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Zhang Z, He J, Liang Y, Wang Y, Zheng J, Ma L, Su L. Adverse events associated with azithromycin and clarithromycin in adults aged ≥65: a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database. Expert Opin Drug Saf 2024:1-8. [PMID: 39354723 DOI: 10.1080/14740338.2024.2412226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 08/29/2024] [Accepted: 09/10/2024] [Indexed: 10/03/2024]
Abstract
BACKGROUND Azithromycin and clarithromycin are commonly used to treat community-acquired pneumonia in adults aged ≥ 65, such as mycoplasma pneumonia. This study aims to evaluate adverse events (AEs) associated with azithromycin and clarithromycin in this age group by analyzing the FDA Adverse Event Reporting System (FAERS), providing insights for clinical use and management of AEs in this population. RESEARCH DESIGN AND METHODS We retrieved reports of AEs related to azithromycin and clarithromycin from the FAERS database. Disproportionality analysis was conducted using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Gamma Poisson Shrinkage (MGPS) to identify AEs associated with azithromycin and clarithromycin in adults aged ≥ 65. RESULTS A total of 2,019 adverse event reports were retrieved for azithromycin, and 2,392 for clarithromycin. Off-label use (n = 349) and drug interactions (n = 487) were the most reported AEs in adults aged ≥ 65 for azithromycin and clarithromycin, respectively. Prolonged QT interval showed the strongest signal among AEs for azithromycin in this age group. Drug interaction-related medication errors had the strongest signal for clarithromycin. Seven signals not explicitly included in the azithromycin package insert were identified in adults aged ≥ 65. Fourteen signals not explicitly included in the clarithromycin package insert were identified. CONCLUSIONS Among adults aged ≥ 65, cardiac-related adverse events are more closely associated with azithromycin than with clarithromycin. Conversely, AEs related to drug interactions and psychiatric symptoms are more associated with clarithromycin. Additionally, clinicians should be vigilant regarding AEs not specified in the package inserts. The findings of this study may help optimize the selection of azithromycin and clarithromycin based on patient circumstances and assist clinicians in focusing on relevant AEs for early intervention.
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Affiliation(s)
- Zhenpo Zhang
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Jiaxin He
- Department of Pharmacy, Guangdong Food and Drug Vocational College, Guangzhou, Guangdong, China
| | - Yankun Liang
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Yuting Wang
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Jingping Zheng
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
| | - Lin Ma
- Department of Pharmacy, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Ling Su
- Department of Pharmacy, Jinan University, Guangzhou, Guangdong, China
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Motola D, Bonaldo G, Montanaro N. Safety profile of hydroxychloroquine used off‐label for the treatment of patients with COVID‐19: A descriptive study based on EudraVigilance data. Fundam Clin Pharmacol 2022; 36:1099-1105. [PMID: 35526987 PMCID: PMC9348099 DOI: 10.1111/fcp.12797] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/02/2022] [Accepted: 05/06/2022] [Indexed: 12/26/2022]
Abstract
At the beginning of the COVID‐19 pandemic, worldwide attempts were made to identify potential drugs effective against the COVID‐19. Hydroxychloroquine was among the first receiving attention. However, following its use in therapy, it has been shown that hydroxychloroquine was not only ineffective but probably, due to its known side effects, even responsible of increased mortality of patients. The objective of this study was to review the safety profile of hydroxychloroquine used off‐label for the treatment of COVID‐19. We analyze the reports of suspected adverse drug reactions (ADRs) collected in EudraVigilance, the European database of ADR reports. We collected 2266 reports for 2019 and 6525 for 2020. The most reported ADRs during 2020 were those relating to cardiac, hepatic, renal toxicity such as QT prolongation with 400 cases in 2020 (of which, 345 cases—9.97%—with COVID‐19 as a therapeutic indication) versus 1 case only in 2019 (0.01%), long QT syndrome: 38 cases in 2020 (36 as COVID‐19 treatment) versus 0 in 2019, hepatitis: 13 cases in 2019 (0.11%) and 132 in 2020, and 32 cases (24, 0.69%) of acute kidney injury in 2020 and only 3 cases in 2019. Moreover, some important vision‐related ADRs also increased significantly during 2020, such as retinal toxicity with 92 cases in 2020 versus 7 in 2019. Even though with its intrinsic limitations, our results may be added to the most recent scientific evidence to confirm the unfavorable risk profile of hydroxychloroquine in its off‐label use in the treatment of COVID‐19 disease.
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Affiliation(s)
- Domenico Motola
- Unit of Pharmacology, Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna Bologna
| | - Giulia Bonaldo
- Unit of Pharmacology, Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna Bologna
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Rasouli M, Vakilian F, Ranjbari J. Therapeutic and protective potential of mesenchymal stem cells, pharmaceutical agents and current vaccines against covid-19. Curr Stem Cell Res Ther 2021; 17:166-185. [PMID: 33349221 DOI: 10.2174/1574888x16666201221151853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 07/07/2021] [Accepted: 07/19/2021] [Indexed: 11/22/2022]
Abstract
It has been almost 18 months since the first outbreak of COVID-19 disease was reported in Wuhan, China. This unexpected devastating phenomenon, raised a great deal of concerns and anxiety among people around the world and imposed a huge economic burden on the nations' health care systems. Accordingly, clinical scientists, pharmacologists and physicians worldwide felt an urgent demand for a safe, effective therapeutic agent, treatment strategy or vaccine in order to prevent or cure the recently-emerged disease. Initially, due to lack of specific pharmacological agents and approved vaccines to combat the COVID-19, the disease control in the confirmed cases was limited to supportive care. Accordingly, repositioning or repurposing current drugs and examining their possible therapeutic efficacy received a great deal of attention. Despite revealing promising results in some clinical trials, the overall results are conflicting. For this reason, there is an urgent to seek and investigate other potential therapeutics. Mesenchymal stem cells (MSC) representing immunomodulatory and regenerative capacity to treat both curable and intractable diseases, have been investigated in COVID-19 clinical trials carried out in different parts of the world. Nevertheless, up to now, none of MSC-based approaches has been approved in controlling COVID-19 infection. Thanks to the fact that the final solution for defeating the pandemic is developing a safe, effective vaccine, enormous efforts and clinical research have been carried out. In this review, we will concisely discuss the safety and efficacy of the most relevant pharmacological agents, MSC-based approaches and candidate vaccines for treating and preventing COVID-19 infection.
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Affiliation(s)
- Mehdi Rasouli
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
| | | | - Javad Ranjbari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran. Iran
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Hydroxychloroquine versus hydroxychloroquine-azithromycin combination therapy on QT interval prolongation of COVID-19 patients: a systematic review and meta-analysis. COR ET VASA 2021. [DOI: 10.33678/cor.2021.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Mahajan A, Bhattacharyya S. A brief review on potential application of mesenchymal stem cell and secretome in combating mortality and morbidity in COVID-19 patients. Biomed J 2021; 44:63-73. [PMID: 33727050 PMCID: PMC7521921 DOI: 10.1016/j.bj.2020.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 09/16/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by novel Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV2), is typically associated with severe respiratory distress and has claimed more than 525,000 lives already. The most fearful aspect is the unavailability of any concrete guidelines and treatment or protective strategies for reducing mortality or morbidity caused by this virus. Repurposing of drugs, antivirals, convalescent plasma and neutralizing antibodies are being considered for treatment but are still questionable in lieu of the conflicting data, study design and induction of secondary infections. Stem cell therapy has seen substantial advancements over the past decade for the treatment of various diseases including pulmonary disorders with severe complications similar to COVID-19. Recently, mesenchymal stem cells (MSCs) have received particular attention as a potential therapeutic modality for SARS-CoV2 infection due to their ability to inhibit cytokine storm, a hallmark of severe COVID-19. MSCs secretion of trophic factors and extracellular vesicles mediated intercellular signaling are considered as principal contributing factors for tissue recovery. Although, recent preliminary studies have established the safety and efficacy of these cells without any severe secondary complications in the treatment of SARS-CoV2 infection, the rational use of MSCs on a large scale would still require additional relevant clinical investigations and validation of postulated mechanisms of these cells. This review presents the current clinical findings and update on the potential use of stem cell therapy and its secretome in combating the symptoms associated with COVID-19.
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Affiliation(s)
- Aditi Mahajan
- Department of Biophysics, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Shalmoli Bhattacharyya
- Department of Biophysics, Post Graduate Institute of Medical Education & Research, Chandigarh, India.
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Fresse A, Viard D, Romani S, Gérard A, Lepelley M, Rocher F, Salem JE, Drici MD. Spontaneous reported cardiotoxicity induced by lopinavir/ritonavir in COVID-19. An alleged past-resolved problem. Int J Cardiol 2021; 324:255-260. [PMID: 33075384 PMCID: PMC7566676 DOI: 10.1016/j.ijcard.2020.10.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/17/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022]
Abstract
The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19. Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious. Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%. These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly.
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Affiliation(s)
- Audrey Fresse
- Department of Clinical Pharmacology, Université Côte d'Azur Medical Center Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, Nice Cedex 01 06001, France.
| | - Delphine Viard
- Department of Clinical Pharmacology, Université Côte d'Azur Medical Center Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, Nice Cedex 01 06001, France.
| | - Serena Romani
- Department of Clinical Pharmacology, Université Côte d'Azur Medical Center Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, Nice Cedex 01 06001, France.
| | - Alexandre Gérard
- Department of Clinical Pharmacology, Université Côte d'Azur Medical Center Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, Nice Cedex 01 06001, France.
| | - Marion Lepelley
- RCPV of Grenoble. University of Grenoble Medical Center, Grenoble 38043, France.
| | - Fanny Rocher
- Department of Clinical Pharmacology, Université Côte d'Azur Medical Center Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, Nice Cedex 01 06001, France.
| | - Joe-Elie Salem
- INSERM, AP-HP. Sorbonne Université, Clinical Investigation Center, Department of Pharmacology, Pitié-Salpêtrière Hospital, Sorbonne Université, CIC-1901, Paris 75013, France; Departments of Medicine and Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States of America.
| | - Milou-Daniel Drici
- Department of Clinical Pharmacology, Université Côte d'Azur Medical Center Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, Nice Cedex 01 06001, France.
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Zahr N, Urien S, Llopis B, Pourcher V, Paccoud O, Bleibtreu A, Mayaux J, Gandjbakhch E, Hekimian G, Combes A, Benveniste O, Saadoun D, Allenbach Y, Pinna B, Cacoub P, Funck-Brentano C, Salem JE. Pharmacokinetics and pharmacodynamics of hydroxychloroquine in hospitalized patients with COVID-19. Therapie 2021; 76:285-295. [PMID: 33558079 PMCID: PMC7842207 DOI: 10.1016/j.therap.2021.01.056] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/03/2021] [Accepted: 01/22/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hydroxychloroquine (HCQ) dosage required to reach circulating levels that inhibit SARS-Cov-2 are extrapolated from pharmacokinetic data in non-COVID-19 patients. METHODS We performed a population-pharmacokinetic analysis from 104 consecutive COVID-19 hospitalized patients (31 in intensive care units, 73 in medical wards, n=149 samples). Plasma HCQ concentration were measured using high performance liquid chromatography with fluorometric detection. Modelling used Monolix-2019R2. RESULTS HCQ doses ranged from 200 to 800mg/day administered for 1 to 11days and median HCQ plasma concentration was 151ng/mL. Among the tested covariates, only bodyweight influenced elimination oral clearance (CL) and apparent volume of distribution (Vd). CL/F (F for unknown bioavailability) and Vd/F (relative standard-error, %) estimates were 45.9L/h (21.2) and 6690L (16.1). The derived elimination half-life (t1/2) was 102h. These parameters in COVID-19 differed from those reported in patients with lupus, where CL/F, Vd/F and t1/2 are reported to be 68L/h, 2440 L and 19.5h, respectively. Within 72h of HCQ initiation, only 16/104 (15.4%) COVID-19 patients had HCQ plasma levels above the in vitro half maximal effective concentration of HCQ against SARS-CoV-2 (240ng/mL). HCQ did not influence inflammation status (assessed by C-reactive protein) or SARS-CoV-2 viral clearance (assessed by real-time reverse transcription-PCR nasopharyngeal swabs). CONCLUSION The interindividual variability of HCQ pharmacokinetic parameters in severe COVID-19 patients was important and differed from that previously reported in non-COVID-19 patients. Loading doses of 1600mg HCQ followed by 600mg daily doses are needed to reach concentrations relevant to SARS-CoV-2 inhibition within 72hours in≥60% (95% confidence interval: 49.5-69.0%) of COVID-19 patients.
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Affiliation(s)
- Noël Zahr
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France.
| | - Saik Urien
- AP-HP, Université de Paris, INSERM, Cochin Hospital, Department of Pediatric and Perinatal Pharmacology, 75014 Paris, France
| | - Benoit Llopis
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
| | - Valérie Pourcher
- AP-HP, Sorbonne Université, INSERM 1136, Institut Pierre-Louis d'Épidémiologie et de Santé Publique, Pitié-Salpêtrière Hospital, Service de Maladies Infectieuses et Tropicales, 75013 Paris, France
| | - Olivier Paccoud
- AP-HP, Sorbonne Université, INSERM 1136, Institut Pierre-Louis d'Épidémiologie et de Santé Publique, Pitié-Salpêtrière Hospital, Service de Maladies Infectieuses et Tropicales, 75013 Paris, France
| | - Alexandre Bleibtreu
- AP-HP, Sorbonne Université, INSERM 1136, Institut Pierre-Louis d'Épidémiologie et de Santé Publique, Pitié-Salpêtrière Hospital, Service de Maladies Infectieuses et Tropicales, 75013 Paris, France
| | - Julien Mayaux
- AP-HP, Sorbonne Université, Service de Pneumologie, Médecine intensive - Réanimation (Département "R3S"), Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Estelle Gandjbakhch
- AP-HP, Sorbonne Université, Service de Cardiologie, Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Guillaume Hekimian
- AP-HP, Sorbonne Université, Médecine intensive-Réanimation Médicale Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Alain Combes
- AP-HP, Sorbonne Université, Médecine intensive-Réanimation Médicale Groupe Hospitalier Universitaire Pitié-Salpêtrière-Charles-Foix, 75013 Paris, France
| | - Olivier Benveniste
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - David Saadoun
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - Yves Allenbach
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - Bruno Pinna
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
| | - Patrice Cacoub
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes et Systémiques Rares, 75013 Paris, France
| | - Christian Funck-Brentano
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
| | - Joe-Elie Salem
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Center, INSERM, CIC-1901, Sorbonne Université, Faculty of Medicine, 75013 Paris, France
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Romani S, Gérard A, Fresse A, Viard D, Van‐Obberghen É, Micallef J, Rocher F, Drici M, the French Pharmacovigilance Network. Insights on the Evidence of Cardiotoxicity of Hydroxychloroquine Prior and During COVID-19 Epidemic. Clin Transl Sci 2021; 14:163-169. [PMID: 32964653 PMCID: PMC7877831 DOI: 10.1111/cts.12883] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 08/31/2020] [Indexed: 12/20/2022] Open
Abstract
The recent empirical use of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID-19) revived the interest in its cardiac toxicity, increasingly sidelined over time. We aimed to assess and compare the profile of cardiac adverse drug reactions (CADRs) associated with HCQ before and during COVID-19. We performed a retrospective comparative observational study using the French Pharmacovigilance network database between 1985 and May 2020 to assess all postmarketing CADRs associated with HCQ notified before COVID-19 in its approved indications for lupus and rheumatoid arthritis (preCOV), and those concerning its empirical use in COVID-19 (COV). Eighty-five CADR in preCOV were compared with 141 CADRs in COV. The most common CADR of preCOV were cardiomyopathies (42.4%) and conduction disorders (28.2%), both statistically more frequent than in COV (P < 0.001). COV notifications significantly highlighted repolarization and ventricular rhythm disorders (78.0%, P < 0.001) as well as sinus bradycardias (14.9%, P = 0.01) as compared with preCOV. Estimated incidence of CADR was significantly higher among patients exposed to off-label use of HCQ in COVID-19 (2.9%) than before COVID-19 in its approved indications (0.01%, P < 0.001). The use of HCQ in COVID-19 sheds a new light on the spectrum of its cardiac toxicity. This fosters the value of a closer monitoring of all patients treated with HCQ, regardless of its indication, and the importance of an update of its summary of product characteristics.
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Affiliation(s)
- Serena Romani
- PharmacovigilanceDepartment of Clinical PharmacologyUniversité Côte d’Azur Medical CenterPasteur HospitalNiceFrance
| | - Alexandre Gérard
- PharmacovigilanceDepartment of Clinical PharmacologyUniversité Côte d’Azur Medical CenterPasteur HospitalNiceFrance
| | - Audrey Fresse
- PharmacovigilanceDepartment of Clinical PharmacologyUniversité Côte d’Azur Medical CenterPasteur HospitalNiceFrance
| | - Delphine Viard
- PharmacovigilanceDepartment of Clinical PharmacologyUniversité Côte d’Azur Medical CenterPasteur HospitalNiceFrance
| | - Élise Van‐Obberghen
- PharmacovigilanceDepartment of Clinical PharmacologyUniversité Côte d’Azur Medical CenterPasteur HospitalNiceFrance
| | - Joëlle Micallef
- PharmacovigilanceDepartment of Clinical Pharmacology and PharmacovigilanceAix Marseille UniversityAPHMINSERMInstitute for Neuroscience SystemsUMR 1106MarseilleFrance
| | - Fanny Rocher
- PharmacovigilanceDepartment of Clinical PharmacologyUniversité Côte d’Azur Medical CenterPasteur HospitalNiceFrance
| | - Milou‐Daniel Drici
- PharmacovigilanceDepartment of Clinical PharmacologyUniversité Côte d’Azur Medical CenterPasteur HospitalNiceFrance
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Bolarin JA, Oluwatoyosi MA, Orege JI, Ayeni EA, Ibrahim YA, Adeyemi SB, Tiamiyu BB, Gbadegesin LA, Akinyemi TO, Odoh CK, Umeobi HI, Adeoye ABE. Therapeutic drugs for SARS-CoV-2 treatment: Current state and perspective. Int Immunopharmacol 2021; 90:107228. [PMID: 33302035 PMCID: PMC7691844 DOI: 10.1016/j.intimp.2020.107228] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/19/2020] [Accepted: 11/19/2020] [Indexed: 12/19/2022]
Abstract
The disease caused by viral pneumonia called severe acute respiratory syndrome coronavirus type-2 (SARS-CoV-2) declared by the World Health Organization is a global pandemic that the world has witnessed since the last Ebola epidemic, SARS and MERS viruses. Many chemical compounds with antiviral activity are currently undergoing clinical investigation in order to find treatments for SARS-CoV-2 infected patients. On-going drug-drug interaction examinations on new, existing, and repurposed antiviral drugs are yet to provide adequate safety, toxicological, and effective monitoring protocols. This review presents an overview of direct and indirect antiviral drugs, antibiotics, and immune-stimulants used in the management of SARS-CoV-2. It also seeks to outline the recent development of drugs with anti-coronavirus effects; their mono and combination therapy in managing the disease vis-à-vis their biological sources and chemistry. Co-administration of these drugs and their interactions were discussed to provide significant insight into how adequate monitoring of patients towards effective health management could be achieved.
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Affiliation(s)
- Joshua Adedeji Bolarin
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mercy Adaramodu Oluwatoyosi
- Institute of Botany, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Joshua Iseoluwa Orege
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Emmanuel Ayodeji Ayeni
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu PMB 610041, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Yusuf Ajibola Ibrahim
- School of Chemical Sciences, Chinese Academy of Science, Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | | | - Bashir Bolaji Tiamiyu
- Wuhan Botanical Garden, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Lanre Anthony Gbadegesin
- Institute of Mountain Hazards and Environment, Chinese Academy of Sciences, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Toluwanimi Oluwadara Akinyemi
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chuks Kenneth Odoh
- Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Happiness Ijeoma Umeobi
- Institute of Rock and Soil Mechanics, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Adenike Bernice-Eloise Adeoye
- Institute of Urban Environment, Chinese Academy of Sciences, Xiamen, China; University of Chinese Academy of Sciences, Beijing 100049, China
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10
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Charitos IA, Ballini A, Bottalico L, Cantore S, Passarelli PC, Inchingolo F, D'Addona A, Santacroce L. Special features of SARS-CoV-2 in daily practice. World J Clin Cases 2020; 8:3920-3933. [PMID: 33024749 PMCID: PMC7520789 DOI: 10.12998/wjcc.v8.i18.3920] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/31/2020] [Accepted: 09/01/2020] [Indexed: 02/05/2023] Open
Abstract
The severe acute respiratory syndrome-coronavirus-2 (commonly known as SARS-CoV-2) is a novel coronavirus (designated as 2019-nCoV), which was isolated for the first time after the Chinese health authorities reported a cluster of pneumonia cases in Wuhan, China in December 2019. Optimal management of the Coronavirus Disease-2019 disease is evolving quickly and treatment guidelines, based on scientific evidence and experts' opinions with clinical experience, are constantly being updated. On January 30, 2020, the World Health Organization declared the SARS-CoV-2 outbreak as a "Public Health Emergency of International Concern". The total lack of immune protection brought about a severe spread of the contagion all over the world. For this reason, diagnostic tools, patient management and therapeutic approaches have been tested along the way, in the desperate race to break free from the widespread infection and its fatal respiratory complications. Current medical knowledge and research on severe and critical patients' management and experimental treatments are still evolving, but several protocols on minimizing risk of infection among the general population, patients and healthcare workers have been approved and diffused by International Health Authorities.
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Affiliation(s)
- Ioannis A Charitos
- Department of Emergency and Urgency, National Poisoning Centre, Riuniti University Hospital of Foggia, Foggia 71122, Italy
| | - Andrea Ballini
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University Campus "E. Quagliariello", University of Bari “Aldo Moro”, Bari 70125, Italy
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Lucrezia Bottalico
- Interdepartmental Research Center for Pre-Latin, Latin and Oriental Rights and Culture Studies (CEDICLO), University of Bari, Bari 70121, Italy
| | - Stefania Cantore
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari 70124, Italy
- Sorriso & Benessere - Ricerca e Clinica S.R.L, Bari 70129, Italy
| | - Pier Carmine Passarelli
- Department of Head, Neck and Sense Organs, Division of Oral Surgery and Implantology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome 00168, Italy
| | - Francesco Inchingolo
- Department of Interdisciplinary Medicine, Section of Dental Medicine, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Antonio D'Addona
- Department of Head and Neck and Sensory Organs, Division of Oral Surgery and Implantology, Fondazione Policlinico Universitario A. Gemelli IRCCS — Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Luigi Santacroce
- Interdepartmental Research Center for Pre-Latin, Latin and Oriental Rights and Culture Studies (CEDICLO), University of Bari, Bari 70121, Italy
- Ionian Department, Microbiology and Virology Laboratory, Policlinico University Hospital, University of Bari “Aldo Moro”, Bari 70124, Italy
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11
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Liang J, Karagiannis C, Pitsillou E, Darmawan KK, Ng K, Hung A, Karagiannis TC. Site mapping and small molecule blind docking reveal a possible target site on the SARS-CoV-2 main protease dimer interface. Comput Biol Chem 2020; 89:107372. [PMID: 32911432 PMCID: PMC7833639 DOI: 10.1016/j.compbiolchem.2020.107372] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 08/28/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023]
Abstract
The SARS-CoV-2 main protease (Mpro) has an important role in the viral life cycle. Inhibition of the active site or dimerization site of Mpro can mitigate activity. Mapping reveals a reactive pocket in the dimerization pocket at the apex of Mpro. Blind docking shows that ligands may preferentially bind at the apex of Mpro. Stable ligand interactions are formed at the active and apex sites of Mpro. The SARS-CoV-2 virus is causing COVID-19 resulting in an ongoing pandemic with serious health, social, and economic implications. Much research is focused in repurposing or identifying new small molecules which may interact with viral or host-cell molecular targets. An important SARS-CoV-2 target is the main protease (Mpro), and the peptidomimetic α-ketoamides represent prototypical experimental inhibitors. The protease is characterised by the dimerization of two monomers each which contains the catalytic dyad defined by Cys145 and His41 residues (active site). Dimerization yields the functional homodimer. Here, our aim was to investigate small molecules, including lopinavir and ritonavir, α-ketoamide 13b, and ebselen, for their ability to interact with the Mpro. The sirtuin 1 agonist SRT1720 was also used in our analyses. Blind docking to each monomer individually indicated preferential binding of the ligands in the active site. Site-mapping of the dimeric protease indicated a highly reactive pocket in the dimerization region at the domain III apex. Blind docking consistently indicated a strong preference of ligand binding in domain III, away from the active site. Molecular dynamics simulations indicated that ligands docked both to the active site and in the dimerization region at the apex, formed relatively stable interactions. Overall, our findings do not obviate the superior potency with respect to inhibition of protease activity of covalently-linked inhibitors such as α-ketoamide 13b in the Mpro active site. Nevertheless, along with those from others, our findings highlight the importance of further characterisation of the Mpro active site and any potential allosteric sites.
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Affiliation(s)
- Julia Liang
- Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; School of Science, College of Science, Engineering & Health, RMIT University, VIC 3001, Australia
| | - Chris Karagiannis
- School of Science, College of Science, Engineering & Health, RMIT University, VIC 3001, Australia; School of Agriculture and Food, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 3052, Australia
| | - Eleni Pitsillou
- Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; School of Science, College of Science, Engineering & Health, RMIT University, VIC 3001, Australia
| | - Kevion K Darmawan
- School of Science, College of Science, Engineering & Health, RMIT University, VIC 3001, Australia
| | - Ken Ng
- School of Agriculture and Food, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 3052, Australia
| | - Andrew Hung
- School of Science, College of Science, Engineering & Health, RMIT University, VIC 3001, Australia
| | - Tom C Karagiannis
- Epigenomic Medicine, Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3052, Australia.
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12
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Funck-Brentano C, Nguyen LS, Salem JE. Retraction and republication: cardiac toxicity of hydroxychloroquine in COVID-19. Lancet 2020; 396:e2-e3. [PMID: 32653079 PMCID: PMC7347305 DOI: 10.1016/s0140-6736(20)31528-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 07/01/2020] [Indexed: 12/21/2022]
Affiliation(s)
- Christian Funck-Brentano
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Centre, Paris 75013, France; INSERM, CIC-1901 and UMR-S 1166, Sorbonne Université, Faculty of Medicine, Paris, France.
| | - Lee S Nguyen
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Centre, Paris 75013, France; INSERM, CIC-1901 and UMR-S 1166, Sorbonne Université, Faculty of Medicine, Paris, France
| | - Joe-Elie Salem
- AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology and Clinical Investigation Centre, Paris 75013, France; INSERM, CIC-1901 and UMR-S 1166, Sorbonne Université, Faculty of Medicine, Paris, France
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13
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Nguyen LS, Dolladille C, Drici MD, Fenioux C, Alexandre J, Mira JP, Moslehi JJ, Roden DM, Funck-Brentano C, Salem JE. Cardiovascular Toxicities Associated With Hydroxychloroquine and Azithromycin: An Analysis of the World Health Organization Pharmacovigilance Database. Circulation 2020; 142:303-305. [PMID: 32442023 PMCID: PMC7365677 DOI: 10.1161/circulationaha.120.048238] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Lee S Nguyen
- Sorbonne Université, Institut national de la santé et de la recherche médicale (INSERM), Assistance Publique - Hopitaux de Paris, Clinical Investigation Center, Department of Pharmacology, Pitié-Salpêtrière Hospital, Paris, France (L.S.N., C.F., C.F.-B., J.-E.S.).,Centre Medico-Chirurgical Ambroise Paré, Research & Innovation, Neuilly-sur-Seine, France (L.S.N.)
| | - Charles Dolladille
- Pharmacoepidemiology Unit, Department of Pharmacology, Centre Hospitalo-Universitaire de Caen, Equipe d'accueil EA4650, Signalisation, Electrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Normandie University, Caen, France (C.D., J.A.)
| | - Milou-Daniel Drici
- Department of Pharmacology and Toxicology, PharmacoVigilance Center, University of Nice Côte d'Azur Medical Center, Hôpital de Cimiez, France (M.-D.D.)
| | - Charlotte Fenioux
- Sorbonne Université, Institut national de la santé et de la recherche médicale (INSERM), Assistance Publique - Hopitaux de Paris, Clinical Investigation Center, Department of Pharmacology, Pitié-Salpêtrière Hospital, Paris, France (L.S.N., C.F., C.F.-B., J.-E.S.)
| | - Joachim Alexandre
- Pharmacoepidemiology Unit, Department of Pharmacology, Centre Hospitalo-Universitaire de Caen, Equipe d'accueil EA4650, Signalisation, Electrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Normandie University, Caen, France (C.D., J.A.)
| | - Jean-Paul Mira
- Groupe Hospitalier Paris Centre-Université de Paris, Cochin University Hospital, Medical Intensive Care Unit, France (J.-P.M.)
| | - Javid J Moslehi
- Vanderbilt University Medical Center, Departments of Medicine and Pharmacology (J.J.M., D.M.R., J.-E.S.), Nashville, TN
| | - Dan M Roden
- Vanderbilt University Medical Center, Departments of Medicine and Pharmacology (J.J.M., D.M.R., J.-E.S.), Nashville, TN.,Department of Biomedical Informatics (D.M.R.), Nashville, TN
| | - Christian Funck-Brentano
- Sorbonne Université, Institut national de la santé et de la recherche médicale (INSERM), Assistance Publique - Hopitaux de Paris, Clinical Investigation Center, Department of Pharmacology, Pitié-Salpêtrière Hospital, Paris, France (L.S.N., C.F., C.F.-B., J.-E.S.)
| | - Joe-Elie Salem
- Sorbonne Université, Institut national de la santé et de la recherche médicale (INSERM), Assistance Publique - Hopitaux de Paris, Clinical Investigation Center, Department of Pharmacology, Pitié-Salpêtrière Hospital, Paris, France (L.S.N., C.F., C.F.-B., J.-E.S.).,Vanderbilt University Medical Center, Departments of Medicine and Pharmacology (J.J.M., D.M.R., J.-E.S.), Nashville, TN
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14
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Gérard A, Romani S, Fresse A, Viard D, Parassol N, Granvuillemin A, Chouchana L, Rocher F, Drici MD. "Off-label" use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers. Therapie 2020; 75:371-379. [PMID: 32418730 PMCID: PMC7204701 DOI: 10.1016/j.therap.2020.05.002] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 05/05/2020] [Indexed: 12/20/2022]
Abstract
INTRODUCTION COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences. METHODS Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with "off-label" use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019. RESULTS In one month, 120 reports of cardiac adverse drug reactions have been notified, 103 of which associated with hydroxychloroquine alone (86%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7%), 90 reports of prolonged QTc (75%) most of them "serious" (64%), 48 of which proved ≥ 500ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication. DISCUSSION AND CONCLUSION "Off-label" use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.
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Affiliation(s)
- Alexandre Gérard
- Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France
| | - Serena Romani
- Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France
| | - Audrey Fresse
- Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France
| | - Delphine Viard
- Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France
| | - Nadège Parassol
- Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France
| | | | - Laurent Chouchana
- Centre régional de pharmacovigilance Paris-Cochin, 75014 Paris, France
| | - Fanny Rocher
- Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France
| | - Milou-Daniel Drici
- Pharmacovigilance, department of pharmacology, Pasteur hospital, Bât J4, 30, avenue de la Voie-Romaine, CS51069, 06001 Nice Cedex 01, France.
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