tabula Rasa HealthCare, Orlando, Florida, USA
- Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada
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12
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Banai A, Taieb P, Furie N, Hochstadt A, Merdler I, Sapir O, Granot Y, Lupu L, Ghantous E, Borohovitz A, Gal-Oz A, Ingbir M, Arbel Y, Banai S, Topilsky Y, Lichter Y, Szekely Y. COVID-19, a tale of two peaks: patients' characteristics, treatments, and clinical outcomes. Intern Emerg Med 2021; 16:1629-1639. [PMID: 33797029 PMCID: PMC8016151 DOI: 10.1007/s11739-021-02711-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 01/21/2021] [Indexed: 12/27/2022]
Abstract
Coronavirus 2019 disease (COVID-19) continues to challenge healthcare systems globally as many countries are currently experiencing an increase in the morbidity and mortality. Compare baseline characteristics, clinical presentation, treatments, and clinical outcomes of patients admitted during the second peak to those admitted during the first peak. Retrospective analysis of 258 COVID-19 patients consecutively admitted to the Tel Aviv Medical Center, of which, 131 during the first peak (March 21-May 30, 2020) and 127 during the second peak (May 31-July 16, 2020). First and second peak patients did not differ in baseline characteristics and clinical presentation at admission. Treatment with dexamethasone, full-dose anticoagulation, tocilizumab, remdesivir, and convalescent plasma transfusion were significantly more frequent during the second peak, as well as regimens combining 3-4 COVID-19-directed drugs. Compared to the first peak, 30-day mortality and invasive mechanical ventilation rates as well as adjusted risk were significantly lower during the second peak (10.2%, vs 19.8% vs p = 0.028, adjusted HR 0.39, 95% CI 0.19-0.79, p = 0.009 and 8.8% vs 19.3%, p = 0.002, adjusted HR 0.29, 95% CI 0.13-0.64, p = 0.002; respectively). Rates of 30-day mortality and invasive mechanical ventilation, as well as adjusted risks, were lower in the second peak of the COVID-19 pandemic among hospitalized patients. The change in treatment strategy and the experienced gained during the first peak may have contributed to the improved outcomes.
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Affiliation(s)
- Ariel Banai
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Philippe Taieb
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Nadav Furie
- Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aviram Hochstadt
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Ilan Merdler
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Orly Sapir
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yoav Granot
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Lior Lupu
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Eihab Ghantous
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Ariel Borohovitz
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Amir Gal-Oz
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Merav Ingbir
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yaron Arbel
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shmuel Banai
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yan Topilsky
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yael Lichter
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yishay Szekely
- Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
- Department of Cardiology, Tel Aviv Sourasky Medical Center, 6 Weizmann St., 64239, Tel Aviv, Israel.
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13
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Montnach J, Baró I, Charpentier F, De Waard M, Loussouarn G. Modelling sudden cardiac death risks factors in patients with coronavirus disease of 2019: the hydroxychloroquine and azithromycin case. Europace 2021; 23:1124-1133. [PMID: 34009333 PMCID: PMC8135857 DOI: 10.1093/europace/euab043] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 02/16/2021] [Indexed: 12/23/2022] Open
Abstract
AIMS Coronavirus disease of 2019 (COVID-19) has rapidly become a worldwide pandemic. Many clinical trials have been initiated to fight the disease. Among those, hydroxychloroquine and azithromycin had initially been suggested to improve clinical outcomes. Despite any demonstrated beneficial effects, they are still in use in some countries but have been reported to prolong the QT interval and induce life-threatening arrhythmia. Since a significant proportion of the world population may be treated with such COVID-19 therapies, evaluation of the arrhythmogenic risk of any candidate drug is needed. METHODS AND RESULTS Using the O'Hara-Rudy computer model of human ventricular wedge, we evaluate the arrhythmogenic potential of clinical factors that can further alter repolarization in COVID-19 patients in addition to hydroxychloroquine (HCQ) and azithromycin (AZM) such as tachycardia, hypokalaemia, and subclinical to mild long QT syndrome. Hydroxychloroquine and AZM drugs have little impact on QT duration and do not induce any substrate prone to arrhythmia in COVID-19 patients with normal cardiac repolarization reserve. Nevertheless, in every tested condition in which this reserve is reduced, the model predicts larger electrocardiogram impairments, as with dofetilide. In subclinical conditions, the model suggests that mexiletine limits the deleterious effects of AZM and HCQ. CONCLUSION By studying the HCQ and AZM co-administration case, we show that the easy-to-use O'Hara-Rudy model can be applied to assess the QT-prolongation potential of off-label drugs, beyond HCQ and AZM, in different conditions representative of COVID-19 patients and to evaluate the potential impact of additional drug used to limit the arrhythmogenic risk.
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Affiliation(s)
- Jérôme Montnach
- Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes F-44000, France
| | - Isabelle Baró
- Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes F-44000, France
| | - Flavien Charpentier
- Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes F-44000, France
| | - Michel De Waard
- Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes F-44000, France
- Laboratory of Excellence, Ion Channels, Science & Therapeutics, Valbonne F-06560, France
| | - Gildas Loussouarn
- Université de Nantes, CNRS, INSERM, l’institut du thorax, Nantes F-44000, France
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14
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Yuan M, Zathar Z, Nihaj F, Apostolakis S, Abdul F, Connolly D, Varma C, Sharma V. ECG changes in hospitalised patients with COVID-19 infection. THE BRITISH JOURNAL OF CARDIOLOGY 2021; 28:24. [PMID: 35747459 PMCID: PMC8822529 DOI: 10.5837/bjc.2021.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The coronavirus disease 2019 (COVID-19) commonly involves the respiratory system but increasingly cardiovascular involvement is recognised. We assessed electrocardiogram (ECG) abnormalities in patients with COVID-19. We performed retrospective analysis of the hospital's COVID-19 database from April to May 2020. Any ECG abnormality was defined as: 1) new sinus bradycardia; 2) new/worsening bundle-branch block; 3) new/worsening heart block; 4) new ventricular or atrial bigeminy/trigeminy; 5) new-onset atrial fibrillation (AF)/atrial flutter or ventricular tachycardia (VT); and 6) new-onset ischaemic changes. Patients with and without any ECG change were compared. There were 455 patients included of whom 59 patients (12.8%) met criteria for any ECG abnormality. Patients were older (any ECG abnormality 77.8 ± 12 years vs. no ECG abnormality 67.4 ± 18.2 years, p<0.001) and more likely to die in-hospital (any ECG abnormality 44.1% vs. no ECG abnormality 27.8%, p=0.011). Coxproportional hazard analysis demonstrated any ECG abnormality (hazard ratio [HR] 1.97, 95% confidence interval [CI] 1.12 to 3.47, p=0.019), age (HR 1.03, 95%CI 1.01 to 1.05, p=0.0009), raised high sensitivity troponin I (HR 2.22, 95%CI 1.27 to 3.90, p=0.006) and low estimated glomerular filtration rate (eGFR) (HR 1.73, 95%CI 1.04 to 2.88, p=0.036) were independent predictors of in-hospital mortality. In conclusion, any new ECG abnormality is a significant predictor of in-hospital mortality.
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Affiliation(s)
- Mengshi Yuan
- Cardiology Registar Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
| | - Zafraan Zathar
- Internal Medicine Training Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
| | - Frantisek Nihaj
- Cardiology Research Fellow Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
| | - Stavros Apostolakis
- Consultant Cardiologist and Clinical Lead Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
| | - Fairoz Abdul
- Consultant Cardiologist Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
| | - Derek Connolly
- Consultant Cardiologist and Research Director Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
| | - Chetan Varma
- Consultant Cardiologist and Group Director Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
| | - Vinoda Sharma
- Consultant Cardiologist and Departmental Research Lead Birmingham City Hospital, SWBH NHS Trust, Dudley Road, Birmingham, B18 7QH
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15
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Mallah SI, Ghorab OK, Al-Salmi S, Abdellatif OS, Tharmaratnam T, Iskandar MA, Sefen JAN, Sidhu P, Atallah B, El-Lababidi R, Al-Qahtani M. COVID-19: breaking down a global health crisis. Ann Clin Microbiol Antimicrob 2021; 20:35. [PMID: 34006330 PMCID: PMC8129964 DOI: 10.1186/s12941-021-00438-7] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 04/26/2021] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is the second pandemic of the twenty-first century, with over one-hundred million infections and over two million deaths to date. It is a novel strain from the Coronaviridae family, named Severe Acute Respiratory Distress Syndrome Coronavirus-2 (SARS-CoV-2); the 7th known member of the coronavirus family to cause disease in humans, notably following the Middle East Respiratory syndrome (MERS), and Severe Acute Respiratory Distress Syndrome (SARS). The most characteristic feature of this single-stranded RNA molecule includes the spike glycoprotein on its surface. Most patients with COVID-19, of which the elderly and immunocompromised are most at risk, complain of flu-like symptoms, including dry cough and headache. The most common complications include pneumonia, acute respiratory distress syndrome, septic shock, and cardiovascular manifestations. Transmission of SARS-CoV-2 is mainly via respiratory droplets, either directly from the air when an infected patient coughs or sneezes, or in the form of fomites on surfaces. Maintaining hand-hygiene, social distancing, and personal protective equipment (i.e., masks) remain the most effective precautions. Patient management includes supportive care and anticoagulative measures, with a focus on maintaining respiratory function. Therapy with dexamethasone, remdesivir, and tocilizumab appear to be most promising to date, with hydroxychloroquine, lopinavir, ritonavir, and interferons falling out of favour. Additionally, accelerated vaccination efforts have taken place internationally, with several promising vaccinations being mass deployed. In response to the COVID-19 pandemic, countries and stakeholders have taken varying precautions to combat and contain the spread of the virus and dampen its collateral economic damage. This review paper aims to synthesize the impact of the virus on a global, micro to macro scale.
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Affiliation(s)
- Saad I Mallah
- School of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom of Bahrain.
- The National Taskforce for Combating the Coronavirus (COVID-19), Bahrain, Kingdom of Bahrain.
| | - Omar K Ghorab
- School of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom of Bahrain
| | - Sabrina Al-Salmi
- School of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom of Bahrain
| | - Omar S Abdellatif
- Department of Political Science, Faculty of Arts and Science, University of Toronto, Toronto, Canada
- G7 and G20 Research Groups, Munk School of Global Affairs and Public Policy, University of Toronto, Toronto, Canada
| | - Tharmegan Tharmaratnam
- School of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom of Bahrain
- School of Medicine, RCSI University of Medicine and Health Sciences, Dublin, Ireland
| | - Mina Amin Iskandar
- School of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom of Bahrain
| | | | - Pardeep Sidhu
- School of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom of Bahrain
| | - Bassam Atallah
- Department of Pharmacy Services, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, United Arab Emirates
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
| | - Rania El-Lababidi
- Department of Pharmacy Services, Cleveland Clinic Abu Dhabi, Al Maryah Island, Abu Dhabi, United Arab Emirates
| | - Manaf Al-Qahtani
- The National Taskforce for Combating the Coronavirus (COVID-19), Bahrain, Kingdom of Bahrain.
- Department of Medicine, Royal College of Surgeons in Ireland, Bahrain, Kingdom of Bahrain.
- Department of Infectious Diseases, Royal Medical Services, Bahrain Defence Force Hospital, Riffa, Kingdom of Bahrain.
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16
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Al-Moubarak E, Sharifi M, Hancox JC. In silico Exploration of Interactions Between Potential COVID-19 Antiviral Treatments and the Pore of the hERG Potassium Channel-A Drug Antitarget. Front Cardiovasc Med 2021; 8:645172. [PMID: 34017865 PMCID: PMC8129016 DOI: 10.3389/fcvm.2021.645172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/30/2021] [Indexed: 12/24/2022] Open
Abstract
Background: In the absence of SARS-CoV-2 specific antiviral treatments, various repurposed pharmaceutical approaches are under investigation for the treatment of COVID-19. Antiviral drugs considered for this condition include atazanavir, remdesivir, lopinavir-ritonavir, and favipiravir. Whilst the combination of lopinavir and ritonavir has been previously linked to prolongation of the QTc interval on the ECG and risk of torsades de pointes arrhythmia, less is known in this regard about atazanavir, remdesivir, and favipiravir. Unwanted abnormalities of drug-induced QTc prolongation by diverse drugs are commonly mediated by a single cardiac anti-target, the hERG potassium channel. This computational modeling study was undertaken in order to explore the ability of these five drugs to interact with known determinants of drug binding to the hERG channel pore. Methods: Atazanavir, remdesivir, ritonavir, lopinavir and favipiravir were docked to in silico models of the pore domain of hERG, derived from cryo-EM structures of hERG and the closely related EAG channel. Results: Atazanavir was readily accommodated in the open hERG channel pore in proximity to the S6 Y652 and F656 residues, consistent with published experimental data implicating these aromatic residues in atazanavir binding to the channel. Lopinavir, ritonavir, and remdesivir were also accommodated in the open channel, making contacts in a model-dependent fashion with S6 aromatic residues and with residues at the base of the selectivity filter/pore helix. The ability of remdesivir (at 30 μM) to inhibit the channel was confirmed using patch-clamp recording. None of these four drugs could be accommodated in the closed channel structure. Favipiravir, a much smaller molecule, was able to fit within the closed channel and could adopt multiple binding poses in the open channel, but with few simultaneous interactions with key binding residues. Only favipiravir and remdesivir showed the potential to interact with lateral pockets below the selectivity filter of the channel. Conclusions: All the antiviral drugs studied here can, in principle, interact with components of the hERG potassium channel canonical binding site, but are likely to differ in their ability to access lateral binding pockets. Favipiravir's small size and relatively paucity of simultaneous interactions may confer reduced hERG liability compared to the other drugs. Experimental structure-function studies are now warranted to validate these observations.
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Affiliation(s)
- Ehab Al-Moubarak
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, United Kingdom
| | | | - Jules C. Hancox
- School of Physiology, Pharmacology and Neuroscience, University of Bristol, Biomedical Sciences Building, University Walk, Bristol, United Kingdom
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17
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Szendrey M, Guo J, Li W, Yang T, Zhang S. COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels. J Pharmacol Exp Ther 2021; 377:265-272. [PMID: 33674391 DOI: 10.1124/jpet.120.000484] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/02/2021] [Indexed: 12/27/2022] Open
Abstract
Drug-induced long QT syndrome (LQTS) is an established cardiac side effect of a wide range of medications and represents a significant concern for drug safety. The rapidly and slowly activating delayed rectifier K+ currents, mediated by channels encoded by the human ether-a-go-go-related gene (hERG) and KCNQ1 + KCNE1, respectively, are two main currents responsible for ventricular repolarization. The common cause for drugs to induce LQTS is through impairing the hERG channel. For the recent emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus 2, several drugs have been investigated as potential therapies; however, there are concerns about their QT prolongation risk. Here, we studied the effects of chloroquine, hydroxychloroquine, azithromycin, and remdesivir on hERG channels. Our results showed that although chloroquine acutely blocked hERG current (IhERG), with an IC50 of 3.0 µM, hydroxychloroquine acutely blocked IhERG 8-fold less potently, with an IC50 of 23.4 µM. Azithromycin and remdesivir did not acutely affect IhERG When these drugs were added at 10 µM to the cell culture medium for 24 hours, remdesivir increased IhERG by 2-fold, which was associated with an increased mature hERG channel expression. In addition, these four drugs did not acutely or chronically affect KCNQ1 + KCNE1 channels. Our data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns. SIGNIFICANCE STATEMENT: This work demonstrates that, among off-label potential COVID-19 treatment drugs chloroquine, hydroxychloroquine, azithromycin, and remdesivir, the former two drugs block hERG potassium channels, whereas the latter two drugs do not. All four drugs do not affect KCNQ1 + KCNE1. As hERG and KCNQ1 + KCNE1 are two main K+ channels responsible for ventricular repolarization, and most drugs that induce long QT syndrome (LQTS) do so by impairing hERG channels, these data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns.
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Affiliation(s)
- Mark Szendrey
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Jun Guo
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Wentao Li
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Tonghua Yang
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
| | - Shetuan Zhang
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada
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18
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Jordaan P, Dumotier B, Traebert M, Miller PE, Ghetti A, Urban L, Abi-Gerges N. Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes. Toxicol Sci 2021; 180:356-368. [PMID: 33483756 PMCID: PMC7928616 DOI: 10.1093/toxsci/kfaa194] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Substantial efforts have been recently committed to develop coronavirus disease-2019 (COVID-19) medications, and Hydroxychloroquine alone or in combination with Azithromycin has been promoted as a repurposed treatment. Although these drugs may increase cardiac toxicity risk, cardiomyocyte mechanisms underlying this risk remain poorly understood in humans. Therefore, we evaluated the proarrhythmia risk and inotropic effects of these drugs in the cardiomyocyte contractility-based model of the human heart. We found Hydroxychloroquine to have a low proarrhythmia risk, whereas Chloroquine and Azithromycin were associated with high risk. Hydroxychloroquine proarrhythmia risk changed to high with low level of K+, whereas high level of Mg2+ protected against proarrhythmic effect of high Hydroxychloroquine concentrations. Moreover, therapeutic concentration of Hydroxychloroquine caused no enhancement of elevated temperature-induced proarrhythmia. Polytherapy of Hydroxychloroquine plus Azithromycin and sequential application of these drugs were also found to influence proarrhythmia risk categorization. Hydroxychloroquine proarrhythmia risk changed to high when combined with Azithromycin at therapeutic concentration. However, Hydroxychloroquine at therapeutic concentration impacted the cardiac safety profile of Azithromycin and its proarrhythmia risk only at concentrations above therapeutic level. We also report that Hydroxychloroquine and Chloroquine, but not Azithromycin, decreased contractility while exhibiting multi-ion channel block features, and Hydroxychloroquine's contractility effect was abolished by Azithromycin. Thus, this study has the potential to inform clinical studies evaluating repurposed therapies, including those in the COVID-19 context. Additionally, it demonstrates the translational value of the human cardiomyocyte contractility-based model as a key early discovery path to inform decisions on novel therapies for COVID-19, malaria, and inflammatory diseases.
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Affiliation(s)
- Pierre Jordaan
- Chief Medical Officer and Patient Safety, Novartis AG, Basel, Switzerland
| | - Bérengère Dumotier
- Novartis Institutes for Biomedical Research, Preclinical Safety, Basel, Switzerland
| | - Martin Traebert
- Novartis Institutes for Biomedical Research, Preclinical Safety, Basel, Switzerland
| | - Paul E Miller
- AnaBios Corporation, San Diego, California 92109, USA
| | - Andre Ghetti
- AnaBios Corporation, San Diego, California 92109, USA
| | - Laszlo Urban
- Novartis Institutes for Biomedical Research, Preclinical Secondary Pharmacology, Cambridge, Massachusetts, USA
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19
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Hache G, Rolain JM, Gautret P, Deharo JC, Brouqui P, Raoult D, Honoré S. Combination of Hydroxychloroquine Plus Azithromycin As Potential Treatment for COVID-19 Patients: Safety Profile, Drug Interactions, and Management of Toxicity. Microb Drug Resist 2021; 27:281-290. [PMID: 33729874 PMCID: PMC7987362 DOI: 10.1089/mdr.2020.0232] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2, has recently emerged worldwide. In this context, there is an urgent need to identify safe and effective therapeutic strategies for treatment of such highly contagious disease. We recently reported promising results of combining hydroxychloroquine and azithromycin as an early treatment option. Although ongoing clinical trials are challenging the efficacy of this combination, many clinicians claim the authorization to or have already begun to use it to treat COVID-19 patients worldwide. The aim of this article is to share pharmacology considerations contributing to the rationale of this combination, and to provide safety information to prevent toxicity and drug-drug interactions, based on available evidence.
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Affiliation(s)
- Guillaume Hache
- Service de Pharmacie, Hôpital de la Timone, APHM, Marseille, France
- Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
| | - Jean Marc Rolain
- IHU-Méditerranée Infection, Marseille, France
- Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Philippe Gautret
- IHU-Méditerranée Infection, Marseille, France
- Aix Marseille Univ, IRD, AP-HM, SSA, VITROME, Marseille, France
| | - Jean-Claude Deharo
- Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France
- Service de Cardiologie, Hôpital de la Timone, APHM, Marseille, France
| | - Philippe Brouqui
- IHU-Méditerranée Infection, Marseille, France
- Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Didier Raoult
- IHU-Méditerranée Infection, Marseille, France
- Aix Marseille Univ, IRD, APHM, MEPHI, Marseille, France
| | - Stéphane Honoré
- Service de Pharmacie, Hôpital de la Timone, APHM, Marseille, France
- Aix Marseille Univ, Laboratoire de Pharmacie Clinique, Marseille, France
- Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, Marseille, France
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20
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Brazão SC, Autran LJ, Lopes RDO, Scaramello CBV, Brito FCFD, Motta NAV. Effects of Chloroquine and Hydroxychloroquine on the Cardiovascular System - Limitations for Use in the Treatment of COVID-19. INTERNATIONAL JOURNAL OF CARDIOVASCULAR SCIENCES 2021. [DOI: 10.36660/ijcs.20200162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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21
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Malaty M, Kayes T, Amarasekera AT, Kodsi M, MacIntyre CR, Tan TC. Incidence and treatment of arrhythmias secondary to coronavirus infection in humans: A systematic review. Eur J Clin Invest 2021; 51:e13428. [PMID: 33043453 PMCID: PMC7646010 DOI: 10.1111/eci.13428] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/20/2020] [Accepted: 10/07/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people worldwide resulting in significant morbidity and mortality. Arrhythmias are prevalent and reportedly, the second most common complication. Several mechanistic pathways are proposed to explain the pro-arrhythmic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A number of treatment approaches have been trialled, each with its inherent unique challenges. This rapid systematic review aimed to examine the current incidence and available treatment of arrhythmias in COVID-19, as well as barriers to implementation. METHODS Our search of scientific databases identified relevant published studies from 1 January 2000 until 1 June 2020. We also searched Google Scholar for grey literature. We identified 1729 publications of which 1704 were excluded. RESULTS The incidence and nature of arrhythmias in the setting of COVID-19 were poorly documented across studies. The cumulative incidence of arrhythmia across studies of hospitalised patients was 6.9%. Drug-induced long QT syndrome secondary to antimalarial and antimicrobial therapy was a significant contributor to arrhythmia formation, with an incidence of 14.15%. Torsades de pointes (TdP) and sudden cardiac death (SCD) were reported. Treatment strategies aim to minimise this through risk stratification and regular monitoring of corrected QT interval (QTc). CONCLUSION Patients with SARS-CoV-2 are at an increased risk of arrhythmias. Drug therapy is pro-arrhythmogenic and may result in TdP and SCD in these patients. Risk assessment and regular QTc monitoring are imperative for safety during the treatment course. Further studies are needed to guide future decision-making.
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Affiliation(s)
- Michael Malaty
- Department of Cardiology, Blacktown Hospital, Sydney, NSW, Australia
| | - Tahrima Kayes
- Department of Cardiology, Blacktown Hospital, Sydney, NSW, Australia
| | - Anjalee T Amarasekera
- School of Medicine, Western Sydney University, Sydney, NSW, Australia.,School of Nursing and Midwifery, Western Sydney University, Sydney, NSW, Australia
| | - Matthew Kodsi
- Department of Cardiology, Blacktown Hospital, Sydney, NSW, Australia
| | - C Raina MacIntyre
- Faculty of Medicine, The Kirby Institute, University of New South Wales, Sydney, NSW, Australia
| | - Timothy C Tan
- Department of Cardiology, Blacktown Hospital, Sydney, NSW, Australia.,School of Medicine, Western Sydney University, Sydney, NSW, Australia
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22
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Zequn Z, Yujia W, Dingding Q, Jiangfang L. Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel. Eur J Pharmacol 2020; 893:173813. [PMID: 33345848 PMCID: PMC7746509 DOI: 10.1016/j.ejphar.2020.173813] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 11/29/2020] [Accepted: 12/11/2020] [Indexed: 12/20/2022]
Abstract
Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an enormous challenge to the medical system, especially the lack of safe and effective COVID-19 treatment methods, forcing people to look for drugs that may have therapeutic effects as soon as possible. Some old drugs have shown clinical benefits after a few small clinical trials that attracted great attention. Clinically, however, many drugs, including those currently used in COVID-19, such as chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir, may cause cardiotoxicity by acting on cardiac potassium channels, especially hERG channel through their off-target effects. The blocking of the hERG channel prolongs QT intervals on electrocardiograms; thus, it might induce severe ventricular arrhythmias and even sudden cardiac death. Therefore, while focusing on the efficacy of COVID-19 drugs, the fact that they block hERG channels to cause arrhythmias cannot be ignored. To develop safer and more effective drugs, it is necessary to understand the interactions between drugs and the hERG channel and the molecular mechanism behind this high affinity. In this review, we focus on the biochemical and molecular mechanistic aspects of drug-related blockade of the hERG channel to provide insights into QT prolongation caused by off-label use of related drugs in COVID-19, and hope to weigh the risks and benefits when using these drugs.
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Affiliation(s)
- Zheng Zequn
- Medical College, Ningbo University, Ningbo, Zhejiang, 315000, China
| | - Wu Yujia
- Medical College, Ningbo University, Ningbo, Zhejiang, 315000, China
| | - Qian Dingding
- Department of Cardiovascular, Lihuili Hospital Affiliated to Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Lian Jiangfang
- Department of Cardiovascular, Lihuili Hospital Affiliated to Ningbo University, Ningbo, Zhejiang, 315211, China.
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23
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Yasmin Kusumawardhani N, Huang I, Martanto E, Sihite TA, Nugraha ES, Prodjosoewojo S, Hamijoyo L, Hartantri Y. Lethal Arrhythmia ( Torsade de Pointes) in COVID-19: An Event Synergistically Induced by Viral Associated Cardiac Injury, Hyperinflammatory Response, and Treatment Drug? CLINICAL MEDICINE INSIGHTS-CASE REPORTS 2020; 13:1179547620972397. [PMID: 33402858 PMCID: PMC7739200 DOI: 10.1177/1179547620972397] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/13/2020] [Indexed: 01/08/2023]
Abstract
Arrhythmias in patients with coronavirus disease 2019 (COVID-19) are prevalent and deserve special attention because they are associated with an increased risk of fatal outcome. The mechanism of arrhythmia in COVID-19 remains unclear. Here, we report our first case of confirmed COVID-19 with documented Torsade de Pointes (TdP). A 64-year-old woman, previously healthy, presented to our emergency department with progressive shortness of breath, dry cough, and 1 week of fever. She was treated with chloroquine phosphate, meropenem, and ciprofloxacin. After 5 days of admission, her condition deteriorated and she was admitted to the intensive care unit. The patient had two episodes of malignant arrhythmias within 24 hours. The former was TdP, and the latter was a fatal pulseless ventricular tachycardia that occured even after chloroquine was discontinued. There was evidence of cardiac injury shown by increased serum level of troponin I. We propose a synergistic concept of lethal arrhythmia due to direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2-associated cardiac injury, hyperinflammatory response, and drug-induced arrhythmia.
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Affiliation(s)
- Nuraini Yasmin Kusumawardhani
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Ian Huang
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Erwan Martanto
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Teddy Arnold Sihite
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Eka Surya Nugraha
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Susantina Prodjosoewojo
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Laniyati Hamijoyo
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
| | - Yovita Hartantri
- Department of Internal Medicine, Faculty of Medicine Universitas Padjadjaran/Hasan Sadikin General Hospital, Bandung, Indonesia
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24
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Alnefaie A, Albogami S. Current approaches used in treating COVID-19 from a molecular mechanisms and immune response perspective. Saudi Pharm J 2020; 28:1333-1352. [PMID: 32905015 PMCID: PMC7462599 DOI: 10.1016/j.jsps.2020.08.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 08/27/2020] [Indexed: 12/15/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared by the World Health Organization (WHO) as a global pandemic on March 11, 2020. SARS-CoV-2 targets the respiratory system, resulting in symptoms such as fever, headache, dry cough, dyspnea, and dizziness. These symptoms vary from person to person, ranging from mild to hypoxia with acute respiratory distress syndrome (ARDS) and sometimes death. Although not confirmed, phylogenetic analysis suggests that SARS-CoV-2 may have originated from bats; the intermediary facilitating its transfer from bats to humans is unknown. Owing to the rapid spread of infection and high number of deaths caused by SARS-CoV-2, most countries have enacted strict curfews and the practice of social distancing while awaiting the availability of effective U.S. Food and Drug Administration (FDA)-approved medications and/or vaccines. This review offers an overview of the various types of coronaviruses (CoVs), their targeted hosts and cellular receptors, a timeline of their emergence, and the roles of key elements of the immune system in fighting pathogen attacks, while focusing on SARS-CoV-2 and its genomic structure and pathogenesis. Furthermore, we review drugs targeting COVID-19 that are under investigation and in clinical trials, in addition to progress using mesenchymal stem cells to treat COVID-19. We conclude by reviewing the latest updates on COVID-19 vaccine development. Understanding the molecular mechanisms of how SARS-CoV-2 interacts with host cells and stimulates the immune response is extremely important, especially as scientists look for new strategies to guide their development of specific COVID-19 therapies and vaccines.
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Key Words
- ACE2, angiotensin-converting enzyme 2
- AHFS, American Hospital Formula Service
- ANGII, angiotensin II
- APCs, antigen presenting cells
- ARDS, acute respiratory distress syndrome
- COVID-19, coronavirus disease
- CoVs, coronaviruses
- Coronavirus
- GVHD, graft versus host disease
- HCoVs, human coronoaviruses
- IBV, infectious bronchitis coronavirus
- IFN-γ, interferon-gamma
- ILCs, innate lymphoid cells
- Investigational medications
- MERS-CoV, Middle East respiratory syndrome
- NKs, natural killer cells
- ORFs, open reading frames
- PAMPs, pathogen-associated molecular patterns
- Pandemic
- Pathophysiology
- RdRp, RNA-dependent RNA polymerase
- SARS-CoV-2
- SARS-CoV-2, severe acute respiratory syndrome coronavirus 2
- SLE, systemic lupus erythematosus
- TMPRSS2, transmembrane serine protease 2
- Viral immune response
- WHO, World Health Organization
- nsps, nonstructural proteins
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Affiliation(s)
- Alaa Alnefaie
- Department of Biotechnology, Faculty of Science, Taif University, Taif, Saudi Arabia
| | - Sarah Albogami
- Department of Biotechnology, Faculty of Science, Taif University, Taif, Saudi Arabia
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25
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Doyno C, Sobieraj DM, Baker WL. Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose. Clin Toxicol (Phila) 2020; 59:12-23. [DOI: 10.1080/15563650.2020.1817479] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Cassandra Doyno
- Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA
| | - Diana M. Sobieraj
- Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA
| | - William L. Baker
- Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, CT, USA
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26
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Abstract
The novel coronavirus spread all over the world in 2019 and became a serious international health concern of this century. Coronavirus disease 2019 (COVID-19) had a wide range of clinical manifestations; it can cause mild-to-severe multiorgan diseases, mostly affecting the respiratory system, but cardiovascular symptoms and complications are also frequently presented in COVID-19 patients. Herein, we report a type A aortic dissection in a confirmed case of COVID-19.
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Affiliation(s)
- Shiva Tabaghi
- Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Akbarzadeh
- Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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27
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Chorin E, Wadhwani L, Magnani S, Dai M, Shulman E, Nadeau-Routhier C, Knotts R, Bar-Cohen R, Kogan E, Barbhaiya C, Aizer A, Holmes D, Bernstein S, Spinelli M, Park DS, Stefano C, Chinitz LA, Jankelson L. QT interval prolongation and torsade de pointes in patients with COVID-19 treated with hydroxychloroquine/azithromycin. Heart Rhythm 2020; 17:1425-1433. [PMID: 32407884 PMCID: PMC7214283 DOI: 10.1016/j.hrthm.2020.05.014] [Citation(s) in RCA: 196] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background There is no known effective therapy for patients with coronavirus disease 2019 (COVID-19). Initial reports suggesting the potential benefit of hydroxychloroquine/azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns about the potential risk of QT interval prolongation and induction of torsade de pointes (TdP). Objective The purpose of this study was to assess the change in corrected QT (QTc) interval and arrhythmic events in patients with COVID-19 treated with HY/AZ. Methods This is a retrospective study of 251 patients from 2 centers who were diagnosed with COVID-19 and treated with HY/AZ. We reviewed electrocardiographic tracings from baseline and until 3 days after the completion of therapy to determine the progression of QTc interval and the incidence of arrhythmia and mortality. Results The QTc interval prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc interval prolongation to >500 ms, a known marker of high risk of TdP, had developed in 23% of patients. One patient developed polymorphic ventricular tachycardia suspected as TdP, requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc interval of patients exhibiting extreme QTc interval prolongation was normal. Conclusion The combination of HY/AZ significantly prolongs the QTc interval in patients with COVID-19. This prolongation may be responsible for life-threatening arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in light of its unproven efficacy. Strict QTc interval monitoring should be performed if the regimen is given.
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Affiliation(s)
- Ehud Chorin
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Lalit Wadhwani
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Silvia Magnani
- Division of Cardiology, Department of Health Science, San Paolo Hospital, University of Milan, Milan, Italy
| | - Matthew Dai
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Eric Shulman
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Charles Nadeau-Routhier
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Robert Knotts
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Roi Bar-Cohen
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Edward Kogan
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Chirag Barbhaiya
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Anthony Aizer
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Douglas Holmes
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Scott Bernstein
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Michael Spinelli
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - David S Park
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Carugo Stefano
- Division of Cardiology, Department of Health Science, San Paolo Hospital, University of Milan, Milan, Italy
| | - Larry A Chinitz
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York
| | - Lior Jankelson
- Leon H. Charney Division of Cardiology, Cardiac Electrophysiology, NYU Langone Health, New York University Grossman School of Medicine, New York, New York.
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28
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Multiple drugs. REACTIONS WEEKLY 2020. [PMCID: PMC7486156 DOI: 10.1007/s40278-020-83306-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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29
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White NJ, Watson JA, Hoglund RM, Chan XHS, Cheah PY, Tarning J. COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med 2020; 17:e1003252. [PMID: 32881895 PMCID: PMC7470382 DOI: 10.1371/journal.pmed.1003252] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Nicholas White and coauthors discuss chloroquine and hydroxychloroquine pharmacology in the context of possible treatment of SARS-CoV-2 infection.
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Affiliation(s)
- Nicholas J. White
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - James A. Watson
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Richard M. Hoglund
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Xin Hui S. Chan
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Phaik Yeong Cheah
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Joel Tarning
- Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
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30
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Offerhaus JA, Wilde AAM, Remme CA. Prophylactic (hydroxy)chloroquine in COVID-19: Potential relevance for cardiac arrhythmia risk. Heart Rhythm 2020; 17:1480-1486. [PMID: 32622993 PMCID: PMC7332460 DOI: 10.1016/j.hrthm.2020.07.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 06/30/2020] [Accepted: 07/01/2020] [Indexed: 02/06/2023]
Abstract
(Hydroxy)chloroquine ((H)CQ) is being investigated as a treatment for COVID-19, but studies have so far demonstrated either no or a small benefit. However, these studies have been mostly performed in patients admitted to the hospital and hence likely already (severely) affected. Another suggested approach uses prophylactic (H)CQ treatment aimed at preventing either severe acute respiratory syndrome coronavirus 2 infection or the development of disease. A substantial number of clinical trials are planned or underway aimed at assessing the prophylactic benefit of (H)CQ. However, (H)CQ may lead to QT prolongation and potentially induce life-threatening arrhythmias. This may be of particular relevance to patients with preexisting cardiovascular disease and those taking other QT-prolonging drugs. In addition, it is known that a certain percentage of the population carries genetic variant(s) that reduces their repolarization reserve, predisposing them to (H)CQ-induced QT prolongation, and this may be more relevant to female patients who already have a longer QT interval to start with. This review provides an overview of the current evidence on (H)CQ therapy in patients with COVID-19 and discusses different strategies for prophylactic (H)CQ therapy (ie, preinfection, postexposure, and postinfection). In particular, the potential cardiac effects, including QT prolongation and arrhythmias, will be addressed. Based on these insights, recommendations will be presented as to which preventive measures should be taken when giving (H)CQ prophylactically, including electrocardiographic monitoring.
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Affiliation(s)
- Joost A Offerhaus
- Amsterdam UMC, location AMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Arthur A M Wilde
- Amsterdam UMC, location AMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARDHEART; https://guardheart.ern-net.eu); European Cardiac Arrhythmia Genetics Focus Group (ECGen) of the European Heart Rhythm Association (EHRA)
| | - Carol Ann Remme
- Amsterdam UMC, location AMC, University of Amsterdam, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; European Cardiac Arrhythmia Genetics Focus Group (ECGen) of the European Heart Rhythm Association (EHRA).
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31
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Al Rihani SB, Smith MK, Bikmetov R, Deodhar M, Dow P, Turgeon J, Michaud V. Risk of Adverse Drug Events Following the Virtual Addition of COVID-19 Repurposed Drugs to Drug Regimens of Frail Older Adults with Polypharmacy. J Clin Med 2020; 9:E2591. [PMID: 32785135 PMCID: PMC7463624 DOI: 10.3390/jcm9082591] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/27/2020] [Accepted: 08/04/2020] [Indexed: 12/16/2022] Open
Abstract
Determination of the risk-benefit ratio associated with the use of novel coronavirus disease 2019 (COVID-19) repurposed drugs in older adults with polypharmacy is mandatory. Our objective was to develop and validate a strategy to assess risk for adverse drug events (ADE) associated with COVID-19 repurposed drugs using hydroxychloroquine (HCQ) and chloroquine (CQ), alone or in combination with azithromycin (AZ), and the combination lopinavir/ritonavir (LPV/r). These medications were virtually added, one at a time, to drug regimens of 12,383 participants of the Program of All-Inclusive Care for the Elderly. The MedWise Risk Score (MRSTM) was determined from 198,323 drug claims. Results demonstrated that the addition of each repurposed drug caused a rightward shift in the frequency distribution of MRSTM values (p < 0.05); the increase was due to an increase in the drug-induced Long QT Syndrome (LQTS) or CYP450 drug interaction burden risk scores. Increases in LQTS risk observed with HCQ + AZ and CQ + AZ were of the same magnitude as those estimated when terfenadine or terfenadine + AZ, used as positive controls for drug-induced LQTS, were added to drug regimens. The simulation-based strategy performed offers a way to assess risk of ADE for drugs to be used in people with underlying medical comorbidities and polypharmacy at risk of COVID-19 infection without exposing them to these drugs.
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Affiliation(s)
- Sweilem B. Al Rihani
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Matt K. Smith
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Ravil Bikmetov
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Malavika Deodhar
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Pamela Dow
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
| | - Jacques Turgeon
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
- Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada
| | - Veronique Michaud
- Tabula Rasa HealthCare Precision Pharmacotherapy Research & Development Institute, Orlando, FL 32827, USA; (S.B.A.R.); (M.K.S.); (R.B.); (M.D.); (P.D.); (J.T.)
- Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada
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32
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Watson JA, Tarning J, Hoglund RM, Baud FJ, Megarbane B, Clemessy JL, White NJ. Concentration-dependent mortality of chloroquine in overdose. eLife 2020; 9:e58631. [PMID: 32639233 PMCID: PMC7417172 DOI: 10.7554/elife.58631] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 07/07/2020] [Indexed: 12/18/2022] Open
Abstract
Hydroxychloroquine and chloroquine are used extensively in malaria and rheumatological conditions, and now in COVID-19 prevention and treatment. Although generally safe they are potentially lethal in overdose. In-vitro data suggest that high concentrations and thus high doses are needed for COVID-19 infections, but as yet there is no convincing evidence of clinical efficacy. Bayesian regression models were fitted to survival outcomes and electrocardiograph QRS durations from 302 prospectively studied French patients who had taken intentional chloroquine overdoses, of whom 33 died (11%), and 16 healthy volunteers who took 620 mg base chloroquine single doses. Whole blood concentrations of 13.5 µmol/L (95% credible interval 10.1-17.7) were associated with 1% mortality. Prolongation of ventricular depolarization is concentration-dependent with a QRS duration >150 msec independently highly predictive of mortality in chloroquine self-poisoning. Pharmacokinetic modeling predicts that most high dose regimens trialled in COVID-19 are unlikely to cause serious cardiovascular toxicity.
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Affiliation(s)
- James A Watson
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol UniversityBangkokThailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Joel Tarning
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol UniversityBangkokThailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Richard M Hoglund
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol UniversityBangkokThailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Frederic J Baud
- Assistance Publique - Hôpitaux de ParisParisFrance
- Université de ParisParisFrance
| | - Bruno Megarbane
- Université de Paris, INSERM UMRS-11 44ParisFrance
- Reanimation Medicale et Toxicologique, Hopital LariboisiereParisFrance
| | - Jean-Luc Clemessy
- Assistance Publique - Hôpitaux de ParisParisFrance
- Reanimation Medicale et Toxicologique, Hopital LariboisiereParisFrance
- Clinique du SportParisFrance
| | - Nicholas J White
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol UniversityBangkokThailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of OxfordOxfordUnited Kingdom
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Dehelean CA, Lazureanu V, Coricovac D, Mioc M, Oancea R, Marcovici I, Pinzaru I, Soica C, Tsatsakis AM, Cretu O. SARS-CoV-2: Repurposed Drugs and Novel Therapeutic Approaches-Insights into Chemical Structure-Biological Activity and Toxicological Screening. J Clin Med 2020; 9:E2084. [PMID: 32630746 PMCID: PMC7409030 DOI: 10.3390/jcm9072084] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/22/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023] Open
Abstract
SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) pandemic represents the primary public health concern nowadays, and great efforts are made worldwide for efficient management of this crisis. Considerable scientific progress was recorded regarding SARS-CoV-2 infection in terms of genomic structure, diagnostic tools, viral transmission, mechanism of viral infection, symptomatology, clinical impact, and complications, but these data evolve constantly. Up to date, neither an effective vaccine nor SARS-CoV-2 specific antiviral agents have been approved, but significant advances were enlisted in this direction by investigating repurposed approved drugs (ongoing clinical trials) or developing innovative antiviral drugs (preclinical and clinical studies). This review presents a thorough analysis of repurposed drug admitted for compassionate use from a chemical structure-biological activity perspective highlighting the ADME (absorption, distribution, metabolism, and excretion) properties and the toxicophore groups linked to potential adverse effects. A detailed pharmacological description of the novel potential anti-COVID-19 therapeutics was also included. In addition, a comprehensible overview of SARS-CoV-2 infection in terms of general description and structure, mechanism of viral infection, and clinical impact was portrayed.
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Affiliation(s)
- Cristina Adriana Dehelean
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (C.A.D.); (I.M.); (I.P.); (C.S.)
| | - Voichita Lazureanu
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (V.L.); (O.C.)
- “Dr. Victor Babes” Clinical Hospital for Infectious Diseases and Pneumophthisiology, 300310 Timisoara, Romania
| | - Dorina Coricovac
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (C.A.D.); (I.M.); (I.P.); (C.S.)
| | - Marius Mioc
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (C.A.D.); (I.M.); (I.P.); (C.S.)
| | - Roxana Oancea
- Faculty of Dental Medicine, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania;
| | - Iasmina Marcovici
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (C.A.D.); (I.M.); (I.P.); (C.S.)
| | - Iulia Pinzaru
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (C.A.D.); (I.M.); (I.P.); (C.S.)
| | - Codruta Soica
- Faculty of Pharmacy, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (C.A.D.); (I.M.); (I.P.); (C.S.)
| | - Aristidis M. Tsatsakis
- Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, Heraklion, 71003 Crete, Greece;
| | - Octavian Cretu
- Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania; (V.L.); (O.C.)
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Affiliation(s)
- A A M Wilde
- Department of Clinical and Experimental Cardiology, Amsterdam UMC, Heart Centre, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands.
| | - J A Offerhaus
- Department of Clinical and Experimental Cardiology, Amsterdam UMC, Heart Centre, Amsterdam Cardiovascular Sciences, University of Amsterdam, Amsterdam, The Netherlands
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Hooks M, Bart B, Vardeny O, Westanmo A, Adabag S. Effects of hydroxychloroquine treatment on QT interval. Heart Rhythm 2020; 17:1930-1935. [PMID: 32610165 PMCID: PMC7321659 DOI: 10.1016/j.hrthm.2020.06.029] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 01/18/2023]
Abstract
Background Hydroxychloroquine (HCQ) has been promoted as a potential treatment of coronavirus disease 2019 (COVID-19), but there are safety concerns. Objective The purpose of this study was to determine the effects of HCQ treatment on QT interval. Methods We retrospectively studied the electrocardiograms of 819 patients treated with HCQ for rheumatologic diseases from 2000 to 2020. The primary outcome was corrected QT (QTc) interval, by Bazett formula, during HCQ therapy. Results Mean patient age was 64.0 ± 10.9 years, and 734 patients (90%) were men. Median dosage of HCQ was 400 mg daily, and median (25th–75th percentile) duration of HCQ therapy was 1006 (471–2075) days. Mean on-treatment QTc was 430.9 ± 31.8 ms. In total, 55 patients (7%) had QTc 470–500 ms, and 12 (1.5%) had QTc >500 ms. Chronic kidney disease (CKD), history of atrial fibrillation (AF), and heart failure were independent risk factors for prolonged QTc. In a subset of 591 patients who also had a pretreatment electrocardiogram, mean QTc increased from 424.4 ± 29.7 ms to 432.0 ± 32.3 ms (P <.0001) during HCQ treatment. Of these patients, 23 (3.9%) had either prolongation of QTc >15% or on-treatment QTc >500 ms. Over median 5.97 (3.33–10.11) years of follow-up, 269 patients (33%) died. QTc >470 ms during HCQ treatment was associated with a greater mortality risk (hazard ratio 1.78; 95% confidence interval 1.16–2.71; P = .008) in univariable but not in multivariable analysis. Conclusion HCQ is associated with QT prolongation in a significant fraction of patients. The risk of QT prolongation is higher among patients with CKD, AF, and heart failure, who may benefit from greater scrutiny.
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Affiliation(s)
- Matthew Hooks
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Bradley Bart
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Division of Cardiology, Minneapolis VA Health Care System, Minneapolis, Minnesota
| | - Orly Vardeny
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Center for Care Delivery & Outcomes Research, Minneapolis VA Health Care System, Minneapolis, Minnesota
| | - Anders Westanmo
- Department of Pharmacy, Minneapolis VA Health Care System, Minneapolis, Minnesota
| | - Selçuk Adabag
- Department of Medicine, University of Minnesota, Minneapolis, Minnesota; Division of Cardiology, Minneapolis VA Health Care System, Minneapolis, Minnesota.
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Fatal arrhythmias: Another reason why doctors remain cautious about chloroquine/hydroxychloroquine for treating COVID-19. Heart Rhythm 2020; 17:1445-1451. [PMID: 32479900 PMCID: PMC7256542 DOI: 10.1016/j.hrthm.2020.05.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/27/2022]
Abstract
Background Early during the current coronavirus disease 19 (COVID-19) pandemic, hydroxychloroquine (HCQ) received a significant amount of attention as a potential antiviral treatment, such that it became one of the most commonly prescribed medications for COVID-19 patients. However, not only has the effectiveness of HCQ remained questionable, but mainly based on preclinical and a few small clinical studies, HCQ is known to be potentially arrhythmogenic, especially as a result of QT prolongation. Objective The purpose of this study was to investigate the arrhythmic effects of HCQ, as the heightened risk is especially relevant to COVID-19 patients, who are at higher risk for cardiac complications and arrhythmias at baseline. Methods An optical mapping technique utilizing voltage-sensitive fluorescent dyes was used to determine the arrhythmic effects of HCQ in ex vivo guinea pig and rabbit hearts perfused with the upper therapeutic serum dose of HCQ (1000 ng/mL). Results HCQ markedly increased action potential dispersion, resulted in development of repolarization alternans, and initiated polymorphic ventricular tachycardia. Conclusion The study results further highlight the proarrhythmic effects of HCQ.
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Haseeb S, Gul EE, Çinier G, Bazoukis G, Alvarez-Garcia J, Garcia-Zamora S, Lee S, Yeung C, Liu T, Tse G, Baranchuk A. Value of electrocardiography in coronavirus disease 2019 (COVID-19). J Electrocardiol 2020; 62:39-45. [PMID: 32805546 PMCID: PMC7409871 DOI: 10.1016/j.jelectrocard.2020.08.007] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/02/2020] [Accepted: 08/04/2020] [Indexed: 01/08/2023]
Abstract
In December 2019, reports of an unknown pneumonia not responsive to traditional treatments arose in Wuhan, China. The pathogen was subsequently identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to be responsible for the coronavirus disease-2019 (COVID-19) illness, and public health emergency of international concern was declared by the World Health Organization. There is increasing awareness of the cardiovascular manifestations of COVID-19 disease, and the adverse impact of cardiovascular involvement on its prognosis. In this setting, the electrocardiogram (ECG) is one of the leading tools to assess the extent of cardiac involvement in COVID-19 patients, due to its wide disponibility, low cost, and the possibility of remote evaluation. In this article, we review the role of the ECG in the identification of cardiac involvement in COVID-19, highlighting relevant clinical implications.
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Affiliation(s)
- Sohaib Haseeb
- College of Medicine and Dentistry, James Cook University, Townsville, Queensland, Australia
| | - Enes Elvin Gul
- Division of Cardiac Electrophysiology, Madinah Cardiac Centre, Madinah, Saudi Arabia
| | - Göksel Çinier
- Department of Cardiology, Dr Siyami Ersek Hospital Thoracic and Cardiovascular Surgery Training and Research Hospital, Istanbul, Turkey
| | - George Bazoukis
- Second Department of Cardiology, Evangelismos General Hospital of Athens, Athens, Greece
| | - Jesus Alvarez-Garcia
- Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, USA,Cardiology Department, Hospital de la Santa Creu i Sant Pau, CIBERCV, Barcelona, Spain
| | - Sebastian Garcia-Zamora
- South American Center of Excellence for Cardiovascular Health (CESCAS), Institute for Clinical Effectiveness and Health Policy (IECS), Buenos Aires, Argentina
| | - Sharen Lee
- Laboratory of Cardiovascular Physiology, Chinese University Shenzhen Research Institute, PR China
| | - Cynthia Yeung
- Heart Rhythm Service, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada
| | - Tong Liu
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, PR China
| | - Gary Tse
- Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, PR China.
| | - Adrian Baranchuk
- Heart Rhythm Service, Kingston General Hospital, Queen's University, Kingston, Ontario, Canada.
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Mendis S. Cardiovascular disease in the context of the COVID-19 pandemic. INTERNATIONAL JOURNAL OF NONCOMMUNICABLE DISEASES 2020. [DOI: 10.4103/jncd.jncd_31_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
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