# pos

id: cord-281411-la8njxc1
pos: NNP
token:
  https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/enforcement-policy-non-invasive-remote-monitoring-devices-used-support-patientmonitoring-during

lemma:
  https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/enforcement-policy-non-invasive-remote-monitoring-devices-used-support-patientmonitoring-during


id: cord-341377-mjdg84ny
pos: .
token:
  https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reportingsystem-faers/fda-adverse-event-reporting-system-faers-latest-quarterly-data-files

lemma:
  https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reportingsystem-faers/fda-adverse-event-reporting-system-faers-latest-quarterly-data-files


# ent

id: cord-026811-6bdzut3d
type: LAW
entity:
  Food and Drug AdministrationRequest for Emergency Use Authorization For Use of Chloroquine Phosphate


id: cord-270723-cjfglili
type: ORG
entity:
  the American College of Cardiology Foundation Determination and Interpretation of the QT Interval Hydroxychloroquine


id: cord-262467-epqqd8n8
type: CELL_TYPE
entity:
  bronchoalveolar lavage fluid BALF 93 positive pharyngeal swabs 32 fibrobronchoscope brush 46 nasal swabs 63 feces 29 sputum 72 and blood 1 24


id: cord-031079-9lxhvyyb
type: GGP
entity:
  interleukin IL 1ꞵ tumor necrosis factor α TNFα interferon γ IFN γ C X C motif chemokine ligand CXCL 10


id: cord-031079-9lxhvyyb
type: ORG
entity:
  China Medical Treatment Expert Group for C Clinical Characteristics of Coronavirus Disease Transmission


id: cord-031079-9lxhvyyb
type: LOC
entity:
  Middle East Respiratory Syndrome Coronavirus Spike Protein Is Not Activated Directly by Cellular Furin


id: cord-031079-9lxhvyyb
type: FAC
entity:
  Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome


id: cord-275340-q8d7rvnj
type: PROTEIN
entity:
  trypsin furin proprotein convertase PC family cathepsins transmembrane protease serine TMPRSS proteases


id: cord-028530-hpgrbhkl
type: CHEMICAL
entity:
  azithromycin clarithromycin levofloxacin moxifloxacin ciprofloxacin haloperidol quetiapine risperidone domperidone


id: cord-278246-mnj0zmkn
type: GGP
entity:
  Cureus DOI 10 7759 cureus 10005 sha 6cff8dd1f1b092a0665285c502c88254902c2ba8 doc_id 278246 cord_uid mnj0zmkn Introduction


id: cord-278068-3kg71nf4
type: CELL_LINE
entity:
  Coronavirus Disease 19 COVID 19 Should chloroquine and hydroxychloroquine be used to treat COVID 19 A rapid review BJGP open


id: cord-278068-3kg71nf4
type: WORK_OF_ART
entity:
  Early Treatment of Adults with Mild Covid 19 A Randomized Controlled Trial Hydroxychloroquine in Nonhospitalized Adults With Early COVID 19


id: cord-275037-sji0u8nu
type: ORG
entity:
  Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid 19 Association of Treatment With Hydroxychloroquine or Azithromycin With In Hospital Mortality in Patients


id: cord-253609-vi2fb43t
type: CELL_LINE
entity:
  HRS COVID 19 Rapid Response Task Force The survey was active from March 27 2020 to April 13 2020 The audience for the survey was electrophysiology EP professionals physicians nurse practitioners physician assistants nurses EP lab technicians scientists and other allied professionals across the globe The survey consisted of 25 questions Supplemental Appendix Demographic questions included primary occupation practice setting and practice location state province and country The goal of the survey was to understand the cumulative experience as well as the variability in incidence and management strategies of arrhythmias associated with COVID 19


id: cord-296649-h6oyjz56
type: ORG
entity:
  Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease


id: cord-296649-h6oyjz56
type: FAC
entity:
  Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute


id: cord-262454-bccrvapy
type: CHEMICAL
entity:
  Szente Fonseca Silvia Nunes Queiroz de Sousa Anastasio Wolkoff Alexandre Giandoni Moreira Marcelo Sampaio


id: cord-286579-u87lx38h
type: GGP
entity:
  SARS CoV 2 covid 19 date 2020 06 26 journal Revista de saude publica DOI 10 11606 s1518 8787 2020054002631 sha 39ba3347fafe062c68f2407def86554e0c8a8e2d doc_id 286579 cord_uid u87lx38h Chloroquine CQ


id: cord-286579-u87lx38h
type: ORG
entity:
  NIH Grants National Institutes of Aging NIA 2 PO1AG039355 NIA R01AG060341 National Institutes of Neurological Disorders


id: cord-277916-b4yqek29
type: WORK_OF_ART
entity:
  the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 SARS CoV 2 Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid 19 Urgent Guidance for Navigating and Circumventing the QTc Prolonging and Torsadogenic Potential of Possible Pharmacotherapies


id: cord-277916-b4yqek29
type: WORK_OF_ART
entity:
  The Effect of Chloroquine Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS CoV 2 Infection Circulation Arrhythmia


id: cord-293304-kakxmc14
type: PROTEIN
entity:
  spike glycoprotein S envelope glycoprotein E membrane glycoprotein M nucleocapsid protein N and nonstructural proteins


id: cord-293304-kakxmc14
type: FAC
entity:
  Vitro Introducing New Antimalarial Analogues of Chloroquine and Amodiaquine A Narrative Review Iran Chloroquine Analogs


id: cord-293304-kakxmc14
type: ORG
entity:
  Plasmodium Falciparum Synthesis Biological Evaluation and Docking Simulation Study Asian Pac Pi Interactions


id: cord-293304-kakxmc14
type: ORG
entity:
  Reducing Plasmodium Falciparum Transmission Primaquine Therapy for Malaria Analysis for Antioxidant Activity of Dipicolinic Acid Derivatives QSAR Study of Anti Human African Trypanosomiasis Activity


id: cord-281285-5g1rw202
type: CELL_LINE
entity:
  EC 50 was 2 14 3 13 lM for homoharringtonine and 0 46À1 56 lM for emetine depending on antiviral assay Choy et al 2020 Wang et al found that nitazoxanide a drug with broad spectrum antiparasitic and broad spectrum antiviral effects inhibits SARS


id: cord-272419-y3ebt4jm
type: WORK_OF_ART
entity:
  the Treatment of COVID 19 COVID 19 and Dexamethasone A Potential Strategy to Avoid Steroid Related Strongyloides Hyperinfection Nitazoxanide Azithromycin


id: cord-256294-9gmn4fcj
type: PERSON
entity:
  Prince Mohammed bin Abdulaziz Hospital PMAH WWW Document Association of Treatment with Hydroxychloroquine


id: cord-303819-w1785lap
type: ORG
entity:
  Association of Treatment With Hydroxychloroquine or Azithromycin With In Hospital Mortality in Patients


id: cord-303819-w1785lap
type: WORK_OF_ART
entity:
  The Effect of Chloroquine Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS CoV 2 Infection Experience


id: cord-303819-w1785lap
type: WORK_OF_ART
entity:
  A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid 19 Active Monitoring of Persons Exposed to Patients with Confirmed COVID 19


id: cord-261186-4p1cwb2e
type: DISEASE
entity:
  cord_uid 4p1cwb2e nan and found no significant differences in the likelihood of abnormal electrocardiogram


id: cord-295144-tyyc81uc
type: PROTEIN
entity:
  monocyte chemoattractant protein MCP 1 macrophage inflammatory protein MIP 1α MIP1β tumor necrosis factor TNF


id: cord-295973-41jqgsv0
type: GGP
entity:
  Syndr DOI 10 1016 j dsx 2020 03 011 sha 9962b3791dcb49f7801b5d1827fd90a3f760d0d7 doc_id 295973 cord_uid 41jqgsv0 BACKGROUND AND AIMS No drugs


id: cord-280528-7ivw72l0
type: PROTEIN
entity:
  granulocyte colony stimulating factor GM CSF inhibitor IL 1 antagonists IL 17 antagonists and antitumor necrosis factor TNF


id: cord-293159-oagv4q1u
type: CELL_LINE
entity:
  American Type Culture Collection Virginia MA USA Luciferase expressing murine non small lung cancer NSCLC TC1 Luc cell line


id: cord-312875-gn6hg6oc
type: WORK_OF_ART
entity:
  Pharmacologic Treatments for Coronavirus Disease 2019 COVID 19 A Review Potential Effect of Hydroxychloroquine in Diabetes Mellitus A Systematic Review on Preclinical and Clinical Trial Studies Antidiabetogenic


id: cord-268425-xg8xnjf9
type: PROTEIN
entity:
  nutraceuticals yeast beta glucan zinc vitamin D spirulina phase 2 inducers N acetylcysteine glucosamine quercetin


id: cord-268425-xg8xnjf9
type: WORK_OF_ART
entity:
  The Effect of Chloroquine Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS CoV 2 Infection Risk of QT Interval Prolongation


id: cord-304669-aiuiotds
type: PROTEIN
entity:
  Glucose creatinine aspartate aminotransferase alanine aminotransferase lactate dehydrogenase bilirubin


id: cord-304669-aiuiotds
type: CELL_LINE
entity:
  Tp e QT 0 17 0 03 vs 0 17 0 02 respectively P 0 030 was decreased significantly from day 2 to day 5 In clinical follow up four 5 patients had QTc 500 ms while 10 8


id: cord-307570-8f83k2ce
type: WORK_OF_ART
entity:
  Hydroxychloroquine on Covid 19 in Intensive Care Unit Patients Preliminary Results 271 Hydroxychloroquine


id: cord-306351-ka6asw3m
type: CELL_LINE
entity:
  Coronavirus Disease 19 COVID 19 Relationship to Duration of Infection Associations between immune suppressive and stimulating drugs and novel COVID 19


id: cord-306351-ka6asw3m
type: WORK_OF_ART
entity:
  Different Types of Clinical Specimens Development and Clinical Application of A Rapid IgM IgG Combined Antibody Test for SARS CoV 2 Infection Diagnosis Correlation of Chest CT


id: cord-318092-errwp80i
type: WORK_OF_ART
entity:
  Chloroquine Is Effective for Maintenance of Remission in Autoimmune Hepatitis Controlled Double Blind Comparison of artemether lumefantrine


id: cord-320499-76o2zj0v
type: GGP
entity:
  rheumatoid factor antinuclear factor antideoxyribonucleic acid antismooth muscle and antimitochondrial antibodies


id: cord-319571-fspmgg4s
type: ORG
entity:
  the Directorate General of Scientific Research and Technological Development of the Ministry of High Education and Scientific Research


id: cord-317761-tkqmu1va
type: CELL_LINE
entity:
  China Wuhan Jingzhou Guangzhou Beijing Shanghai Chongqing and Ningbo involving 100 patients the authors proposed that chloroquine


id: cord-316992-fe5u2oi0
type: CELL_LINE
entity:
  tlr4 À À thymoma mouse model Apetoh et al 2007 Along these lines CQ reduced breast cancer growth in mice after irradiation by enhancing apoptotic and immunogenic tumour cell


id: cord-329920-s928u6g3
type: DNA
entity:
  e c t e d Q T I n t e r v a l i n P a t i e n t s w i t h S A R S C o V 2 I n f e c t i o n C i r c A


id: cord-329920-s928u6g3
type: PROTEIN
entity:
  loop diuretics ATC C02L C03A C03B C03D C03E C03X C07X C07C C07D C08G C02DA C09BA C09DA C09XA52 vasodilators ATC C02DB


id: cord-329920-s928u6g3
type: CHEMICAL
entity:
  D 1 9 I n f e c t i o n A S y s t e m a t i c L i t e r a t u r e R e v i e w P r e p r i n t s e r v e r CC


id: cord-341101-5yvjbr5q
type: TAXON
entity:
  herpes simplex viruses coxsackie virus vesicular stomatitis virus VSV vaccinia virus sindbis virus parainfluenza 3 virus


id: cord-328257-kl4wh2zg
type: CL
entity:
  microglia and TNFalpha in the mPFCmediated cognitive inflexibility induced by social stress during adolescence Changing face of microglia The novel object recognition memory neurobiology test procedure and its modifications A simple practice guide for dose conversion between animals


id: cord-328257-kl4wh2zg
type: ORG
entity:
  chloroquine Pharmacokinetics and Pharmacological Properties of Chloroquine and Hydroxychloroquine in the Context of COVID 19 Infection Effect of hydroxychloroquine on progression of dementia


id: cord-339737-7qdjea6f
type: GGP
entity:
  ATE 9 83 0 51 to 20 17 ratio in ATE 1 40 0 98 to 1 81 p 0 062 Conclusions Using a large non selected population of inpatients hospitalized for COVID 19


id: cord-339717-2a8zv9xl
type: GGP
entity:
  Tacrolimus 5 Ondansetron 114 Tamoxifen 1 Propofol 123 Tizanidine 1 Sotalol 5 Tolterodine 8 Tramadol 26 Venlafaxine 3


id: cord-339717-2a8zv9xl
type: ORG
entity:
  the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology Azithromycin


id: cord-339717-2a8zv9xl
type: DISEASE
entity:
  hypertension diabetes mellitus coronary artery disease chronic obstructive pulmonary disease chronic kidney disease


id: cord-342746-2hbcbvt6
type: ORG
entity:
  the Combination of Hydroxychloroquine and Azithromycin in Patients with Severe COVID 19 Infection Safety


id: cord-340090-dqhdws5k
type: PROTEIN
entity:
  K Chandanshive P D S R R Pradhan S K Pentapati S S K Batmanabane G Padhy B M Bal S Singh S R Mohanty R R title


id: cord-333144-gyuh2fvl
type: DISEASE
entity:
  diseases of the respiratory tract gastrointestinal tract liver kidney and nervous system Human coronavirus


id: cord-344120-7t5ce2hb
type: WORK_OF_ART
entity:
  A Trial of Lopinavir Ritonavir in Adults Hospitalized with Severe Covid 19 Efficacy and Safety of Lopinavir Ritonavir or Arbidol in Adult Patients with Mild Moderate COVID 19 An Exploratory Randomized Controlled Trial Ruxolitinib


id: cord-315598-qwh72inx
type: GGP
entity:
  expansión y extensión Colombia reporta a la fecha actual 113 389 casos confirmados y 3984 nuevos casos de COVID 19 confirmados y cerca


id: cord-315598-qwh72inx
type: GGP
entity:
  Ataque cerebrovascular agudo isquémico o hemorrágico con tazas de entre el 5 al 6 por lo que el examen neurológico debe realizarse para documentar


id: cord-315598-qwh72inx
type: PERSON
entity:
  debido al riesgo potencial de contaminación del campo quirúrgico con el aire que sale de la válvula de exhalación


id: cord-315598-qwh72inx
type: PRODUCT
entity:
  con el receptor de la enzima convertidora de angiotensina 2 ACE2 el hemograma puede revelar linfopenia y neutrofilia sin otras anormalidades significativas


id: cord-315598-qwh72inx
type: PERSON
entity:
  además de recibir hidroxicloroquina lopinavir ritonavir y metilprednisolona fueron tratados con plasma


id: cord-315598-qwh72inx
type: ORG
entity:
  Assessment of Self Contamination During Removal of Personal Protective Equipment for Ebola Patient Care


id: cord-315598-qwh72inx
type: ORG
entity:
  Society European Society of Intensive Care Medicine Society of Critical Care Medicine Clinical Practice Guideline Mechanical Ventilation


id: cord-315598-qwh72inx
type: EVENT
entity:
  the Prone Position Outside the Intensive Care Unit Use of Prone Positioning in Nonintubated Patients With COVID 19 and Hypoxemic Acute Respiratory Failure First case


id: cord-315598-qwh72inx
type: ORG
entity:
  CT A Preliminary Study on the Ultrasonic Manifestations of Peripulmonary Lesions of Non Critical Novel Coronavirus Pneumonia Effect of Focused Bedside Ultrasonography


id: cord-315598-qwh72inx
type: EVENT
entity:
  Human Coronaviruses and Other Respiratory Viruses Underestimated Opportunistic Pathogens of the Central Nervous System Viruses Neurological


id: cord-315598-qwh72inx
type: WORK_OF_ART
entity:
  the Acute Disease Quality Initiative ADQI 21 Workgroup Intravascular Volume Assessment in the Critically Ill Patient


id: cord-315598-qwh72inx
type: ORG
entity:
  Dialysis Facilities Additional Guidance for Infection Prevention and Control Recommendations for Patients


id: cord-315598-qwh72inx
type: ORG
entity:
  Covid 19 medRxiv Association of Treatment With Hydroxychloroquine or Azithromycin With In Hospital Mortality in Patients


id: cord-315598-qwh72inx
type: WORK_OF_ART
entity:
  Molecular Mechanism for Antibody Dependent Enhancement of Coronavirus Entry Treatment of 5 Critically Ill Patients With COVID 19 With Convalescent Plasma Effectiveness


id: cord-315598-qwh72inx
type: WORK_OF_ART
entity:
  Treatment With Convalescent Plasma for Critically Ill Patients With Severe Acute Respiratory Syndrome


id: cord-315598-qwh72inx
type: ORG
entity:
  the Difficult Airway Society the Association of Anaesthetists the Intensive Care Society the Faculty of Intensive Care Medicine


id: cord-315598-qwh72inx
type: ORG
entity:
  the Royal College of Anaesthetists Management of Difficult Tracheal Intubation A Closed Claims Analysis Difficult Airway Society


id: cord-315598-qwh72inx
type: WORK_OF_ART
entity:
  Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post


id: cord-315598-qwh72inx
type: ORG
entity:
  Ann Intensive Care Effect of Postextubation High Flow Nasal Cannula vs Noninvasive Ventilation on Reintubation and Postextubation Respiratory Failure in High Risk Patients A Randomized Clinical Trial High


id: cord-315598-qwh72inx
type: ORG
entity:
  American Society for Parenteral and Enteral Nutrition Guidelines for the Provision and Assessment of Nutrition Support Therapy


id: cord-315598-qwh72inx
type: DISEASE
entity:
  acute lung injury acute respiratory distress syndrome Extravascular lung water and pulmonary arterial wedge pressure


id: cord-353749-2vlc11rx
type: WORK_OF_ART
entity:
  Flattening the Risk Pre Exposure Prophylaxis for COVID 19 date 2020 10 19 journal Infect Drug Resist DOI


id: cord-349868-lb2jcl8m
type: GGP
entity:
  Cureus DOI 10 7759 cureus 9151 sha a6c8708472e6520fae11f65860a63332ea18de1e doc_id 349868 cord_uid lb2jcl8m


id: cord-350992-l6l24pco
type: WORK_OF_ART
entity:
  Emerging Regulatory Roles of Dual Specificity Phosphatases in Inflammatory Airway Disease Inhibition


id: cord-350992-l6l24pco
type: WORK_OF_ART
entity:
  Will Complement Inhibition be the New Target in Treating COVID 19 Related Systemic Thrombosis Circulation Antiaggregation


id: cord-354653-m0717ywt
type: DISEASE
entity:
  SLE juvenile idiopathic arthritis rheumatoid arthritis Sjogren syndrome dermatomyositis actinic lichen planus oral lichen planus


id: cord-352557-l7sahv5t
type: WORK_OF_ART
entity:
  The Effect of Hydroxychloroquine and Azithromycin on the Corrected QT Interval in Patients with SARS CoV 2 Infection Blockade


# url

id: cord-281411-la8njxc1
domain: www.fda.gov
url:
  http://www.fda.gov/regulatory-information/search-fda-guidancedocuments/enforcement-policy-non-invasive-remote-monitoring-devices-used-support-patientmonitoring-during


id: cord-341377-mjdg84ny
domain: www.fda.gov
url:
  http://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reportingsystem-faers/fda-adverse-event-reporting-system-faers-latest-quarterly-data-files


# bib

id: cord-024786-f33eb1nf
title: Current evidence for directed and supportive investigational therapies against COVID-19
author: van Rensburg, V
date: 2020-04-24
txt: ./txt/cord-024786-f33eb1nf.txt
cache: ./cache/cord-024786-f33eb1nf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221540/
doi: 10.7196/ajtccm.2020.v26i2.072
summary:
  Multiple trials across the globe are currently underway to assess the efficacy of CQ for the treatment and prevention of COVID-19, but no published, peer-reviewed results are available at the time of writing. [33] The rationale for the use of lopinavir/ritonavir (LPV/r) in COVID-19 stems from its in vitro activity against SARS-CoV-1, [34] as well as from a retrospective, multicentre cohort study evaluating LPV/r as early treatment in SARS-CoV-1, which demonstrated decreased mortality and intubation rates. [50] At the time of writing, there were no published peer-reviewed trials or case studies evaluating favipiravir in COVID-19, and its use is not currently recommended outside of clinical trials. A systematic review of treatment options in SARS-CoV-1 infection included corticosteroids'' effects on mortality, in vitro inhibition of SARS viral replication and acute respiratory distress syndrome. Drugs that purportedly inhibit SARS-CoV-2 replication (such as the investigational antivirals) or viral entry and replication (CQ and HCQ) may therefore be more effective when given earlier in the COVID-19 disease course.

abstract:
  Coronavirus disease 2019 (COVID-19) is a global health crisis. There is currently a great need for effective and safe therapies directed at the disease, but no drugs are presently registered for use in COVID-19. Several directed therapies have been proposed, and most are still in clinical trials. Currently available published, peer-reviewed results mostly involve small sample sizes with study limitations restricting the interpretation of the findings. Many trials currently published also do not have a control group, limiting the interpretation of the effect of the intervention. Investigational directed therapies as well as investigational supportive therapies against COVID-19 are reviewed here. Chloroquine and hydroxychloroquine show promise as directed therapies, but current trial results are conflicting. Lopinavir/ritonavir also shows potential, but was started late in the disease course in most trials. No randomised controlled evidence is currently available for remdesivir and favipiravir. Corticosteroid use is not recommended for directed therapy against COVID-19, and the role of tocilizumab is currently unclear, based on limited evidence. Early initiation of investigational directed therapies may provide benefit in selected patients. The results from larger randomised controlled trials will clarify the place of these therapies in COVID-19 treatment.


id: cord-026340-2nf97zvc
title: Chloroquine: A Potential Drug in the COVID-19 Scenario
author: Singh, Ranjana
date: 2020-06-07
txt: ./txt/cord-026340-2nf97zvc.txt
cache: ./cache/cord-026340-2nf97zvc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275976/
doi: 10.1007/s41403-020-00114-w
summary:
  In this review article, we have systematically searched for details of COVID-19 pandemic till May 2020 and assembled few data pertaining to (i) Corona viruses; (ii) SARS-CoV2, the virus that causes COVID-19'' and (iii) How chloroquine and hydroxychloroquine mediates anti-viral effect in both prophylactic and therapeutic setting. The Corona Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV) after assessing the etiological agent named it SARS-CoV2 (Severe Acute Respiratory Syndrome Corona Virus2) and the disease outbreak as COVID-19 (Corona Virus Disease-Year of Identification). During COVID-19, SARS-CoV2 S-protein binds to host cell''s receptor ACE2 (Belouzard et al. As for the case of SARS-CoV, it was shown that the binding specificity of virus to host cell was due to 3 prime amino acid residues in S1 protein at positions 360, 479, and 487.

abstract:
  Today, the whole world is fighting a public health emergency called ‘COVID-19’ caused by a new infectious virus called SARS-CoV2. Any person can catch COVID-19 from an infected person via aerosol droplets when the person coughs, sneezes, or speaks. To limit such a transmission, World Health Organization (WHO) has recommended people to wear masks and physically distance themselves by staying at least 1 m (3 feet) away from others. As aerosol droplets (by cough or sneeze) land on objects and surfaces around the person such as tables, doorknobs and handrails, and remain active on these surfaces for hours to days, people are advised to use soaps for at least 20 s. and alcohol-based sanitizers as well. As the public made efforts, clinicians and researchers investigated and found that drugs which were initially used to treat other diseases may work as a treatment option for COVID-19. One of those drugs was Chloroquine and its related derivative called hydroxychloroquine. In this review article, we have systematically searched for details of COVID-19 pandemic till May 2020 and assembled few data pertaining to (i) Corona viruses; (ii) SARS-CoV2, the virus that causes COVID-19’ and (iii) How chloroquine and hydroxychloroquine mediates anti-viral effect in both prophylactic and therapeutic setting. These data have been acquired mostly from PubMed and websites of WHO and Indian Council for Medical Research (ICMR). We did a systematic search and found that the properties of chloroquine are very much essential for the COVID-19 scenario. We also bring to you some evidence that the anti-lysosomal activity of chloroquine may be increased by botanicals like betulinic acid.


id: cord-026811-6bdzut3d
title: Emerging Treatment and Prevention Strategies against COVID-19: A Brief Update
author: Jha, Ashish K.
date: 2020-05-16
txt: ./txt/cord-026811-6bdzut3d.txt
cache: ./cache/cord-026811-6bdzut3d.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295303/
doi: 10.1055/s-0040-1712547
summary:
  We have highlighted here the potential therapeutic role of remdesivir, chloroquine/ hydroxychloroquine (HCQ), lopinavir/ritonavir, and convalescent plasma in patients with SARS-CoV-2 infection. However, interpretation of the result of this study is limited by the lack of a randomized control group, small sample size, exclusion of serious cases (creatinine clearance <30 mL/min and >five-time elevation of serum aminotransferase), variable duration of remdesivir administration, noncollection of viral load data, adverse effects, and short-term follow-up. Early results obtained from more than 100 patients enrolled in studies conducted in the China showed the superiority of chloroquine compared with the controls in terms of reduction of exacerbation of pneumonia, duration of symptoms, and delay of viral clearance, all in the absence of severe side effects. A systematic review and exploratory meta-analysis from 32 studies of SARS coronavirus infection and severe influenza showed a statistically significant reduction in the pooled odds of mortality following treatment with convalescent plasma compared with placebo (odds ratio = 0.25; 95% confidence interval [CI]:0.14-0.45; I[2] = 0%).

abstract:
  Patients with novel coronavirus disease 2019 (COVID-19) are at significantly increased risk for mortality and morbidity. Current management remains supportive care, ranging from symptomatic outpatient management to full–intensive care support, including intravenous fluids, invasive, and non-invasive oxygen supplementation. In patients with septic shock, treatment with antibiotics and vasopressors are recommended to keep mean arterial pressure (MAP) ≥ 65 mm Hg and lactate < 2 mmol/L. Because of the lack of effectiveness and possible adverse effects, routine corticosteroids should be avoided unless they are indicated for another reason (exacerbation of asthma or chronic obstructive pulmonary disease [COPD], and septic shock in whom fluids and vasopressors do not restore hemodynamic stability). There is currently no sufficient evidence of efficacy of hydroxychloroquine/chloroquine, remdesivir, and other antivirals in the treatment or prevention of COVID-19. Limited evidence shows that COVID-19 convalescent plasma can be used as a treatment of COVID-19 without the occurrence of severe adverse events. Drug regulatory agencies granted an emergency-use authorization of chloroquine/hydroxychloroquine and remdesivir to treat patients when a clinical trial is not available or participation is not feasible. Chloroquine and hydroxychloroquine are associated with QT interval prolongation and life-threatening cardiac arrhythmia in patients with pre-existing cardiovascular disease. Guidelines are issued for use of convalescent plasma in patients with serious or immediately life-threatening COVID-19. Data from several ongoing randomized controlled trials will provide further evidence regarding the safety and efficacy of these drugs for the treatment of COVID-19.


id: cord-028530-hpgrbhkl
author: Cairoli, Ernesto
date: 2020-07-04
txt: ./txt/cord-028530-hpgrbhkl.txt
cache: ./cache/cord-028530-hpgrbhkl.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334972/
doi: 10.1016/j.medcle.2020.05.003
abstract: nan
summary:
  Hydroxychloroquine in the treatment of COVID-19: how to use it waiting for conclusive scientific evidence Autores: Ernesto Cairoli MD, PhD a, b , Gerard Espinosa MD, PhD c . In the COVID-19 patient, possible cardiac involvement is mainly related to 4 factors: 1) underlying heart disease (often silent in older patients); 2) myocardial involvement caused by the infection and the inflammatory response itself, which leads to myocarditis with elevated troponins; 3) acute toxicity probably associated with the use of antimalarials in high doses, more evident in chloroquine treatments and 4) concomitant use of other treatments that, together with HCQ, prolong the corrected QT interval (QTc), with the risk of serious ventricular arrhythmias 3-5 . -Pending the result of several active studies, HCQ should not be indicated prophylactically as there is no evidence to support its preventive use or postexposure to avoid COVID-19 infection.

title:
  Hydroxychloroquine in the treatment of COVID-19: how to use it waiting for conclusive scientific evidence()


id: cord-029882-kufs0fxe
title: The continued dilemma about usage of Hydroxychloroquine: Respite is in randomized control trials
author: Malviya, Amit
date: 2020-07-29
txt: ./txt/cord-029882-kufs0fxe.txt
cache: ./cache/cord-029882-kufs0fxe.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388893/
doi: 10.1016/j.ijid.2020.07.054
abstract: nan
summary:
  HCQ is touted for treatment of Covid 19 primarily based on its anti-viral properties, thus the timing of administration becomes very important for a meaning full assessment of study results. Recently it been shown that this score is not accurate for predicting severity of disease in Covid 19 patients . Covid 19 is a multisystem disease and the disease itself promotes proarrhythmic milieu with prolonged QT intervals at baseline .5,6 Risk assessment of HCQ therapy is not complete if such patients are excluded. Finally , mechanism of action of HCQ against is a part of its broad anti-viral and immunomodulatory properties and no specific pharmacologic actions are described for SARS-CoV-2 infection. 9,10 Weather HCQ as initial anti-viral agent prevents progression to severe disease is not known clearly . Ventricular arrhythmia risk due to chloroquine / hydroxychloroquine treatment for COVID-19: Should it be given Effects of chloroquine on viral infections: an old drug against today''s diseases?


id: cord-031079-9lxhvyyb
author: Chen, Li
date: 2020-07-27
txt: ./txt/cord-031079-9lxhvyyb.txt
cache: ./cache/cord-031079-9lxhvyyb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454642/
doi: 10.1093/function/zqaa012
summary:
  CQ and HCQ may be potential inhibitors of SARS-CoV-2 entry into host cells, which is mediated via the angiotensin-converting enzyme 2 (ACE2), and may also inhibit subsequent intracellular processes which lead to COVID-19, including damage to the cardiovascular system. CQ and HCQ could potentially be useful drugs in the treatment of COVID-19 and other ACE2 involved virus infections, but the antiviral effects of CQ and HCQ need to be tested in more well-designed clinical randomized studies and their actions on the cardiovascular system need to be further elucidated. CQ and its more soluble and less toxic metabolite HCQ are primarily used for prophylaxis and treatment of malaria, but they have also been reported to effectively inhibit the effects of certain viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N. 40, 41 Several studies have reported that 3% to 29% of COVID-19 patients develop acute respiratory distress syndrome (ARDS) which is a common complication and cause of death as a result of SARS-CoV-2 infection.

title:
  The effects of chloroquine and hydroxychloroquine on ACE2 related coronavirus pathology and the cardiovascular system: An evidence based review

abstract:
  The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a serious threat to global public health and there is currently no effective antiviral therapy. It has been suggested that Chloroquine (CQ) and hydroxychloroquine (HCQ), which were primarily employed as prophylaxis and treatment for malaria, could be used to treat COVID-19. CQ and HCQ may be potential inhibitors of SARS-CoV-2 entry into host cells, which is mediated via the angiotensin-converting enzyme 2 (ACE2), and may also inhibit subsequent intracellular processes which lead to COVID-19, including damage to the cardiovascular system. However, paradoxically, CQ and HCQ have also been reported to cause damage to the cardiovascular system. In this review, we provide a critical examination of the published evidence. CQ and HCQ could potentially be useful drugs in the treatment of COVID-19 and other ACE2 involved virus infections, but the antiviral effects of CQ and HCQ need to be tested in more well-designed clinical randomized studies and their actions on the cardiovascular system need to be further elucidated. However, even if it were to turn out that CQ and HCQ are not useful drugs in practice, further studies of their mechanism of action could be helpful in improving our understanding of COVID-19 pathology.


id: cord-253196-et1ekgdl
author: Yazdany, Jinoos
date: 2020-03-31
txt: ./txt/cord-253196-et1ekgdl.txt
cache: ./cache/cord-253196-et1ekgdl.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32232419/
doi: 10.7326/m20-1334
summary:
  Two medications often used for treatment of immune-mediated conditions, hydroxychloroquine and chloroquine, have recently attracted widespread interest as potential therapies for coronavirus disease 2019. The antimalarials hydroxychloroquine (HCQ) and chloroquine (CQ) have demonstrated antiviral activity against severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) in vitro and in small, poorly controlled or uncontrolled clinical studies (1) (2) (3) . Here, we try to provide guidance regarding clinical decision making both for patients with COVID-19 and those with immune-mediated conditions, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), and strategies to mitigate further harm to these patients. At this time of crisis, it is our ethical obligation as physicians and researchers to organize and refer patients to expedited, well-performed randomized trials that can clarify if, when, and for whom antimalarial medications are helpful in COVID-19. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19)

title:
  Use of Hydroxychloroquine and Chloroquine During the COVID-19 Pandemic: What Every Clinician Should Know

abstract:
  Two medications often used for treatment of immune-mediated conditions, hydroxychloroquine and chloroquine, have recently attracted widespread interest as potential therapies for coronavirus disease 2019. The authors of this commentary provide guidance for clinical decision making for patients with coronavirus disease 2019 as well as for patients with rheumatologic conditions, such as systemic lupus erythematosus and rheumatoid arthritis


id: cord-253513-zn87f1lk
author: Liu, Jia
date: 2020-03-18
txt: ./txt/cord-253513-zn87f1lk.txt
cache: ./cache/cord-253513-zn87f1lk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41421-020-0156-0
doi: 10.1038/s41421-020-0156-0
abstract: nan
summary:
  Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro Jia Liu 1 , Ruiyuan Cao 2 , Mingyue Xu 1,3 , Xi Wang 1 , Huanyu Zhang 1,3 , Hengrui Hu 1,3 , Yufeng Li 1,3 , Zhihong Hu 1 , Wu Zhong 2 and Manli Wang 1 Dear Editor, The outbreak of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2/2019-nCoV) poses a serious threat to global public health and local economies. To better compare the antiviral activity of CQ versus HCQ, the dose-response curves of the two compounds against SARS-CoV-2 were determined at four different multiplicities of infection (MOIs) by quantification of viral RNA copy numbers in the cell supernatant at 48 h post infection (p.i.). Time-of-addition experiment confirmed that HCQ effectively inhibited the entry step, as well as the post-entry stages of SARS-CoV-2, which was also found upon CQ treatment (Supplementary Fig. S2 ).

title:
  Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro


id: cord-253609-vi2fb43t
author: Gopinathannair, Rakesh
date: 2020-06-03
txt: ./txt/cord-253609-vi2fb43t.txt
cache: ./cache/cord-253609-vi2fb43t.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32494896/
doi: 10.1007/s10840-020-00789-9
summary:
  Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. To better understand the cardiac arrhythmic manifestations and treatment strategies employed in hospitalized COVID-19 patients through a worldwide cross-sectional survey of arrhythmia professionals. The major findings of this global survey include the following: (a) In hospitalized COVID-19 patients, EP professionals across the globe reported a wide variety of arrhythmic manifestations, with several reporting potentially life-threatening ventricular arrhythmias (sustained monomorphic VT, polymorphic VT/Torsade de Pointes, VT/VF arrest) as well as Fig. 3 Difference between US and non-US respondents regarding the percentage of hospitalized COVID-19 patients being treated with HCQ/chloroquine + azithromycin Fig. 2 Characteristics of bradyarrhythmias observed in hospitalized COVID-19 patients pulseless electrical activity.

title:
  COVID-19 and cardiac arrhythmias: a global perspective on arrhythmia characteristics and management strategies

abstract:
  BACKGROUND: Cardiovascular and arrhythmic events have been reported in hospitalized COVID-19 patients. However, arrhythmia manifestations and treatment strategies used in these patients have not been well-described. We sought to better understand the cardiac arrhythmic manifestations and treatment strategies in hospitalized COVID-19 patients through a worldwide cross-sectional survey. METHODS: The Heart Rhythm Society (HRS) sent an online survey (via SurveyMonkey) to electrophysiology (EP) professionals (physicians, scientists, and allied professionals) across the globe. The survey was active from March 27 to April 13, 2020. RESULTS: A total of 1197 respondents completed the survey with 50% of respondents from outside the USA, representing 76 countries and 6 continents. Of respondents, 905 (76%) reported having COVID-19-positive patients in their hospital. Atrial fibrillation was the most commonly reported tachyarrhythmia whereas severe sinus bradycardia and complete heart block were the most common bradyarrhythmias. Ventricular tachycardia/ventricular fibrillation arrest and pulseless electrical activity were reported by 4.8% and 5.6% of respondents, respectively. There were 140 of 631 (22.2%) respondents who reported using anticoagulation therapy in all COVID-19-positive patients who did not otherwise have an indication. One hundred fifty-five of 498 (31%) reported regular use of hydroxychloroquine/chloroquine (HCQ) + azithromycin (AZM); concomitant use of AZM was more common in the USA. Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. Amiodarone was the most common antiarrhythmic drug used for ventricular arrhythmia management. CONCLUSIONS: In this global survey of > 1100 EP professionals regarding hospitalized COVID-19 patients, a variety of arrhythmic manifestations were observed, ranging from benign to potentially life-threatening. Observed adverse events related to use of HCQ + AZM included prolonged QTc requiring drug discontinuation as well as Torsade de Pointes. Large prospective studies to better define arrhythmic manifestations as well as the safety of treatment strategies in COVID-19 patients are warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10840-020-00789-9) contains supplementary material, which is available to authorized users.


id: cord-255690-xc4bxin4
author: Rolain, Jean-Marc
date: 2007-07-16
txt: ./txt/cord-255690-xc4bxin4.txt
cache: ./cache/cord-255690-xc4bxin4.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0924857907002580
doi: 10.1016/j.ijantimicag.2007.05.015
summary:
  Here we review available in vitro and in vivo data on the effects of CQ/HCQ on bacterial, fungal and viral infections, with the concept that manipulation of the intracellular pH in cells and modification of glycosylation of proteins by lysosomotropic agents instead of antimicrobial compounds is a powerful approach as new therapeutic strategies for the prevention and therapeutic management of several infectious diseases, including some of great public health concern worldwide. Coxiella burnetii [5, 13] Histoplasma capsulatum [24] HIV [2, [29] [30] [31] [32] ] Tropheryma whipplei [7, 8] Cryptococcus neoformans [15, 25] SARS-CoV [33, 34] Legionella pneumophila [11] Paracoccidioides brasiliensis [26] Influenza viruses [35] [36] [37] [38] Francisella tularensis [12] Penicillium marneffei [15, 27] Flavivirus, including yellow fever virus [39] Mycobacterium tuberculosis [14] Aspergillus fumigatus [28] Rubella virus [ tetracycline and quinolone regimen for at least 4 years, with a high percentage of relapses [6] .

title:
  Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century

abstract:
  Chloroquine (CQ) and its hydroxyl analogue hydroxychloroquine (HCQ) are weak bases with a half-century long use as antimalarial agents. Apart from this antimalarial activity, CQ and HCQ have gained interest in the field of other infectious diseases. One of the most interesting mechanisms of action is that CQ leads to alkalinisation of acid vesicles that inhibit the growth of several intracellular bacteria and fungi. The proof of concept of this effect was first used to restore intracellular pH allowing antibiotic efficacy for Coxiella burnetii, the agent of Q fever, and doxycycline plus HCQ is now the reference treatment for chronic Q fever. There is also strong evidence of a similar effect in vitro against Tropheryma whipplei, the agent of Whipple's disease, and a clinical trial is in progress. Other bacteria and fungi multiply in an acidic environment and encouraging in vitro data suggest that this concept may be generalised for all intracellular organisms that multiply in an acidic environment. For viruses, CQ led to inhibition of uncoating and/or alteration of post-translational modifications of newly synthesised proteins, especially inhibition of glycosylation. These effects have been well described in vitro for many viruses, with human immunodeficiency virus (HIV) being the most studied. Preliminary in vivo clinical trials suggest that CQ alone or in combination with antiretroviral drugs might represent an interesting way to treat HIV infection. In conclusion, our review re-emphasises the paradigm that activities mediated by lysosomotropic agents may offer an interesting weapon to face present and future infectious diseases worldwide.


id: cord-256294-9gmn4fcj
author: Almazrou, Saja H.
date: 2020-10-01
txt: ./txt/cord-256294-9gmn4fcj.txt
cache: ./cache/cord-256294-9gmn4fcj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33020690/
doi: 10.1016/j.jsps.2020.09.019
summary:
  title: Comparing the impact of Hydroxychloroquine based regimens and standard treatment on COVID-19 patient outcomes: A retrospective cohort study Despite the recommendation to use HCQ in COVID-19 patients in the MOH protocol, no observational studies or RCTs that evaluate the efficacy of these drugs in the Saudi Arabian population have been published. Therefore, the objective of this observational study is to compare the effects of HCQ and standard care (SC) on length of hospital stay, ICU admission, and mechanical ventilation use among COVID-19 patients. Collected data included patients'' basic information (e.g. age, gender, nationality); medication prescribed; and information on hospitalization, cases requiring ICU care, and mechanical ventilation. Despite the shorter length of hospital stay and time in ICU among patients who received HCQ based treatment, as well as the smaller proportions of patients who needed ICU care and mechanical ventilation in this group, the results indicated no significant differences in these outcomes between the two cohorts.

title:
  Comparing the impact of Hydroxychloroquine based regimens and standard treatment on COVID-19 patient outcomes: A retrospective cohort study

abstract:
  Background Pharmacological treatments including antivirals (Lopinavir/Ritonavir), Immuno-modulatory and anti-inflammatory drugs including, Tocilizumab and Hydroxychloroquine (HCQ) has been widely investigated as a treatment for COVID-19. Despite the ongoing controversies, HCQ was recommended for managing mild to moderate cases in Saudi Arabia . However, to our knowledge, no previous studies have been conducted in Saudi Arabia to assess its effectiveness. Methods A hospital-based retrospective cohort study involving 161 patients with COVID-19 was conducted from March 1 to May 20, 2020. The study was conducted at Prince Mohammed bin Abdul Aziz Hospital (PMAH). The population included hospitalized adults (age ≥18 years) with laboratory-confirmed COVID-19. Each eligible patient was followed from the time of admission until the time of discharge. Patients were classified into two groups according to treatment type: in the HCQ group, patients were treated with HCQ; in the SC group, patients were treated with other antiviral or antibacterial treatments according to Ministry of Health (MOH) protocols The outcomes were hospitalization days, ICU admission, and the need for mechanical ventilation. We estimated the differences in hospital length of stay and time in the ICU between the HCQ group and the standard care (SC) group using a multivariate generalized linear regression. The differences in ICU admission and mechanical ventilation were compared via logistic regression. All models were adjusted for age and gender variables. Results A total of 161 patients fulfilled the inclusion criteria. Approximately 59% (n=95) received HCQ-based treatment, and 41% (n=66) received SC. Length of hospital stay and time in ICU in for patients who received HCQ based treatment was shorter than those who received SC. Similarly, there was less need for ICU admission and mechanical ventilation among patients who received HCQ based treatment compared with SC, (8.6% vs. 10.7 and 3.1% vs. 9.1%). However, the regression analysis showed no significant difference between the two groups in terms of patient outcomes. Conclusion HCQ had a modest effect on hospital length stay and days in ICU compared with SC. However, these results need to be interpreted with caution. Larger observational studies and RCTs that evaluate the efficacy of HCQ in COVID-19 patients in the Saudi population are urgently needed.


id: cord-257144-3q0un5rl
author: Giri, Allan
date: 2020-09-02
txt: ./txt/cord-257144-3q0un5rl.txt
cache: ./cache/cord-257144-3q0un5rl.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32884603/
doi: 10.1186/s41021-020-00164-0
summary:
  title: Mutagenic, Genotoxic and Immunomodulatory effects of Hydroxychloroquine and Chloroquine: a review to evaluate its potential to use as a prophylactic drug against COVID-19 Hydroxychloroquine (HCQ) and Chloroquine (CQ) are two anti-malarial drugs that are now being extensively used by front-line healthcare workers and other common people as a prophylactic drug against the Corona Virus Disease − 19 (COVID-19) in India and as well as in many parts of the world. Thus, we recognize the need to critically review the mutagenic, genotoxic, and immunomodulatory effects of these drugs, to find out whether it is safe to use as a prophylactic drug against COVID-19. Moreover, the potentials of these drugs as Fig. 5 Endosomal TLR 7 and 9 inhibition by HCQ and CQ: Mammalian Toll-like receptors (TLR) 7 and 9 initiate immune response when it encounters microbial nucleic acids (only shown here is a viral particle).

title:
  Mutagenic, Genotoxic and Immunomodulatory effects of Hydroxychloroquine and Chloroquine: a review to evaluate its potential to use as a prophylactic drug against COVID-19

abstract:
  Hydroxychloroquine (HCQ) and Chloroquine (CQ) are two anti-malarial drugs that are now being extensively used by front-line healthcare workers and other common people as a prophylactic drug against the Corona Virus Disease − 19 (COVID-19) in India and as well as in many parts of the world. While only a few in vitro studies have pointed to some efficacy of these drugs as a prophylactic against COVID-19, to date, there are no clinical studies that have established any clinical efficacy of these drugs as a prophylactic. These drugs are commonly used for the treatment of Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) because of its immunomodulatory effects. Previously, we have evaluated the genetic toxicology of different drugs and chemicals including antimalarial drug CQ both in vitro and in vivo. Thus, we recognize the need to critically review the mutagenic, genotoxic, and immunomodulatory effects of these drugs, to find out whether it is safe to use as a prophylactic drug against COVID-19. Existing literature suggests that CQ can induce mutagenic and genotoxic effects in multiple test systems and both the drugs have immunomodulatory effects. There was no data available to evaluate the mutagenicity and genotoxicity for HCQ. However, during metabolism about 60% of both the drugs remain unchanged and about 40% of the drugs are metabolized into two metabolites, desethylchloroquine and bisdesethylchloroquine by the action of the cytochrome P450 (CYP) enzymes in the liver. Both HCQ and CQ are immunomodulatory drugs and have the potential to suppress normal immune system activation. In this review, we have elucidated the mechanism of immunomodulation by both HCQ and CQ and highlighted the mutagenic and genotoxic effects from the available literature. This article is written with the sole objective that the reader will be able to recognize the adverse effects of these drugs when consumed by healthy individuals as a prophylactic. Current literature indicates that healthy individuals should refrain from the use of these drugs until further investigation.


id: cord-258684-lq4knxgf
author: Takano, Tomomi
date: 2020-05-24
txt: ./txt/cord-258684-lq4knxgf.txt
cache: ./cache/cord-258684-lq4knxgf.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3390/v12050576
doi: 10.3390/v12050576
summary:
  Hydroxychloroquine (HCQ) is a drug approved by several countries to treat malaria and immune-mediated diseases in humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2, dengue virus) have been confirmed. Interestingly, the combination of 100 μM of HCQ and 10(4) U/mL of recombinant feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral activity against type I FIPV infection. As shown in Figure 4 , type I FIPV replication was significantly inhibited by HCQ and rfIFN-ω, and the combination of these drugs strongly decreased the replication of virus. As shown in Figure 4 , type I FIPV replication was significantly inhibited by HCQ and rfIFN-ω, and the combination of these drugs strongly decreased the replication of virus. As shown in Figure 4 , type I FIPV replication was significantly inhibited by HCQ and rfIFN-ω, and the combination of these drugs strongly decreased the replication of virus.

title:
  Antiviral Effects of Hydroxychloroquine and Type I Interferon on In Vitro Fatal Feline Coronavirus Infection

abstract:
  Feline infectious peritonitis (FIP) is a viral disease with a high morbidity and mortality by the FIP virus (FIPV, virulent feline coronavirus). Several antiviral drugs for FIP have been identified, but many of these are expensive and not available in veterinary medicine. Hydroxychloroquine (HCQ) is a drug approved by several countries to treat malaria and immune-mediated diseases in humans, and its antiviral effects on other viral infections (e.g., SARS-CoV-2, dengue virus) have been confirmed. We investigated whether HCQ in association with interferon-ω (IFN-ω) is effective for FIPV in vitro. A total of 100 μM of HCQ significantly inhibited the replication of types I and II FIPV. Interestingly, the combination of 100 μM of HCQ and 10(4) U/mL of recombinant feline IFN-ω (rfIFN-ω, veterinary registered drug) increased its antiviral activity against type I FIPV infection. Our study suggested that HCQ and rfIFN-ω are applicable for treatment of FIP. Further clinical studies are needed to verify the combination of HCQ and rIFN-ω will be effective and safe treatment for cats with FIP.


id: cord-259663-fjvumaby
title: Side Effects of Chloroquine and Hydroxychloroquine on Skeletal Muscle: a Narrative Review
author: Carvalho, Alzira Alves de Siqueira
date: 2020-10-31
txt: ./txt/cord-259663-fjvumaby.txt
cache: ./cache/cord-259663-fjvumaby.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33163329/
doi: 10.1007/s40495-020-00243-4
summary:
  PURPOSE OF REVIEW: Concerning adverse neuromuscular effects, there are quite a few reports about the incidence and prevalence of chloroquine (CQ) and hydroxychloroquine (HCQ) myopathy. Currently, emerging therapies and repurposing of old drugs have been considered therapeutic strategies, including chloroquine (CQ) and hydroxychloroquine (HCQ) [1, 2] , both drugs showing activity against COVID-19 in vitro [3] ; however, the level of preclinical and clinical data is not strong and must be approved by a higher level of evidence [4, 5] . The rimmed vacuolar changes found in muscle have been considered the most representative aspect in muscle biopsies of patients with myopathy induced by antimalarials; however, the absence of these vacuoles in some cases does not exclude the diagnosis [25] . By contrast, Kalajian and Callen [55] did not find an association between elevated serum muscle enzymes and underlying antimalarial-induced myopathy in patients taking CQ or HCQ.

abstract:
  PURPOSE OF REVIEW: Concerning adverse neuromuscular effects, there are quite a few reports about the incidence and prevalence of chloroquine (CQ) and hydroxychloroquine (HCQ) myopathy. Given the above, I decided to explore the relationships of these drugs with skeletal muscle in an attempt to clarify how they affect the muscle now and in the future, as millions of people are using CQ and HCQ. RECENT FINDINGS: The literature review identified 28 publications about CQ/HCQ myopathy, totaling 56 patients, from 1963 to 2020. A compilation of all patients was carried out by computing demographic features, clinical aspects, laboratory exams, and clinical evolution. All articles but two represented a large series about incidence and prevalence of the myopathy. Fifty-nine percent used QC, mean daily dose was 393 mg per day, and mean duration of treatment was 37 months. The predominant underlying diseases were rheumatoid arthritis (42.8%) and lupus erythematosus (26.8%). Respiratory distress was present in 12.5% in patients with proximal muscle weakness (87.2%). Dysphagia and cervical and axial weakness were observed in a smaller percentage. Creatine kinase was elevated in 60.7%, and EMG showed a myopathic pattern in 54%. Muscle biopsy showed a vacuolar pattern in 53.7%, and curvilinear bodies (CB) were the predominant ultrastructural finding (86.8%). After drug withdrawal, 85.4% of patients improved, and 12.7% died from other causes than myopathy. SUMMARY: CQ and HCQ myopathy has been known for a long time, but the incidence is low, being described only with long-term use. The use of these drugs for a short period has not been reported, although a prolonged elimination half-life of these drugs actually exists.


id: cord-259957-temt8b6f
title: Hydroxychloroquine and “off-label” utilization in the treatment of oral conditions
author: Brown, Ronald
date: 2020-04-11
txt: ./txt/cord-259957-temt8b6f.txt
cache: ./cache/cord-259957-temt8b6f.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.oooo.2020.03.047
doi: 10.1016/j.oooo.2020.03.047
abstract: nan
summary:
  Both drugs are approved to treat malaria, lupus, and rheumatoid arthritis but must still be assessed in clinical trials before being declared a safe and effective COVID-19 treatment. However, it is utilized extensively by both physicians and dentists (oral medicine clinicians) in the treatment of rheumatologic conditions, such as systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis, chronic ulcerative stomatitis, immune thrombocytopenia purpura, lichen planopilaris, and oral lichen planus. Therefore, there appears to be the possibility of additive drug interactions when prescribing HCQ to patients already taking citalopram and other drugs that significantly prolong the QT duration and increase the risk of a torsade de pointes arrhythmia. However, oral medicine clinicians and other health care providers should be advised of the potential issues with the use of HCQ, such as drugÀdrug interactions, the additive toxicity of QT duration prolongation, and the association with sudden death, in the treatment of older patients.


id: cord-260857-oxxle915
author: Samuel, Sharmeen
date: 2020-07-01
txt: ./txt/cord-260857-oxxle915.txt
cache: ./cache/cord-260857-oxxle915.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1547527120306329?v=s5
doi: 10.1016/j.hrthm.2020.06.033
summary:
  BACKGROUND: There is limited data regarding the electrophysiological abnormalities and arrhythmias in children with COVID-19, including those associated with treatment using potentially pro-arrhythmic Hydroxychloroquine (HCQ) and Azithromycin (AZN). Additionally, some of the medications that have been used for treatment of COVID-19 infection, such as Hydroxychloroquine (HCQ) and Azithromycin (AZN), are known to cause corrected QT (QTc) interval prolongation, therefore potentially predisposing patients to malignant ventricular arrhythmia.s 6, 7 However, there is little current data on the electrophysiologic consequences of these drugs in the setting of active COVID-19 in pediatric patients. As per hospital protocol, COVID-19 specific medications including HCQ with or without AZN were initiated at the discretion of the Infectious Disease team for patients needing supplemental oxygen for hypoxia in the setting of positive SARS-CoV-2, if the baseline QTc was less than 480 milliseconds (msec) measured on lead II via 15 lead ECG or telemetry.

title:
  INCIDENCE OF ARRHYTHMIAS AND ELECTROCARDIOGRAPHIC ABNORMALITIES IN SYMPTOMATIC PEDIATRIC PATIENTS WITH PCR POSITIVE SARS-CoV-2 INFECTION INCLUDING DRUG INDUCED CHANGES IN THE CORRECTED QT INTERVAL (QTc).

abstract:
  BACKGROUND: There is limited data regarding the electrophysiological abnormalities and arrhythmias in children with COVID-19, including those associated with treatment using potentially pro-arrhythmic Hydroxychloroquine (HCQ) and Azithromycin (AZN). OBJECTIVES: To describe the electrophysiologic findings and arrhythmias associated with pediatric COVID-19 and its treatment. METHODS: A single center retrospective chart review was undertaken and included all patients with 1) symptoms of COVID-19, and 2) PCR (+) nasopharyngeal swabs for SARS-CoV-2 who were placed on continuous telemetry for the duration of their hospitalization during March through May, 2020. RESULTS: Thirty-six patients were included in the study. Significant arrhythmias were found in 6 (non-sustained (ns) ventricular tachycardia in 5 and sustained atrial tachycardia in 1). All were self-resolving and half prompted prophylactic anti-arrhythmic therapy. Patients with significant arrhythmias were likely to have non-cardiac co-morbidities (4/6), but these were not more common than in patients without arrhythmias (20/30, p=1). The use of HCQ with or without AZN was associated with statistically significant QTc prolongation (411+19 msec vs 426+15 msec, p<0.0001). QTc was not statistically different in patients with and without arrhythmias (425+15 msec vs 425+15 msec, p=1). CONCLUSIONS: In pediatric patients with PCR positive active COVID-19 infection, significant arrhythmias are infrequent, but more common than expected in a general pediatric population. Comorbidities are not more common in patients with arrhythmias than in patients without arrhythmias. COVID-19 treatment using HCQ is associated with QTc prolongation, but was not associated with arrhythmias in pediatric patients.


id: cord-261186-4p1cwb2e
author: Guzman-Prado, Yuli
date: 2020-06-09
url: https://www.sciencedirect.com/science/article/pii/S0002914920305592?v=s5
doi: 10.1016/j.amjcard.2020.06.003
abstract: nan
title:
  Recent findings on cardiovascular safety with the use of chloroquine and hydroxychloroquine for COVID-19.


id: cord-262193-p7foay4k
author: Ahmad, I.
date: 2020-05-22
txt: ./txt/cord-262193-p7foay4k.txt
cache: ./cache/cord-262193-p7foay4k.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.05.18.20066902v1?rss=1
doi: 10.1101/2020.05.18.20066902
summary:
  title: Doxycycline and Hydroxychloroquine as Treatment for High-Risk COVID-19 Patients: Experience from Case Series of 54 Patients in Long-Term Care Facilities The effectiveness of doxycycline (DOXY) and hydroxychloroquine (HCQ) combination therapy in high risk COVID-19 patients in long-term care facilities is not yet understood. Results: A series of fifty-four (54) high-risk patients, who developed a sudden onset of fever, cough, and shortness of breath (SOB) and were diagnosed or presumed to have COVID-19, were started with a combination of DOXY-HCQ and 85% (n=46) patients showed clinical recovery defined as: resolution of fever and SOB, or a return to baseline setting if patients are ventilator-dependent. From March 19 to March 30, 2020, we analyzed the clinical outcomes of fifty-four (54) high-risk patients who developed a sudden onset of fever, cough, and SOB, were diagnosed or presumed to have COVID-19, and were treated with DOXY (100 mg PO BID for 7 days) and HCQ (two regimens: i) 200 mg PO TID for 7 days or ii) 400 mg PO BID one day, then 400 mg daily for 6 days).

title:
  Doxycycline and Hydroxychloroquine as Treatment for High-Risk COVID-19 Patients: Experience from Case Series of 54 Patients in Long-Term Care Facilities

abstract:
  Importance: Patients in long-term care facilities (LTCF) are at a high-risk of contracting COVID-19 due to advanced age and multiple comorbidities. Without effective treatments, outbreaks in such facilities will become commonplace and will result in severe morbidity and mortality. The effectiveness of doxycycline (DOXY) and hydroxychloroquine (HCQ) combination therapy in high risk COVID-19 patients in long-term care facilities is not yet understood. Objective: The goal of this analysis is to describe outcomes after use of DOXY-HCQ combination in high-risk COVID-19 patients in LTCF. Design: Case-series analysis. Setting: Three (3) LTCFs in New York. Participants: From March 19 to March 30, 2020, fifty-four (54) patients, residents of three (3) LTCFs in New York and diagnosed (confirmed or presumed) with COVID-19, were included in this analysis. Exposure: All patients who were diagnosed (confirmed or presumed) with COVID-19 received DOXY-HCQ combination therapy along with standard of care. Main Outcomes and Measures: Patients characteristics, clinical recovery, radiological improvements, medication side-effects, hospital transfer, and death were assessed as outcome measures. Results: A series of fifty-four (54) high-risk patients, who developed a sudden onset of fever, cough, and shortness of breath (SOB) and were diagnosed or presumed to have COVID-19, were started with a combination of DOXY-HCQ and 85% (n=46) patients showed clinical recovery defined as: resolution of fever and SOB, or a return to baseline setting if patients are ventilator-dependent. A total of 11% (n=6) patients were transferred to acute care hospitals due to clinical deterioration and 6% (n=3) patients died in the facilities. Naive Indirect Comparison suggests these data were significantly better outcomes than the data reported in MMWR (reported on March 26, 2020) from a long-term care facility in King County, Washington where 57% patients were hospitalized, and 22% patients died. Conclusion: The clinical experience of this case series indicates DOXY-HCQ treatment in high-risk COVID-19 patients is associated with a reduction in clinical recovery, decreased transfer to hospital and decreased mortality were observed after treatment with DOXY-HCQ.


id: cord-262454-bccrvapy
author: Szente Fonseca, Silvia Nunes
date: 2020-10-31
url: https://www.sciencedirect.com/science/article/pii/S1477893920304026?v=s5
doi: 10.1016/j.tmaid.2020.101906
title:
  Risk of Hospitalization for Covid-19 Outpatients Treated with Various Drug Regimens in Brazil: Comparative Analysis

abstract:
  BACKGROUND: For the past few months, HMOs have faced crowded emergency rooms and insufficient hospital and intensive-care-unit beds, all from the worst pandemic of this century, COVID-19. METHODS: In a large HMO in Brazil, our approach was to allow treating physicians to prescribe antiviral medications immediately at presentation, and prednisone starting on day-6 of symptoms to treat pulmonary inflammation. We implemented this COVID-19 protocol for outpatients and studied 717 consecutive SARS-CoV-2-positive patients age 40 years or older presenting at our emergency rooms. RESULTS: Use of hydroxychloroquine (HCQ), prednisone or both significantly reduced hospitalization risk by 50-60%. Ivermectin, azithromycin and oseltamivir did not substantially reduce risk further. Hospitalization risk was doubled for people with type-2 diabetes or obesity, increased by two-thirds for people with heart disease, and by 75% for each decade of age over age 40. Similar magnitudes of reduced risk with HCQ and prednisone use were seen for mortality risk, though were not significant because of only 11 deaths among the 717 patients. No cardiac arrhythmias requiring medication termination were observed for any of the medications. CONCLUSIONS: This work adds to the growing literature of studies that have found substantial benefit for use of HCQ combined with other agents in the early outpatient treatment of COVID-19, and adds the possibility of steroid use to enhance treatment efficacy.


id: cord-262467-epqqd8n8
title: COVID-19 infection: the China and Italy perspectives
author: Chen, Jun
date: 2020-06-08
txt: ./txt/cord-262467-epqqd8n8.txt
cache: ./cache/cord-262467-epqqd8n8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32513951/
doi: 10.1038/s41419-020-2603-0
summary:
  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 disease as originally shown in Wuhan, China, as early as documented from 1 December 2019 (ref. A recent prospective study failed to find antiviral activity or clinical benefit of this combination for the treatment of our hospitalized patients with severe COVID-19 (ref. More recently, a randomized, controlled study conducted in Wuhan, China also failed to identify beneficial effect of LPV/r beyond standard therapy in hospitalized patients with severe Covid-19 (ref. Clinical trials also showed that in patients with severe H1N1 influenza A, in the 2009 pandemic, therapy with convalescent plasma from patients who recovered, especially within 5 days of symptom onset, resulted in a lower viral load and lower mortality 66, 67 . The duration from onset of symptoms to viral clearance is significantly longer in severe and critical ill SARS-CoV-2infected patients compared with that in the mild cases 48 .

abstract:
  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Since its first report in December 2019, despite great efforts made in almost every country worldwide, this disease continues to spread globally, especially in most parts of Europe, Iran, and the United States. Here, we update the recent understanding in clinical characteristics, diagnosis strategies, as well as clinical management of COVID-19 in China as compared to Italy, with the purpose to integrate the China experience with the global efforts to outline references for prevention, basic research, treatment as well as final control of the disease. Being the first two countries we feel appropriate to evaluate the evolution of the disease as well as the early result of the treatment, in order to offer a different baseline to other countries. It is also interesting to compare two countries, with a very significant difference in population, where the morbidity and mortality has been so different, and unrelated to the size of the country.


id: cord-262780-ilu5oskk
author: Sattui, Sebastian E.
date: 2020-08-11
txt: ./txt/cord-262780-ilu5oskk.txt
cache: ./cache/cord-262780-ilu5oskk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1080/1744666x.2020.1792778
doi: 10.1080/1744666x.2020.1792778
summary:
  The use of chloroquine (CQ) and hydroxychloroquine (HCQ) for COVID-19 exemplifies the risks of both overinterpreting and amplifying preliminary data by those outside of the scientific community and was followed by swift corrective measures by researchers. By early March, interest in HCQ abruptly transitioned from mechanistic plausibility that would support its study in a clinical trial setting to rapid off-label use in patients with COVID-19, primarily fueled by promotion on social media, lay press, and celebrity influence [8] . By late March, two new studies became publicly available: a second study from the group of IHU-Méditerranée Infection using HCQ and AZM in 80 patients with mild COVID-19 infection released on their webpage, and a preprint of the first randomized controlled trial of 62 patients from Wuhan reporting a difference in clinical time to recovery and radiologic findings with HCQ treatment [22, 23] .

title:
  Swinging the pendulum: lessons learned from public discourse concerning hydroxychloroquine and COVID-19

abstract:
  INTRODUCTION: Several months into the COVID-19 pandemic, safe and effective treatments against this global health disaster have yet to be identified. Clinical research trials around the world are underway testing a wide array of possible medications. In particular, the off-label use of hydroxychloroquine for COVID-19 prophylaxis and treatment has created many unprecedented challenges for the scientific community and the public. AREAS COVERED: We critically assessed major events from February – May 2020 that contributed to widespread use of hydroxychloroquine for the treatment and prophylaxis of COVID-19. We aimed to explore how opinions toward hydroxychloroquine may shift from early enthusiasm (based on in vitro and preliminary clinical data) to the hope for a miracle cure (through communication and promotion of questionable results) and, finally, to a rise of skepticism as more in-depth analyses are emerging. EXPERT OPINION: Mindful and rigorous acquisition of data, as well as its interpretation, are essential to an effective pandemic response. The rapid and premature promotion of results has had major implications for global crisis management, even creating distrust among the public. It is crucial for the medical and scientific community to incorporate the lessons learned from this situation.


id: cord-267762-mzon01fd
title: Chronic treatment with hydroxychloroquine and SARS-CoV-2 infection.
author: Ferreira, A.
date: 2020-06-29
txt: ./txt/cord-267762-mzon01fd.txt
cache: ./cache/cord-267762-mzon01fd.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.06.26.20056507v1?rss=1
doi: 10.1101/2020.06.26.20056507
summary:
  Methods: By analyzing the Portuguese anonymized data on private and public based medical prescriptions we have identified all cases chronically receiving HCQ for the management of diseases such as systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases of SARS-CoV-2 infection with laboratory confirmed negative cases. Several in vitro studies have shown chloroquine phosphate and hydroxychloroquine sulphate (HCQ) to be effective in both preventing and treating SARS-CoV-2 infection in isolated cells (1) (2) (3) . By analyzing these sets of data, we were able to detect all patients with SARS-CoV-2 confirmed infections and all clinically suspected but non-confirmed patients between Mars 2, 2020 (the date of the first Portuguese case) and the moment of the analysis. The proportion of HCQ chronic treatment was higher in negative patients is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

abstract:
  Background: Hydroxychloroquine sulphate (HCQ) is being scrutinized for repositioning in the treatment and prevention of SARS-Cov-2 infection. This antimalarial drug is also chronically used to treat patients with autoimmune diseases. Methods: By analyzing the Portuguese anonymized data on private and public based medical prescriptions we have identified all cases chronically receiving HCQ for the management of diseases such as systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. Additionally, we have detected all laboratory confirmed cases of SARS-CoV-2 infection and all laboratory confirmed negative cases in the Portuguese population (mandatorily registered in a centrally managed database). Cross linking the two sets of data has allowed us to compare the proportion of HCQ chronic treatment (at least 2 grams per month) in laboratory confirmed cases of SARS-CoV-2 infection with laboratory confirmed negative cases. Results: Out of 26,815 SARS-CoV-2 positive patients, 77 (0.29%) were chronically treated with HCQ, while 1,215 (0.36%) out of 333,489 negative patients were receiving it chronically (P=0.04). After adjustment for age, sex, and chronic treatment with corticosteroids and/or immunosuppressants, the odds ratio of SARS-CoV-2 infection for chronic treatment with HCQ has been 0.51 (0.37-0.70). Conclusions: Our data suggest that chronic treatment with HCQ confer protection against SARS-CoV-2 infection.


id: cord-268425-xg8xnjf9
author: DiNicolantonio, James J.
date: 2020-07-02
url: https://api.elsevier.com/content/article/pii/S0306987720317382
doi: 10.1016/j.mehy.2020.110051
title:
  Harnessing Adenosine A2A Receptors as a Strategy for Suppressing the Lung Inflammation and Thrombotic Complications of COVID-19: Potential of Pentoxifylline and Dipyridamole

abstract:
  Counterproductive lung inflammation and dysregulated thrombosis contribute importantly to the lethality of advanced COVID-19. Adenosine A2A receptors (A2AR), expressed by a wide range of immune cells, as well as endothelial cells and platelets, exert cAMP-mediated anti-inflammatory and anti-thrombotic effects that potentially could be highly protective in this regard. The venerable drug pentoxifylline (PTX) exerts both anti-inflammatory and antithrombotic effects that reflect its ability to boost the responsiveness of A2AR to extracellular adenosine. The platelet-stabilizing drug dipyridamole (DIP) blocks intracellular uptake of extracellularly-generated adenosine, thereby up-regulating A2AR signaling in a way that should be functionally complementary to the impact of PTX in that regard. Moreover, DIP has recently been reported to slow the cellular replication of SARS-CoV-2 in clinically feasible concentrations. Both PTX and DIP are reasonably safe, well-tolerated, widely available, and inexpensive drugs. When COVID-19 patients can be treated within several days of symptom onset, using PTX + DIP in conjunction with hydroxychloroquine (HCQ) and an antibiotic - azithromycin (AZM) or doxycycline – might be warranted. HCQ and AZM can suppress SARS-CoV-2 proliferation in vitro and may slow the cell-to-cell spread of the virus; a large case series evaluating this combination in early-stage patients reported an impressively low mortality rate. However, whereas HCQ and AZM can promote QT interval lengthening and may be contraindicated in more advanced COVID-19 entailing cardiac damage, doxycycline has no such effect and exerts a potentially beneficial anti-inflammatory action. In contrast to HCQ, we propose that the combination of PTX + DIP can be used in both early and advanced stages of COVID-19. Concurrent use of certain nutraceuticals – yeast beta-glucan, zinc, vitamin D, spirulina, phase 2 inducers, N-acetylcysteine, glucosamine, quercetin, and magnesium – might also improve therapeutic outcomes in COVID-19.


id: cord-268453-87b298uk
title: Hydroxychloroquine and chloroquine in COVID-19: should they be used as standard therapy?
author: Ibáñez, Sebastián
date: 2020-06-03
txt: ./txt/cord-268453-87b298uk.txt
cache: ./cache/cord-268453-87b298uk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32495226/
doi: 10.1007/s10067-020-05202-4
summary:
  In the absence of a vaccine and specifically designed antivirals, the medical community has proposed the use of various previously available medications in order to reduce the number of patients requiring prolonged hospitalizations, oxygen therapy, and mechanical ventilation and to decrease mortality from coronavirus disease 2019 (COVID-19). HCQ was, in vitro, at least as effective as chloroquine in inhibiting SARS-CoV-2 infection, although it should be noted that studies on its mechanisms of action are not as extensive as with CQ [30] . The evidence for the use of hydroxychloroquine or chloroquine in COVID-19 is not good so far, not only because of the negative results of most of the studies but also because of their design, when publishing results of a very low number of patients, when reporting favorable results but without having a control group that allows comparison, when choosing results for which it will be very difficult to find significant differences, such as mortality, or for which their clinical relevance is uncertain.

abstract:
  The pandemic of the new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has urged the nations to an unprecedented world-wide reaction, including an accelerated exploration of therapeutic options. In the absence of a vaccine and specifically designed antivirals, the medical community has proposed the use of various previously available medications in order to reduce the number of patients requiring prolonged hospitalizations, oxygen therapy, and mechanical ventilation and to decrease mortality from coronavirus disease 2019 (COVID-19). Hydroxychloroquine and chloroquine are among the proposed drugs and are the most widely used so far, despite the lack of robust evidence on their usefulness. The objective of this article is to review and discuss the possible role of these drugs in the therapy of COVID-19.


id: cord-268519-t15yvy5s
author: Pothen, Lucie
date: 2020-06-12
txt: ./txt/cord-268519-t15yvy5s.txt
cache: ./cache/cord-268519-t15yvy5s.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S1477893920302787
doi: 10.1016/j.tmaid.2020.101788
abstract: nan
summary:
  title: Safety use of hydroxychloroquine and its combination with azithromycin in the context of Sars-CoV-2 outbreak: Clinical experience in a Belgian tertiary center Despite some encouraging preliminary clinical data (2,3), major concerns have been raised about the use of HCQ to treat COVID-19 (5), particularly regarding potential cardiac toxicity (i.e. QTc increase and risk of torsade de pointe). Repeat ECG was not systematically performed during HCQ treatment, except in case of drug-drug interaction which could potentially increase QTc (see foot note of Table1). The efficacy of HCQ and its combination with azithromycin on COVID-19 infection needs, of course, to be strengthened with further evidence from large randomized clinical trials. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study

title:
  Safety use of hydroxychloroquine and its combination with azithromycin in the context of Sars-CoV-2 outbreak: Clinical experience in a Belgian tertiary center


id: cord-270290-i4p4p0o4
title: Chloroquine and Hydroxychloroquine Retinal Toxicity Consideration in the Treatment of COVID-19
author: Ruamviboonsuk, Paisan
date: 2020-04-29
txt: ./txt/cord-270290-i4p4p0o4.txt
cache: ./cache/cord-270290-i4p4p0o4.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1097/apo.0000000000000289
doi: 10.1097/apo.0000000000000289
summary:
  The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. [6] [7] [8] [9] [10] [11] As the therapeutic doses of CQ and HCQ recommended in the trials and guidelines are relatively high compared with the maximum daily safe dose that is related to CQ and HCQ retinal toxicity, this issue of retinal toxicity should be taken into consideration when employing these 2 medications for treatment of COVID-19 worldwide. According to the recommendation by the American Academy of Ophthalmology, the most significant major risk factors for CQ and HCQ retinal toxicity are high dose and long duration of use.

abstract:
  The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. Irreversible retinal damage can occur if the exposure to the safe doses is >5 years. It is not known whether exposure to high doses over a short period of time can also cause the damage. We recommend that before prescribing CQ or HCQ, history of ocular disease should be obtained to avoid the prescription if appropriate. If either agent is to be used, routine baseline ocular examination is not absolutely necessary. Patients who do not have ocular disease should also be informed about the potential risk of retinal toxicity. Both agents, however, have not yet been proven to be beneficial to COVID-19.


id: cord-270723-cjfglili
title: QTc prolongation among hydroxychloroquine sulfate‐treated COVID‐19 patients: An observational study
author: Fteiha, Bashar
date: 2020-10-15
txt: ./txt/cord-270723-cjfglili.txt
cache: ./cache/cord-270723-cjfglili.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33063447/
doi: 10.1111/ijcp.13767
summary:
  Age > 65 years, congestive heart failure, severity of disease, C‐reactive protein level, hypokalemia and furosemide treatment, were all associated with QTc prolongation. CONCLUSION: In patients treated with HCQ, QTc prolongation was associated with the presence of traditional risk factors such as hypokalemia and furosemide treatment. All rights reserved Univariate analysis revealed that in COVID-19 patients treated with HCQ, age above 65 years, severe or critical illness, congestive heart failure, hypokalemia, furosemide treatment and increased CRP level were all significantly associated with the composite endpoint (Table 2) . However, multivariate analysis in this small dataset also suggested that in COVID-19 patients treated with HCQ, concomitant hypokalemia and furosemide treatment were strongly associated with QTc prolongation. In conclusion, our study shows that QTc prolongation among HCQ-treated patients was associated with traditional, modifiable risk factors such as hypokalemia and furosemide treatment which are both commonly observed in COVID-19 patients.

abstract:
  BACKGROUND: The liberal administration of hydroxychloroquine‐sulphate (HCQ) to COVID‐19 patients has raised concern regarding the risk of QTc prolongation and cardiac arrhythmias, particularly when prescribed with azithromycin. We evaluated the incidence of QTc prolongation among moderately and severely ill COVID‐19 patients treated with HCQ and of the existence of concomitant alternative causes. METHODS: All COVID‐19 patients treated with HCQ (between Mar 1 and Apr 14, 2020) in a tertiary medical center were included. Clinical characteristics and relevant risk factors were collected from the electronic medical records. Individual patient QTc intervals were determined before and after treatment with HCQ. The primary outcome measure sought was a composite endpoint comprised of either an increase ≥ 60 milliseconds (ms) in the QTc interval compared with pretreatment QTc, and/or a maximal QTc interval >500 ms. RESULTS: Ninety patients were included. Median age was 65 years (IQR 55‐75) and 57 (63%) were male. Thirty‐nine patients (43%) were severely or critically ill. Hypertension and obesity were common (n=23 each, 26%). QTc prolongation evolved in fourteen patients (16%). Age > 65 years, congestive heart failure, severity of disease, C‐reactive protein level, hypokalemia and furosemide treatment, were all associated with QTc prolongation. Adjusted analysis showed that QTc prolongation was five times more likely with hypokalemia [OR 5, (95% CI, 1.3‐20)], and three times more likely with furosemide treatment [ OR 3 (95% CI, 1.01‐13.7)]. CONCLUSION: In patients treated with HCQ, QTc prolongation was associated with the presence of traditional risk factors such as hypokalemia and furosemide treatment.


id: cord-272296-1gn1zhvt
title: Hydroxychloroquine early in Pregnancy and Risk of Birth Defects
author: HUYBRECHTS, Krista F.
date: 2020-09-19
txt: ./txt/cord-272296-1gn1zhvt.txt
cache: ./cache/cord-272296-1gn1zhvt.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0002937820310644
doi: 10.1016/j.ajog.2020.09.007
summary:
  We compared the risk of congenital malformations in women with HCQ use during the first trimester versus no use, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (N= 1,867 HCQ exposed; 19,080 unexposed pregnancies). [10] [11] [12] [13] However, data 134 regarding the risk of major congenital malformations associated with early pregnancy exposure 135 is very limited, with the largest published cohort study including fewer than 200 exposed 136 pregnancies (Supplementary Table 1 ). Utilizing data from health plans that provide coverage for large populations of both commercially 250 and publicly insured individuals in the US, we identified a cohort of pregnant women with 251 chronic autoimmune rheumatic diseases and assessed the relative prevalence of major 252 congenital malformations in their newborns following exposure to HCQ during early pregnancy.

abstract:
  Background Hydroxychloroquine (HCQ) is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to HCQ is important both in the context of its ongoing use for rheumatological disorders as well as its potential future use for COVID-19 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for COVID-19 treatment having been negative. Objective The study objective was to evaluate the risk of major congenital malformations associated with exposure to HCQ during the first trimester, the period of organogenesis. Study Design We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2,045 HCQ exposed and 3,198,589 unexposed pregnancies continuously enrolled in their respective insurance program from 3 months before the last menstrual period through at least one month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women with HCQ use during the first trimester versus no use, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (N= 1,867 HCQ exposed; 19,080 unexposed pregnancies). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery, and specific malformation types for which there were at least 5 exposed events: oral clefts, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects. Results Overall, 54.8 per 1,000 infants exposed to HCQ were born with a major congenital malformation versus 35.3 per 1,000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% CI, 1.27–1.81). Patient characteristics were balanced in the restricted, propensity score matched cohort. The adjusted relative risk was 1.26 (1.04–1.54); it was 1.33 (1.08-1.65) for a daily dose ≥400mg and 0.95 (0.60-1.50) for <400mg. Among the different malformation groups considered, more substantial increases in the risk for oral clefts, respiratory anomalies and urinary defects were observed, although estimates were imprecise. No pattern of malformations was identified. Conclusions Our findings suggest a small increase in the risk of malformations associated with first trimester HCQ use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If HCQ were shown to be effective for COVID-19 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.


id: cord-272419-y3ebt4jm
author: Monari, Caterina
date: 2020-08-09
url: https://www.ncbi.nlm.nih.gov/pubmed/32784922/
doi: 10.3390/life10080146
title:
  A Focus on the Nowadays Potential Antiviral Strategies in Early Phase of Coronavirus Disease 2019 (Covid-19): A Narrative Review

abstract:
  Background: The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the related disease (COVID-19) has rapidly spread to a pandemic proportion, increasing the demands on health systems for the containment and management of COVID-19. Nowadays, one of the critical issues still to be pointed out regards COVID-19 treatment regimens and timing: which drug, in which phase, for how long? Methods: Our narrative review, developed using MEDLINE and EMBASE, summarizes the main evidences in favor or against the current proposed treatment regimens for COVID-19, with a particular focus on antiviral agents. Results: Although many agents have been proposed as possible treatment, to date, any of the potential drugs against SARS-CoV-2 has shown to be safe and effective for treating COVID-19. Despite the lack of definitive evidence, remdesivir remains the only antiviral with encouraging effects in hospitalized patients with COVID-19. Conclusions: In such a complex moment of global health emergency, it is hard to demand scientific evidence. Nevertheless, randomized clinical trials aiming to identify effective and safe drugs against SARS-CoV-2 infection are urgently needed in order to confirm or reject the currently available evidence.


id: cord-274545-r03g7w0b
author: Ayele Mega, Teshale
date: 2020-10-13
txt: ./txt/cord-274545-r03g7w0b.txt
cache: ./cache/cord-274545-r03g7w0b.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33082891/
doi: 10.1155/2020/4312519
summary:
  In this open-label non-randomized clinical trial, a total of 20 patients were treated with HCQ at a dose of 200 mg three times daily for 10 days, and the data showed a significant reduction in viral carriage at day 6 post-inclusion compared to controls (70.0% clearance by day 6 vs. e outcomes assessed with double-arm studies include virologic efficacy [8, 20, 21] , clinical efficacy (mortality [4, 8, 13, 14, 30, 31] and disease progression [4, 8, 13, 14, 22, 31, 32] ), safety (risk of adverse effects) [8, [20] [21] [22] , and tolerability and QT prolongation [14, 26, 34] . e data from four controlled clinical trials [8, [20] [21] [22] of 278 COVID-19 patients (141 HCQ and 137 from the non-HCQ group) were included to assess overall adverse effects (except QTc prolongation) among HCQ-exposed patients.

title:
  The Outcome of Hydroxychloroquine in Patients Treated for COVID-19: Systematic Review and Meta-Analysis

abstract:
  BACKGROUND: The pandemic of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in an unprecedented public health challenge worldwide. Despite urgent and extensive global efforts, the existing evidence is inconclusive regarding the medications used for the treatment of COVID-19. PURPOSE: To generate an up-to-date evidence for the clinical safety and efficacy of hydroxychloroquine (HCQ) with or without azithromycin (AZ) among patients treated for COVID-19. Data Source. PubMed, Cochrane CENTRAL, LITCOVID, Web of Science, SCOPUS, BioRxiv, Embase, MedRxiv, and Wiley online library were searched from 2019/12/30 to 2020/05/23. Study Selection. Three investigators assessed the quality of the studies. Data Extraction. Data about study characteristics, effect estimates, and the quality of the studies were extracted by two independent reviewers and cross-checked by the third reviewer. Data Synthesis. The data of 6,782 (HCQ group, 3623; HCQ + AZ group, 1,020; control group, 2139) participants were included. HCQ was compared with standard care for virologic efficacy, disease progression, mortality, and adverse effects. HCQ was also compared with HCQ + AZ for QTc prolongation, admission to the intensive care unit, and mortality. The study found HCQ did not alter the rate of virologic cure (OR = 0.78; 95% CI: 0.39–1.56) and the risk of mortality (OR = 1.26; 95% CI: 0.66–2.39). The pooled prevalence for mortality was 5.8% (95% CI: 0.9%–10.8%). Moreover, HCQ did not impact disease progression (OR = 0.9; 95% CI: 0.36–2.29) but resulted in a higher risk of adverse effects (OR = 2.35; 95% CI: 1.15–4.8). HCQ was also compared against HCQ + AZ, and no difference was observed in QTc prolongation above 500 ms (OR = 1.11; 95% CI: 0.54–2.28), admission to the intensive care unit (OR = 0.92; 95% CI: 0.52–1.63), and mortality (OR = 0.88; 95% CI: 0.55–1.43). However, in the analysis of single-arm studies, about 11.2% (95% CI: 7.0%–15.5%) of patients have developed an absolute increase of QTc greater than 500 ms, and 4.1% (95% CI: 1.1%–7.1%) of patients discontinued their medication. CONCLUSION: This meta-analysis and systematic review, which included a limited number of poorly designed studies of patients with COVID-19, revealed HCQ is intolerable, unsafe, and not efficacious. Similarly, HCQ + AZ combination was not different from HCQ alone in curbing mortality and ICU admission.


id: cord-275037-sji0u8nu
title: Large-scale use of hydroxychloroquine for COVID-19 confirms safety, if not effectiveness
author: Cavalli, Giulio
date: 2020-10-28
txt: ./txt/cord-275037-sji0u8nu.txt
cache: ./cache/cord-275037-sji0u8nu.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S095362052030409X
doi: 10.1016/j.ejim.2020.10.023
abstract: nan
summary:
  In this issue of the Journal, Di Castelnuovo and colleagues report the findings of the observational multicentre Italian CORIST Study on the use of hydroxychloroquine (HCQ) in hospitalised COVID-19 patients [1] . While these findings may provide clinical evidence in support of the use of HCQ therapy in patients with COVID-19, the study findings ought to be considered with caution, in light of several limitations, which are inherent to the retrospective, observational design of this study. These include bias by indication (why did some patients receive HCQ in addition to standard management, whereas others did not?), a possible immortal time bias (patients who died before treatment administration tend to be included as controls in retrospective studies), and of the fact that residual confounders typically remain even after stringent propensity matching is applied (not all clinically relevant variables are included in or captured by covariate analyses). Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study GM-CSF blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation: a single-centre, prospective cohort study


id: cord-275041-fcdwitxy
title: The association of treatment with hydroxychloroquine and hospital mortality in COVID-19 patients
author: Ayerbe, Luis
date: 2020-09-30
txt: ./txt/cord-275041-fcdwitxy.txt
cache: ./cache/cord-275041-fcdwitxy.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32997237/
doi: 10.1007/s11739-020-02505-x
summary:
  The following variables were extracted for this study: age, gender, temperature, and saturation of oxygen on admission, treatment with hydroxychloroquine, azithromycin, heparin, steroids, tocilizumab, a combination of lopinavir with ritonavir, and oseltamivir, together with data on mortality. Using limited evidence and clinical experience, doctors have treated COVID-19 patients with different drugs to eliminate or reduce the presence of the virus, including hydroxychloroquine (HCQ) [9] [10] [11] [12] . The association between treatment with HCQ and mortality was examined with four different logistic regression models: model one was adjusted for age and gender; model two included age and gender, together with temperature > 37 °C, and saturation of oxygen < 90% on admission, which were both associated with mortality in an exploratory analysis; model three had all the variables previously mentioned together with treatment with azithromycin, steroids, heparin, tocilizumab, a combination of lopinavir with ritonavir, and oseltamivir; finally, to account for the change in clinical management during the study period, model four was adjusted for all the previously mentioned demographic, clinical severity measures, and drugs, together with a categorical variable for date of admission (before the 10th of March, 11-20th of March, 20-31st March, 1st-10th of April, and 11-20th of April).

abstract:
  This study investigates the association between the treatment with hydroxychloroquine and mortality in patients admitted with COVID-19. Routinely recorded, clinical data, up to the 24th of April 2020, from the 2075 patients with COVID-19, admitted in 17 hospitals in Spain between the 1st of March and the 20th of April 2020 were used. The following variables were extracted for this study: age, gender, temperature, and saturation of oxygen on admission, treatment with hydroxychloroquine, azithromycin, heparin, steroids, tocilizumab, a combination of lopinavir with ritonavir, and oseltamivir, together with data on mortality. Multivariable logistic regression models were used to investigate the associations. At the time of collecting the data, 301 patients had died, 1449 had been discharged home from the hospitals, 240 were still admitted, and 85 had been transferred to hospitals not included in the study. Median follow-up time was 8 (IQR 5–12) days. Hydroxychloroquine had been used in 1857 patients. Hydroxychloroquine was associated with lower mortality when the model was adjusted for age and gender, with OR (95% CI): 0.44 (0.29–0.67). This association remained significant when saturation of oxygen < 90% and temperature > 37 °C were added to de model with OR 0.45 (0.30–0.68) p < 0.001, and also when all the other drugs, and time of admission, were included as covariates. The association between hydroxychloroquine and lower mortality observed in this study can be acknowledged by clinicians in hospitals and in the community. Randomized-controlled trials to assess the causal effects of hydroxychloroquine in different therapeutic regimes are required.


id: cord-275340-q8d7rvnj
title: Advances in the use of chloroquine and hydroxychloroquine for the treatment of COVID-19
author: Sun, JingKang
date: 2020-06-21
txt: ./txt/cord-275340-q8d7rvnj.txt
cache: ./cache/cord-275340-q8d7rvnj.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1080/00325481.2020.1778982
doi: 10.1080/00325481.2020.1778982
summary:
  CQ/HCQ may synergistically exert antiviral and immunomodulatory effects on COVID-19 through multiple mechanisms including hindering the receptor recognition process by influencing the affinity of ACE2 and S protein, and the affinity for sialic acid and ganglioside; inhibiting the membrane fusion process by suppressing endolysosome acidification; suppressing the p38 activation and affecting host defense machinery, and preventing MHC class II expression (block expression of CD154 on the surface of CD4 + T cell) and TLR signaling and reducing the production of cytokines through inhibiting the activation of T cells and B cells. ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; CQ, chloroquine; HCQ, hydroxychloroquine; CoVs, coronaviruses; MAPK, mitogen-activated protein kinase; MHC-II, major histocompatibility complex class II; TLR, toll-like receptor; cGAS, cyclic GMP-AMP synthase; IFN, interferon; IL, interleukin; TNF-α, tumor necrosis factor-α. The authors deemed that the anti-inflammatory effect of low-dose HCQ and the activity of inhibiting viral replication may have important significance in critically ill patients with COVID-19.

abstract:
  Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading worldwide. Antiviral therapy is the most important treatment for COVID-19. Among the drugs under investigation, anti-malarials, chloroquine (CQ) and hydroxychloroquine (HCQ), are being repurposed as treatment for COVID-19. CQ/HCQ were shown to prevent receptor recognition by coronaviruses, inhibit endosome acidification, which interferes with membrane fusion, and exhibit immunomodulatory activity. These multiple mechanisms may work together to exert a therapeutic effect on COVID-19. A number of in vitro studies revealed inhibitory effects of CQ/HCQ on various coronaviruses, including SARS-CoV-2 although conflicting results exist. Several clinical studies showed that CQ/HCQ alone or in combination with a macrolide may alleviate the clinical symptoms of COVID-19, promote viral conversion, and delay disease progression, with less serious adverse effects. However, recent studies indicated that the use of CQ/HCQ, alone or in combination with a macrolide, did not show any favorable effect on patients with COVID-19. Adverse effects, including prolonged QT interval after taking CQ/HCQ, may develop in COVID-19 patients. Therefore, current data are not sufficient enough to support the use of CQ/HCQ as therapies for COVID-19 and increasing caution should be taken about the application of CQ/HCQ in COVID-19 before conclusive findings are obtained by well-designed, multi-center, randomized, controlled studies.


id: cord-277555-tsd6npma
title: The ‘president’s drug’
author: Wilde, A. A. M.
date: 2020-07-10
txt: ./txt/cord-277555-tsd6npma.txt
cache: ./cache/cord-277555-tsd6npma.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32651844/
doi: 10.1007/s12471-020-01441-x
abstract: nan
summary:
  Despite an unconfirmed efficacy and potential serious side-effects the presidents of France, Brazil and the United States subsequently publicly promoted the use of HCQ, resulting in an absolute run on HCQ, a shortage of the drug for patients with traditional indications, and a lively debate in the respective countries [1, 2] . In the study by van den Broek et al., 95 patients were treated with CQ (loading dose 600 mg, followed by 2 × 300 mg for 4 days; 22% of patients in the intensive care unit), which resulted in a mean QTc prolongation of 35 ms (95% confidence interval 28-43 ms) [15] . Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial Chloroquine-induced QTc prolongation in COVID-19 patients The risk for QTc interval prolongation in COVID-19 patients treated with chloroquine


id: cord-277916-b4yqek29
title: QT Interval and Arrhythmic Safety of Hydroxychloroquine Monotherapy in Coronavirus Disease 2019
author: Sridhar, Arun R.
date: 2020-06-11
url: https://www.sciencedirect.com/science/article/pii/S2666501820300751?v=s5
doi: 10.1016/j.hroo.2020.06.002
abstract:
  BACKGROUND: Observational studies have suggested increased arrhythmic and cardiovascular risk with the combination use of hydroxychloroquine (HCQ) and azithromycin in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE: The arrhythmic safety profile of HCQ monotherapy, which remains under investigation as a therapeutic and prophylactic agent in COVID-19, is less established and we sought to evaluate this. METHODS: In 245 consecutive patients with COVID-19 admitted to the University of Washington hospital system between March 9 and May 10, 2020, we identified 111 treated with HCQ monotherapy. Patients treated with HCQ underwent a systematic arrhythmia and QT interval surveillance protocol including serial electrocardiograms (ECG) (baseline, following second HCQ dose). The primary endpoint was in-hospital sustained ventricular arrhythmia or arrhythmic cardiac arrest. Secondary endpoints included clinically significant QTc prolongation. RESULTS: A total of 111 patients with COVID-19 underwent treatment with HCQ monotherapy (mean age 62±16 years, 44 women [39%], serum creatinine 0.9 [interquartile range 0.4] mg/dL). There were no instances of sustained ventricular arrythmia or arrhythmic cardiac arrest. In 75 patients with serial ECGs, clinically significant QTc prolongation was observed in a minority (N=5 [7%]). In patients with serial ECGs, there was no significant change in the QTc interval in pre-specified subgroups of interest, including those with prevalent cardiovascular disease or baseline use of renin-angiotensin-aldosterone axis inhibitors. CONCLUSION: In the context of a systematic monitoring protocol, HCQ monotherapy in hospitalized COVID-19 patients was not associated with malignant ventricular arrhythmia. A minority of patients demonstrated clinically significant QTc prolongation during HCQ therapy.


id: cord-278068-3kg71nf4
author: Chivese, T.
date: 2020-07-30
url: https://doi.org/10.1101/2020.07.28.20164012
doi: 10.1101/2020.07.28.20164012
title:
  A meta-review of systematic reviews and an updated meta-analysis on the efficacy of chloroquine and hydroxychloroquine in treating COVID19 infection

abstract:
  Abstract Background There is an urgent need for an efficacious and safe treatment for COVID19. Several trials testing a variety of therapeutics are on-going. Some in-vitro studies found the anti-malarial drug chloroquine (CQ), and its derivative, hydroxychloroquine (HCQ), are effective against COVID19. However, systematic reviews and meta-analyses of clinical trials in humans have produced conflicting findings on the efficacy and safety of these drugs. Guidelines vary considerably and are hotly debated at political and scientific levels. Therefore, it has become necessary to provide a summary of the effectiveness and safety of these drugs in treating COVID19 infection, using an overview of the existing systematic reviews and meta-analyses. Objective To synthesize the findings presented in systematic reviews and meta-analyses as well as to update the evidence using a meta-analysis in evaluating the efficacy and safety of CQ and HCQ with or without Azithromycin for the treatment of COVID19 infection. Methods The design of this meta-review followed the Preferred Reporting Items for Overviews of Systematic Reviews including harms checklist (PRIO-harms). A comprehensive search included several electronic databases in identifying all systematic reviews and meta-analyses as well as experimental studies which investigated the efficacy and safety of CQ, HCQ with or without antibiotics as COVID19 treatment. Manual searches of the reference list of all included studies and a citation search of the top 20 papers supplemented the search. Findings from the systematic reviews and meta-analyses were reported using a structured summary including tables and forest plots. The updated meta-analysis of experimental studies was carried out using the distributional-assumption-free quality effects model. Risk of bias was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool for reviews and the MethodologicAl STandard for Epidemiological Research (MASTER) scale for the experimental studies. The main outcomes for both the meta-review and the updated meta-analysis were; mortality, transfer to the intensive care unit (ICU), intubation or the need for mechanical ventilation, worsening of illness, viral clearance and the occurrence of adverse events. Results A total of 13 reviews with 40 primary studies comprising 113,000 participants were included. Most of the primary studies were observational (n=27) and the rest were experimental studies. Two meta-analyses reported a high risk of mortality with similar ORs of 2.5 for HCQ with Azithromycin. However, four other meta-analyses reported contradictory results with two reporting a high risk of mortality (OR ~ 2.2 to 3.0) and the other two reporting no significant association between HCQ with mortality. Most reviews reported that HCQ with or without Azithromycin had no significant effect on virological cure, disease exacerbation or the risk of transfer to the ICU, need for intubation or mechanical ventilation. After exclusion of studies that did not meet the eligibility criteria, the updated meta-analysis contained eight experimental studies (7 RCTs and 1 quasi-experimental trial), with a total of 5279 participants of whom 1856 were on either CQ/HCQ or combined with Azithromycin. CQ/HCQ with or without Azithromycin was significantly associated with a higher risk of adverse events (RR 5.7, 95%CI 2.4-13.7, I2 =55%, n = 5 studies). HCQ was not effective in reducing mortality (RR 1.0, 95%CI 1.0-1.2, I2 =0%, n=6 studies), transfer to the ICU, intubation or need for mechanical ventilation (RR 1.1, 95%CI 0.9-1.4, I2 =0%, n=3 studies) virological cure (RR 1.0, 95%CI 0.9-1.2, I2 =55%, n=5 studies) nor disease exacerbation (RR 1.2, 95%CI 0.3-5.0, I2 =29%, n=3 studies). Conclusion There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation.


id: cord-278246-mnj0zmkn
title: A Meta-Analysis on the Effects of Hydroxychloroquine on COVID-19
author: Hussain, Nowair
date: 2020-08-24
txt: ./txt/cord-278246-mnj0zmkn.txt
cache: ./cache/cord-278246-mnj0zmkn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32983702/
doi: 10.7759/cureus.10005
summary:
  HCQ treated patients had higher rates of adverse clinical outcomes and side effects compared with the control populations. The treatment of COVID-19 positive patients with HCQ has been met with controversy, as there have been no large multicenter randomized control trials to support its use. Studies 1 and 2 both do not cross the effect line at 0, indicating that they are not in agreement with the mortality rate of HCQ treated COVID-19 positive patients. All studies, except Study 6, are in agreement with the results of a disease progression rate of HCQ treatment in patients with COVID [19] . These results seem to be in line with the meta-analysis'' of a slight disease improvement in COVID-19 patients treated with HCQ as compared with the controls. Our study looks at three disease outcome measures of treatment with HCQ in patients with COVID-19: mortality rates, progression rates, and severity rates.

abstract:
  Introduction Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread throughout the world with a large medical and economic impact. On March 12, 2020, the World Health Organization (WHO) classified SARS-CoV-2 as a pandemic. As a result of this worldwide public health crisis, politicians, elected officials, and healthcare professionals emergently began trialing hydroxychloroquine (HCQ) in efforts to treat and prevent the transmission of the virus. This meta-analysis was performed to assess the effects of HCQ on patients with COVID-19. Methods This meta-analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMA) guidelines. Selected articles published between December 2019 and July 2020 were found utilizing the following search engines: PubMed, Google Scholar, Cochrane Library, DisasterLit, Clinicaltrials.gov, Medrxiv, and Embase. Two independent physician reviewers screened eligible articles that met the inclusion and exclusion criteria of the analysis. The outcome measures analyzed were mortality rate, rate of disease progression/improvement, rate of disease severity, and adverse effects of treatment. Six out of 14 studies that met the study’s eligibility criteria were selected and further analyzed, with a total of 381 participants (n= 381). Conclusion From the studies analyzed, it was found that groups treated with HCQ had an overall mortality rate that was 2.5 times greater than that of the control group. HCQ treated patients had higher rates of adverse clinical outcomes and side effects compared with the control populations. Lastly, there was a 1.2 times higher rate of improvement in the group of HCQ treated patients with mild to moderate symptoms as compared to the control group.


id: cord-280528-7ivw72l0
title: COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs
author: TUFAN, Abdurrahman
date: 2020-04-21
url: https://www.ncbi.nlm.nih.gov/pubmed/32299202/
doi: 10.3906/sag-2004-168
abstract:
  In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines “cytokine storm” leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.


id: cord-281285-5g1rw202
title: A comparative analysis of remdesivir and other repurposed antivirals against SARS‐CoV‐2
author: Simonis, Alexander
date: 2020-11-03
url: https://doi.org/10.15252/emmm.202013105
doi: 10.15252/emmm.202013105
abstract:
  The ongoing SARS‐CoV‐2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID‐19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID‐19. It is to date the only approved antiviral for treating COVID‐19. Here, we provide a mechanism and evidence‐based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS‐CoV‐2.


id: cord-281411-la8njxc1
author: García-Fernández, Amaya
date: 2020-10-01
txt: ./txt/cord-281411-la8njxc1.txt
cache: ./cache/cord-281411-la8njxc1.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S188558572030428X
doi: 10.1016/j.rec.2020.08.020
abstract: nan
summary:
  During March and April of 2020, a study was conducted in our hospital to analyze the effect of treatment with HCQ (either alone or in combination with AZ) on the QTc and the incidence of ventricular arrhythmias in patients admitted with SARS-CoV-2 pneumonia who met the high-risk criteria for QTc prolongation (female, age░>░65 years, history of heart disease, chronic renal disease, or diabetes, or taking both medications together). This protocol included a series of precautions to be taken before and during treatment: a) review what other medications the patient is taking that could prolong the QTc; b) correct electrolyte imbalances; c) avoid bradycardia; and d) perform close electrocardiographic monitoring.

title:
  Utilidad y seguridad de la automonitorización electrocardiográfica durante el tratamiento con hidroxicloroquina y azitromicina en pacientes con COVID-19


id: cord-283064-ncyhvkwl
author: Rowland Yeo, Karen
date: 2020-06-12
url: https://www.ncbi.nlm.nih.gov/pubmed/32531808/
doi: 10.1002/cpt.1955
title:
  Impact of disease on plasma and lung exposure of chloroquine, hydroxy‐chloroquine and azithromycin: application of PBPK modelling

abstract:
  We use a mechanistic lung model to demonstrate that accumulation of chloroquine (CQ), hydroxychloroquine (HCQ) and azithromycin (AZ) in the lungs is sensitive to changes in lung pH, a parameter that can be affected in patients with COVID‐19. A reduction in pH from 6.7 to 6 in the lung, as observed in respiratory disease, led to 20‐, 4.0‐ and 2.7‐fold increases in lung exposure of CQ, HCQ and AZ, respectively. Simulations indicated that the relatively high concentrations of CQ and HCQ in lung tissue were sustained long after administration of the drugs had stopped. Patients with COVID‐19 often present with kidney failure. Our simulations indicate that renal impairment (plus lung pH reduction) caused 30‐, 8.0‐ and 3.4‐fold increases in lung exposures for CQ, HCQ and AZ, respectively, with relatively small accompanying increases (20 to 30%) in systemic exposure. Although a number of different dosage regimens were assessed, the purpose of our study was not to provide recommendations for a dosing strategy, but to demonstrate the utility of a PBPK modelling approach to estimate lung concentrations. This, used in conjunction with robust in vitro and clinical data, can help in the assessment of COVID‐19 therapeutics going forward.


id: cord-283903-e20v88ge
title: Febuxostat therapy in outpatients with suspected COVID‐19: A clinical trial
author: Davoodi, Lotfollah
date: 2020-06-30
txt: ./txt/cord-283903-e20v88ge.txt
cache: ./cache/cord-283903-e20v88ge.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32603531/
doi: 10.1111/ijcp.13600
summary:
  BACKGROUND: The aim of this clinical trial was to evaluate the effects of febuxostat (FBX) in comparison with hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and chest CT findings in outpatients with moderate symptoms of COVID‐19 infection. The measured variables were needs to hospitalization, clinical and laboratory data including fever, cough, breathing rate, C‐Reactive Protein level, lymphocytes count at onset of admission and was well as at 5 days of treatments. On admission, fever (66.7%), cough (87%), tachypnea (44.4%), dyspnea (35%), elevated CRP value (94.4%) and lung involvement according to chest CT (100%) were documented in enrolled patients with insignificant difference between FBX and HCQ groups. In adult outpatients with moderate COVID‐19 infection, the effectiveness of FBX and HCQ was not different in terms of resolution of clinical manifestations, laboratory tests and lung CT findings. This clinical trial was conducted to assess the effects of FBX and hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and chest CT findings of patients with COVID-19 infection.

abstract:
  BACKGROUND: The aim of this clinical trial was to evaluate the effects of febuxostat (FBX) in comparison with hydroxychloroquine (HCQ) on clinical symptoms, laboratory tests and chest CT findings in outpatients with moderate symptoms of COVID‐19 infection. METHODS: We conducted a clinical trial involving adult outpatients with the moderate respiratory illness following COVID‐19 infection. Patients were randomly assigned to receive either FBX or HCQ for 5 days. The measured variables were needs to hospitalization, clinical and laboratory data including fever, cough, breathing rate, C‐Reactive Protein level, lymphocytes count at onset of admission and was well as at 5 days of treatments. In addition, CT findings were evaluated on admission and 14 days after initiation of treatment. RESULTS: Sixty subjects were enrolled in the study with a 1 to 1 ratio in FBX and HCQ groups. On admission, fever (66.7%), cough (87%), tachypnea (44.4%), dyspnea (35%), elevated CRP value (94.4%) and lung involvement according to chest CT (100%) were documented in enrolled patients with insignificant difference between FBX and HCQ groups. Fever, cough and tachypnea were significantly mitigated in both groups after five days of treatments without any significant differences between groups. The mean percentages of lung involvement were significantly reduced to 7.3% and 8% after 14 days of treatment with FBX and HCQ, respectively. In adult outpatients with moderate COVID‐19 infection, the effectiveness of FBX and HCQ was not different in terms of resolution of clinical manifestations, laboratory tests and lung CT findings. CONCLUSION: This trial suggests that FBX is as an alternative treatment to HCQ for COVID‐19 infection and may be considered in patients with a contraindication or precaution to HCQ.


id: cord-285486-99trkti1
title: Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study
author: Abd-Elsalam, Sherief
date: 2020-08-14
txt: ./txt/cord-285486-99trkti1.txt
cache: ./cache/cord-285486-99trkti1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32828135/
doi: 10.4269/ajtmh.20-0873
summary:
  Univariate logistic regression analysis showed that HCQ treatment was not significantly associated with decreased mortality in COVID-19 patients. So, adding HCQ to standard care did not add significant benefit, did not decrease the need for ventilation, and did not reduce mortality rates in COVID-19 patients. 1. Hydroxychloroquine group: This group included 97 patients who received HCQ 400 mg twice daily (in day 1) followed by 200 mg tablets twice daily added to the standard of care treatment adopted by the Egyptian MOH for 15 days. 18 Although cardiac toxicity is a known adverse event requiring monitoring during treatment, HCQ showed promise in treating SARS-CoV-2-infected patients with multiple comorbidities including coronary artery disease. 12 studied the change in symptom severity over 14 days in nonhospitalized patients between HCQ and control groups and did not find any significant difference (P = 0.12).

abstract:
  The COVID-19 pandemic is showing an exponential growth, mandating an urgent need to develop an effective treatment. Indeed, to date, a well-established therapy is still lacking. We aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) added to standard care in patients with COVID-19. This was a multicenter, randomized controlled trial conducted at three major university hospitals in Egypt. One hundred ninety-four patients with confirmed diagnosis of COVID-19 were included in the study after signing informed consent. They were equally randomized into two arms: 97 patients administrated HCQ plus standard care (HCQ group) and 97 patients administered only standard care as a control arm (control group). The primary endpoints were recovery within 28 days, need for mechanical ventilation, or death. The two groups were matched for age and gender. There was no significant difference between them regarding any of the baseline characteristics or laboratory parameters. Four patients (4.1%) in the HCQ group and 5 (5.2%) patients in the control group needed mechanical ventilation (P = 0.75). The overall mortality did not differ between the two groups, as six patients (6.2%) died in the HCQ group and 5 (5.2%) died in the control group (P = 0.77). Univariate logistic regression analysis showed that HCQ treatment was not significantly associated with decreased mortality in COVID-19 patients. So, adding HCQ to standard care did not add significant benefit, did not decrease the need for ventilation, and did not reduce mortality rates in COVID-19 patients.


id: cord-286038-a62k3lma
author: Klimke, A.
date: 2020-04-27
url: https://doi.org/10.1016/j.mehy.2020.109783
doi: 10.1016/j.mehy.2020.109783
title:
  Hydroxychloroquine as an aerosol might markedly reduce and even prevent severe clinical symptoms after SARS-CoV-2 infection

abstract:
  Covid-19 is a new coronavirus disease first described in December 2019. This respiratory illness is severe and potentially fatal. Severe cases make up to 15%, lethality ranges between 1.5 and more than 10 %. What is urgently needed is an efficient pharmacological treatment for the treatment of severe cases. During the infection of alveolar epithelial cells of the lung, the ACE2 receptor has a central function. The antimalarial drugs chloroquine phosphate (CQ) and hydroxychloroquine (HCQ) impair in vitro the terminal glycosylation of ACE2 without significant change of cell-surface ACE2 and, therefore, might be potent inhibitors of SARS-CoV-2 infections. Starting inhibition at 0.1 µM, CQ completely prevented in vitro infections at 10 µM, suggesting a prophylactic effect and preventing the virus spread 5 hours after infection. In a first clinical trial, CQ was effective in inhibiting exacerbation of pneumonia, improving lung imaging findings, promotion of virus-negative conversion, and shortening the disease. In addition, HCQ, which is three times more potent than CQ in SARS-CoV-2 infected cells (EC50 0.72 µM), was significantly associated with viral load reduction/disappearance in COVID-19 patients compared to controls. Theoretically, CQ and HCQ could thus be effectively used in the treatment of SARS-CoV pneumonia. From a pharmacological standpoint, however, the major problems of oral treatment with these drugs are possible severe side effects and toxicity. Concretely, this relates to (a) the inconsistent individual bioavailability of these drugs at the alveolar target cells, depending on intestinal resorption, hepatic first-pass metabolism and accumulation in liver, spleen and lung, and (b) the need for a relatively high concentration of 1-5 µM at the alveolar surface. Therefore, we propose in a first dose estimation the use of HCQ as an aerosol in a dosage of 2-4 mg per inhalation in order to reach sufficient therapeutic levels at the alveolar epithelial cells. By using a low-dose non-systemic aerosol, adverse drug reactions will markedly be reduced compared with oral application. This increase in tolerability enables a broader use for prevention and after contact with an infected person, which would be an advantage especially for the high-risk, often multi-morbid and elderly patients. Empirical data on self-medication with a one-week aerosol application by two of the authors is presented. Inhalation was well tolerated without relevant side effects.


id: cord-286413-a7wue2e3
author: Cohen, Isaac V.
date: 2020-11-05
url: https://doi.org/10.1038/s41598-020-76258-0
doi: 10.1038/s41598-020-76258-0
title:
  Cardiac adverse events associated with chloroquine and hydroxychloroquine exposure in 20 years of drug safety surveillance reports

abstract:
  Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization’s List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.


id: cord-286579-u87lx38h
author: Biguetti, Claudia
date: 2020-06-26
url: https://doi.org/10.11606/s1518-8787.2020054002631
doi: 10.11606/s1518-8787.2020054002631
title:
  Primum non nocere – Are chloroquine and hydroxychloroquine safe prophylactic/treatment options for SARS-CoV-2 (covid-19)?

abstract:
  Chloroquine (CQ) and its analog hydroxychloroquine (HCQ) were recently included in several clinical trials as potential prophylactic and therapeutic options for SARS-COV-2 infection/covid-19. However, drug effectiveness in preventing, treating, or slowing the progression of the disease is still unknown. Despite some initial promising in vitro results, rigorous pre-clinical animal studies and randomized clinical trials have not been performed yet. On the other hand, while the potential effectiveness of CQ/HCQ is, at best, hypothetical, their side effects are factual and most worrisome, particularly when considering vulnerable groups of patients being treated with these drugs. in this comment, we briefly explain the possible mechanisms of action of CQ/HCQ for treating other diseases, possible actions against covid-19, and their potent side effects, in order to reinforce the necessity of evaluating the benefit-risk balance when widely prescribing these drugs for SARS-COV-2 infection/covid-19. We conclude by strongly recommending against their indiscriminate use.


id: cord-287680-vdrix1cp
title: Chiral switches of chloroquine and hydroxychloroquine: potential drugs to treat COVID-19
author: D’Acquarica, Ilaria
date: 2020-05-01
txt: ./txt/cord-287680-vdrix1cp.txt
cache: ./cache/cord-287680-vdrix1cp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.drudis.2020.04.021
doi: 10.1016/j.drudis.2020.04.021
abstract: nan
summary:
  The strategy of chiral switches has emergedthe development of a single enantiomer from a chiral drug that has previously been developed (and often approved and marketed) as a racemate or as a mixture of diastereomers. The chiral switch of HCQ was initiated in the early 1990swith method-of-use patents US 5,314,894 (priority date 15-09-1992, assignee Sterling Winthrop, New York) and EP 0588439B1 claiming the enantiomer (S)-(+)-hydroxychloroquine [(S)-(+)-HCQ] for treatments of malaria, RA and LE. We aim preferentially at (S)-(+)-hydroxychloroquine [(S)-(+)-HCQ], the more-promising enantiomer (patents: US 5,314,894 and EP 0588430B1, proprietor Sanofi, priority date 15-09-1992, now expired), followed by (S)-(+)-chloroquine [(S)-(+)-CQ]. Our call for repurposing HCQ and/or CQ by urgently developing the chiral switches of these racemates to their (S)-(+)-enantiomers for the treatment of COVID-19 is based on the expectations of safer pharmacological profiles of the selected enantiomers, favorable risk:benefit profiles and shortened development and approval processes.


id: cord-288017-f9b3t0ts
author: Kabeerdoss, Jayakanthan
date: 2020-08-10
url: https://doi.org/10.1111/1756-185x.13909
doi: 10.1111/1756-185x.13909
title:
  Understanding immunopathological fallout of human coronavirus infections including COVID‐19: Will they cross the path of rheumatologists?

abstract:
  Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection causing coronavirus disease 2019 (COVID‐19) is the biggest pandemic of our lifetime to date. No effective treatment is yet in sight for this catastrophic illness. Several antiviral agents and vaccines are in clinical trials, and drug repurposings as immediate and alternative choices are also under consideration. Immunomodulatory agents like hydroxychloroquine (HCQ) as well as biological disease‐modifying anti‐rheumatic drugs (bDMARDs) such as tocilizumab and anakinra received worldwide attention for treatment of critical patients with COVID‐19. This is of interest to rheumatologists, who are well versed with rational use of these agents. This brief review addresses the understandings of some of the common immunopathogenetic mechanisms in the context of autoimmune rheumatic diseases like systemic lupus erythematosus (SLE) and COVID‐19. Apart from demographic comparisons, the role of type I interferons (IFN), presence of antiphospholipid antibodies and finally mechanism of action of HCQ in both the scenarios are discussed here. High risks for fatal disease in COVID‐19 include older age, metabolic syndrome, male gender, and individuals who develop delayed type I IFN response. HCQ acts by different mechanisms including prevention of cellular entry of SARS‐CoV‐2 and inhibition of type I IFN signaling. Recent controversies regarding efficacy of HCQ in management of COVID‐19 warrant more studies in that direction. Autoantibodies were also reported in severe acute respiratory syndrome (SARS) as well as in COVID‐19. Rheumatologists need to wait and see whether SARS‐CoV‐2 infection triggers development of autoimmunity in patients with COVID‐19 infection in the long run.


id: cord-288311-8kcturbn
title: Novel Approach for Low‐Dose Pulmonary Delivery of Hydroxychloroquine in COVID‐19
author: Fassihi, Safa C.
date: 2020-06-19
txt: ./txt/cord-288311-8kcturbn.txt
cache: ./cache/cord-288311-8kcturbn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32562278/
doi: 10.1111/bph.15167
abstract: nan
summary:
  This lack of clinical efficacy in treating asthma cannot be translated to COVID-19, which has a different etiology for pulmonary inflammation and is a disease process that stands to benefit from the anti-viral effects of HCQ. Although further evidence is needed to determine the efficacy of aerosolized HCQ in the treatment of COVID-19, low-dose targeted pulmonary delivery represents a safe and potentially preferred delivery method, particularly given the purported mechanisms by which HCQ acts against SARS-CoV-2. In light of the consequences seen with widespread use of high-dose, orally-administered HCQ in the treatment of COVID-19, clinical testing of the pharmacological parameters of inhaled or nebulized HCQ should be a high priority. However, if HCQ is to be administered in critically ill COVID-19 patients, low-dose inhaled or nebulized therapy may confer the collective benefits of similar or greater drug concentrations in pulmonary tissues, less systemic adverse effects (including cardiotoxicity), decreased burden on the healthcare system, and diminished strain on the existing supply of hydroxychloroquine.


id: cord-289091-djv4syy4
title: Safety and Efficacy of Hydroxychloroquine in COVID-19: A Systematic Review and Meta-Analysis
author: Ullah, Waqas
date: 2020-07-04
url: https://www.ncbi.nlm.nih.gov/pubmed/32849936/
doi: 10.14740/jocmr4233
abstract:
  BACKGROUND: During the initial phases of the coronavirus disease 2019 (COVID-19) epidemic, there was an unfounded fervor surrounding the use of hydroxychloroquine (HCQ); however, recently, the Centers for Disease Control and Prevention (CDC) has recommended against routine use of HCQ outside of study protocols citing possible adverse outcomes. METHODS: Multiple databases were searched to identify articles on COVID-19. An unadjusted odds ratio (OR) was used to calculate the safety and efficacy of HCQ on a random effect model. RESULTS: Twelve studies comprising 3,912 patients (HCQ 2,512 and control 1400) were included. The odds of all-cause mortality (OR: 2.23, 95% confidence interval (CI): 1.58 - 3.13, P value < 0.00001) were significantly higher in patients on HCQ compared to patients on control agent. The response to therapy assessed by negative repeat polymerase chain reaction (PCR) (OR: 1.83, 95% CI: 0.50 - 6.75, P = 0.36), radiological resolution (OR: 1.98, 95% CI: 0.47 - 8.36, P value = 0.36) and the need for invasive mechanical ventilation (IMV) (OR: 1.21, 95% CI: 0.34 - 4.33, P value = 0.76) were identical between the two groups. Overall, four times higher odds of net adverse events (NAEs) were observed in the HCQ group (OR: 4.59, 95% CI 1.73 - 12.20, P value = 0.02). The measures for individual safety endpoints were also numerically lower in the control arm; however, none of these values reached the level of statistical significance. CONCLUSIONS: HCQ might offer no benefits in terms of decreasing the viral load and radiological improvement in patients with COVID-19. HCQ appears to be associated with higher odds of all-cause mortality and NAEs.


id: cord-289916-rgvcimk3
author: Tleyjeh, Imad M.
date: 2020-11-02
url: https://doi.org/10.1016/j.mayocpiqo.2020.10.005
doi: 10.1016/j.mayocpiqo.2020.10.005
title:
  The Cardiac Toxicity of Chloroquine or Hydroxychloroquine in COVID-19 Patients: A Systematic Review and Meta-regression Analysis

abstract:
  Objective To systematically review the literature and estimate the risk of Chloroquine (CQ) and hydroxychloroquine (HCQ) cardiac toxicity in COVID-19 patients. Methods We searched multiple data sources including PubMed/MEDLINE, Ovid Embase, Ovid EBM Reviews, Scopus, and Web of Science, and medrxiv.org from November 2019 through May 27, 2020. We included studies that enrolled COVID-19 patients treated with CQ or HCQ, with or without azithromycin and reported on cardiac toxicities. We performed a meta-analysis using the arcsine transformation of the different incidences. Results A total of 19 studies with a total of 5652 patients were included. The pooled incidence of TdP arrhythmia or VT or cardiac arrest was 3 per 1000, 95% CI (0-21), I2=96%, 18 studies with 3725 patients. Among 13 studies of 4334 patients, the pooled incidence of discontinuation of CQ or HCQ due to prolonged QTc or arrhythmias was 5%, 95% CI (1-11), I2=98%. The pooled incidence of change in QTc from baseline of ≥ 60 ms or QTc ≥ 500 ms was 9%, 95% CI (3-17), I2=97%. Mean/median age, coronary artery disease, hypertension, diabetes, concomitant QT prolonging medications, ICU care, and severity of illness in the study populations explained between-studies heterogeneity. Conclusions Treatment of COVID-19 patients with CQ or HCQ is associated with a significant risk of drug-induced QT prolongation and relatively higher incidence of TdP/VT/cardiac arrest. Therefore, these agents should not be used routinely in the management of COVID-19 disease. COVID-19 patients who are treated with antimalarials for other indications should be adequately monitored.


id: cord-290955-m2igkcxv
author: Asli, Rosmonaliza
date: 2020-05-07
url: https://www.ncbi.nlm.nih.gov/pubmed/32383430/
doi: 10.4269/ajtmh.20-0376
title:
  Case Report: Right Bundle Brunch Block and QTc Prolongation in a Patient with Novel Coronavirus Disease (COVID-19) Treated with Hydroxychloroquine

abstract:
  Novel coronavirus disease (COVID-19) is a highly contagious disease caused by severe adult respiratory syndrome-coronavirus-2 that has resulted in the current global pandemic. Currently, there is no available treatment proven to be effective against COVID-19, but multiple medications, including hydroxychloroquine (HCQ), are used off label. We report the case of a 60-year-old woman without any cardiac history who developed right bundle brunch block and critically prolonged corrected electrocardiographic QT interval (QTc 631 ms) after treatment for 3 days with HCQ, which resolved on discontinuation of the medication. This case highlights a significant and potentially life-threatening complication of HCQ use.


id: cord-293159-oagv4q1u
author: Liu, Peng
date: 2020-07-08
url: https://www.ncbi.nlm.nih.gov/pubmed/32923151/
doi: 10.1080/2162402x.2020.1789284
title:
  Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses

abstract:
  Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses.


id: cord-293304-kakxmc14
author: Achutha, A. S.
date: 2020-09-22
url: https://www.ncbi.nlm.nih.gov/pubmed/32960061/
doi: 10.1021/acs.jproteome.0c00683
title:
  Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors

abstract:
  [Image: see text] Corona virus disease (COVID-19) is a dangerous disease rapidly spreading all over the world today. Currently there are no treatment options for it. Drug repurposing studies explored the potency of antimalarial drugs, chloroquine and hydroxychloroquine, against SARS-CoV-2 virus. These drugs can inhibit the viral protease, called chymotrypsin-like cysteine protease, also known as Main protease (3CL(pro)); hence, we studied the binding efficiencies of 4-aminoquinoline and 8-aminoquinoline analogs of chloroquine. Six compounds furnished better binding energies than chloroquine and hydroxychloroquine. The interactions with the active site residues especially with Cys145 and His41, which are involved in catalytic diad for proteolysis, make these compounds potent main protease inhibitors. A regression model correlating binding energy and the molecular descriptors for chloroquine analogs was generated with R(2) = 0.9039 and Q(2) = 0.8848. This model was used to screen new analogs of primaquine and molecules from the Asinex compound library. The docking and regression analysis showed these analogs to be more potent inhibitors of 3CL(pro) than hydroxychloroquine and primaquine. The molecular dynamic simulations of the hits were carried out to determine the binding stabilities. Finally, we propose four compounds that show drug likeness toward SARS-CoV-2 that can be further validated through in vitro and in vivo studies.


id: cord-293428-8hj06hzt
author: Yang, Jianling
date: 2020-04-24
url: https://doi.org/10.1101/2020.04.22.056762
doi: 10.1101/2020.04.22.056762
title:
  Cytotoxicity evaluation of chloroquine and hydroxychloroquine in multiple cell lines and tissues by dynamic imaging system and PBPK model

abstract:
  Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used in treating COVID-19 patients recently. However, both drugs have some contradictions and rare but severe side effects, such as hypoglycemia, retina and cardiac toxicity. To further uncover the toxicity profile of CQ and HCQ in different tissues, we evaluated the cytotoxicity of them in 8 cell lines, and further adopted the physiologically-based pharmacokinetic models (PBPK) to predict the tissue risk respectively. Retina, myocardium, lung, liver, kidney, vascular endothelium and intestinal epithelium originated cells were included in the toxicity evaluation of CQ and HCQ respectively. The proliferation pattern was monitored in 0-72 hours by IncuCyte S3, which could perform long-term continuous image and video of cells upon CQ or HCQ treatment. CC50 and the ratio of tissue trough concentrations to CC50 (RTTCC) were brought into predicted toxicity profiles. The CC50 at 24 h, 48 h, 72 h of CQ and HCQ decreased in the time-dependent manner, which indicates the accumulative cytotoxic effect. HCQ was found to be less toxic in 7 cell types except cardiomyocytes H9C2 cells (CC50-48 h=29.55 μM; CC50-72 h=15.26 μM). In addition, RTTCC is significant higher in CQ treatment group compared to HCQ group, which indicates that relative safety of HCQ. Both CQ and HCQ have certain cytotoxicity in time dependent manner which indicates the necessity of short period administration clinically. HCQ has the less impact in 7 cell lines proliferation and less toxicity compared to CQ in heart, liver, kidney and lung.


id: cord-295144-tyyc81uc
title: Rheumatic Musculoskeletal Diseases and COVID-19 A Review of the First 6 Months of the Pandemic
author: Stradner, Martin H.
date: 2020-10-09
url: https://www.ncbi.nlm.nih.gov/pubmed/33154972/
doi: 10.3389/fmed.2020.562142
abstract:
  In December 2019, a cluster of severe pneumonia was observed in China, with the subsequent discovery of a new beta-coronavirus (SARS-CoV-2) as the causative agent. The elicited disease COVID-19 is characterized by fever, dry cough, myalgia, or fatigue and has a favorable outcome in the majority of cases. However, in some patients COVID-19 leads to severe pneumonia and sepsis with subsequent respiratory failure and gastrointestinal, hematological, neurological, and cardiovascular complications. A higher risk of infection is intrinsic to active rheumatic and musculoskeletal diseases (RMD) and the use of biological disease modifying anti-rheumatic drugs (DMARDs). With an increasing number of reports on COVID-19 in RMD patients, we are beginning to appraise their risks. In this review, we summarize the published cases of COVID-19 infections in RMD patients, including patients with inflammatory arthritis and connective tissue diseases as well as anti-phospholipid syndrome and Kawasaki syndrome. Overall, patients with inflammatory arthritis do not seem to be at a higher risk for infection or a severe course of COVID-19. Risk for critical COVID-19 in patients with systemic inflammatory diseases such as SLE or vasculitis might be increased, but this needs further confirmation. Furthermore, we summarize the data on DMARDs used to fight SARS-CoV-2 infection and hyperinflammation.


id: cord-295973-41jqgsv0
author: Singh, Awadhesh Kumar
date: 2020-03-26
url: https://www.ncbi.nlm.nih.gov/pubmed/32247211/
doi: 10.1016/j.dsx.2020.03.011
title:
  Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries

abstract:
  BACKGROUND AND AIMS: No drugs are currently approved for Coronavirus Disease-2019 (COVID-19), although some have been tried. In view of recent studies and discussion on chloroquine and hydroxychloroquine (HCQ), we aimed to review existing literature and relevant websites regarding these drugs and COVID-19, adverse effects related to drugs, and related guidelines. AIMS AND METHODS: We systematically searched the PubMed database up till March 21, 2020 and retrieved all the articles published on chloroquine and HCQ and COVID-19. RESULTS: Two small human studies have been conducted with both these drugs in COVID-19, and have shown significant improvement in some parameters in patients with COVID-19. CONCLUSION: Considering minimal risk upon use, a long experience of use in other diseases, cost-effectiveness and easy availability across India, we propose that both these drugs are worthy of fast track clinical trial for treatment, and may be carefully considered for clinical use as experimental drugs. Since HCQ has been approved for treatment of diabetes in India, it should be further researched in diabetes and COVID-19, a subgroup where significant mortality has been shown.


id: cord-296649-h6oyjz56
author: Scherf-Clavel, Oliver
date: 2020-11-06
txt: ./txt/cord-296649-h6oyjz56.txt
cache: ./cache/cord-296649-h6oyjz56.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.09.16.299537
doi: 10.1101/2020.09.16.299537
summary:
  In this study, an adapted mouse model was chosen to demonstrate its suitability to provide sufficient information on the model substances GS-441 524 and HCQ regarding plasma concentration and distribution into relevant tissues a prerequisite for treatment effectiveness. Blood and organ samples were taken at several time points and drug concentrations were quantified in plasma and tissue homogenates by two liquid chromatography/tandem mass spectrometry methods. For GS-441 524, measured tissue concentrations exceeded the reported in vitro EC50 values by more than 10-fold and in consideration of its high efficacy against feline infectious peritonitis, GS-441 524 could indeed be effective against SARS-CoV-2 in vivo. The value obtained from our experiments falls in that range and is comparable to the V z obtained in mice from blood concentrations and to plasma V z measured in humans (see Table 4 ).

title:
  Tissue Level Profiling of SARS-CoV-2 antivirals in mice to predict their effects: comparing Remdesivir’s active metabolite GS-441 524 vs. the clinically failed Hydroxychloroquine

abstract:
  Background and Objectives Remdesivir and hydroxychloroquine are or were among the most promising therapeutic options to tackle the current SARS-CoV-2 pandemic. Besides the use of the prodrug remdesivir itself, the direct administration of GS-441 524, the resulting main metabolite of remdesivir, could be advantageous and even more effective. All substances were not originally developed for the treatment of COVID-19 and especially for GS-441 524 little is known about its pharmacokinetic and physical-chemical properties. To justify the application of new or repurposed drugs in humans, pre-clinical in vivo animal models are mandatory to investigate relevant PK and PD properties and their relationship to each other. In this study, an adapted mouse model was chosen to demonstrate its suitability to provide sufficient information on the model substances GS-441 524 and HCQ regarding plasma concentration and distribution into relevant tissues a prerequisite for treatment effectiveness. Methods GS-441 524 and HCQ were administered intravenously as a single injection to male mice. Blood and organ samples were taken at several time points and drug concentrations were quantified in plasma and tissue homogenates by two liquid chromatography/tandem mass spectrometry methods. In vitro experiments were conducted to investigate the degradation of remdesivir in human plasma and blood. All pharmacokinetic analyses were performed with R Studio using non-compartmental analysis. Results High tissue to plasma ratios for GS-441 524 and HCQ were found, indicating a significant distribution into the examined tissue, except for the central nervous system and fat. For GS-441 524, measured tissue concentrations exceeded the reported in vitro EC50 values by more than 10-fold and in consideration of its high efficacy against feline infectious peritonitis, GS-441 524 could indeed be effective against SARS-CoV-2 in vivo. For HCQ, relatively high in vitro EC50 values are reported, which were not reached in all tissues. Facing its slow tissue distribution, HCQ might not lead to sufficient tissue saturation for a reliable antiviral effect. Conclusion The mouse model was able to characterise the PK and tissue distribution of both model substances and is a suitable tool to investigate early drug candidates against SARS-CoV-2. Furthermore, we could demonstrate a high tissue distribution of GS-441 524 even if not administered as the prodrug remdesivir.


id: cord-297010-imciixde
author: Babayeva, Mariana
date: 2020-10-23
url: https://doi.org/10.2147/pgpm.s275964
doi: 10.2147/pgpm.s275964
title:
  Repurposing Drugs for COVID-19: Pharmacokinetics and Pharmacogenomics of Chloroquine and Hydroxychloroquine

abstract:
  BACKGROUND: A new coronavirus SARS-CoV-2 has been identified as the etiological agent of the severe acute respiratory syndrome, COVID-19, the source and cause of the 2019–20 coronavirus pandemic. Hydroxychloroquine and chloroquine have gathered extraordinary attention as therapeutic candidates against SARS-CoV-2 infections. While there is growing scientific data on the therapeutic effect, there is also concern for toxicity of the medications. The therapy of COVID-19 by hydroxychloroquine and chloroquine is off-label. Studies to analyze the personalized effect and safety are lacking. METHODS: A review of the literature was performed using Medline/PubMed/Embase database. A variety of keywords were employed in keyword/title/abstract searches. The electronic search was followed by extensive hand searching using reference lists from the identified articles. RESULTS: A total of 126 results were obtained after screening all sources. Mechanisms underlying variability in drug concentrations and therapeutic response with chloroquine and hydroxychloroquine in mediating beneficial and adverse effects of chloroquine and hydroxychloroquine were reviewed and analyzed. Pharmacogenomic studies from various disease states were evaluated to elucidate the role of genetic variation in drug response and toxicity. CONCLUSION: Knowledge of the pharmacokinetics and pharmacogenomics of chloroquine and hydroxychloroquine is necessary for effective and safe dosing and to avoid treatment failure and severe complications.


id: cord-303819-w1785lap
author: Cortegiani, Andrea
date: 2020-07-11
url: https://doi.org/10.1016/j.jcrc.2020.06.019
doi: 10.1016/j.jcrc.2020.06.019
title:
  Update I. A systematic review on the efficacy and safety of chloroquine/hydroxychloroquine for COVID-19

abstract:
  PURPOSE: To assess efficacy and safety of chloroquine (CQ)/hydroxychloroquine (HCQ) for treatment or prophylaxis of COVID-19 in adult humans. MATERIALS AND METHODS: MEDLINE, PubMed, EMBASE and two pre-print repositories (bioRxiv, medRxiv) were searched from inception to 8th June 2020 for RCTs and nonrandomized studies (retrospective and prospective, including single-arm, studies) addressing the use of CQ/HCQ in any dose or combination for COVID-19. RESULTS: Thirty-two studies were included (6 RCTs, 26 nonrandomized, 29,192 participants). Two RCTs had high risk, two ‘some concerns’ and two low risk of bias (Rob2). Among nonrandomized studies with comparators, nine had high risk and five moderate risk of bias (ROBINS-I). Data synthesis was not possible. Low and moderate risk of bias studies suggest that treatment of hospitalized COVID-19 with CQ/HCQ may not reduce risk of death, compared to standard care. High dose regimens or combination with macrolides may be associated with harm. Postexposure prophylaxis may not reduce the rate of infection but the quality of the evidence is low. CONCLUSIONS: Patients with COVID-19 should be treated with CQ/HCQ only if monitored and within the context of high quality RCTs. High quality data about efficacy/safety are urgently needed.


id: cord-303968-ikr6eeov
title: Towards Optimization of Hydroxychloroquine Dosing in Intensive Care Unit COVID-19 Patients
author: Perinel, Sophie
date: 2020-04-07
url: https://www.ncbi.nlm.nih.gov/pubmed/32255489/
doi: 10.1093/cid/ciaa394
abstract:
  Hydroxychloroquine (HCQ) appears to be a promising treatment for COVID-19. However, all ongoing clinical trials with HCQ use different dosing regimens, resulting on various concentrations PK studies are therefore needed to define the optimal dosing regimen.


id: cord-304669-aiuiotds
author: Afsin, Abdulmecit
date: 2020-08-15
url: https://doi.org/10.14740/jocmr4288
doi: 10.14740/jocmr4288
title:
  Effects of Short-Term Hydroxychloroquine Plus Moxifloxacin Therapy on Corrected QT Interval and Tp-e Interval in Patients With COVID-19

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


id: cord-306351-ka6asw3m
title: A review of potential treatments to date in COVID-19 patients according to the stage of the disease
author: Alsuliman, Tamim
date: 2020-05-30
url: https://doi.org/10.1016/j.retram.2020.05.004
doi: 10.1016/j.retram.2020.05.004
abstract:
  Abstract Introduction and motivation: Since the end of 2019, the COVID-19 pandemic has affected millions of people worldwide. With the rapid spread of this virus, an immense burden has fallen upon both healthcare and economic systems. As a consequence, there is an unprecedented urgency for researchers and scientific committees from all over the world to find an effective treatment and vaccine. Review Structure: Many potential therapies are currently under investigation, with some, like Hydroxychloroquine, being authorized for emergency use in some countries. The crucial issue is now clearly to find the suitable treatment strategy for patients given comorbidities and the timeline of the illness.Vaccines are also under development and phase 1 clinical trials are rolling. Despite all efforts, no single drug or vaccine has yet been approved. In this review, we aim at presenting the proposed pathophysiological mechanisms of SARS-CoV-2 and to provide clinicians with a brief and solid overview of the current potential treatments classified according to their use at the three different currently proposed disease stages. In light of pathogenesis and proposed clinical classification, this review’s purpose is to summarize and simplify the most important updates on the management and the potential treatment of this emergent disease.


id: cord-307570-8f83k2ce
title: Hydroxychloroquine is effective, and consistently so used early, for Covid-19: A systematic review
author: Prodromos, Chadwick
date: 2020-10-05
url: https://api.elsevier.com/content/article/pii/S2052297520301281
doi: 10.1016/j.nmni.2020.100776
abstract:
  Introduction Hydroxychloroquine (HCQ) has shown efficacy against COVID-19 in some but not all studies. We hypothesized that systematic review would show HCQ to be: effective against COVID-19, more effective when used earlier, not associated with worsening, and safe. Methods We searched PubMed, Cochrane, EmBase, Google Scholar, and Google for all reports on hydroxychloroquine as a treatment for COVID-19 patients. This included pre-prints and preliminary reports on larger COVID-19 studies. We examined the studies for efficacy, time of administration and safety. Results HCQ was found consistently effective against COVID-19 when used early, in the outpatient setting. It was found overall effective also including inpatient studies. No unbiased study found worse outcomes with HCQ use. No mortality or serious safety adverse event was found Conclusions HCQ is consistently effective against COVID-19 when used early in the outpatient setting, it is overall effective against COVID-19, it has not produced worsening, it is safe.


id: cord-312875-gn6hg6oc
author: Infante, Marco
date: 2020-05-13
txt: ./txt/cord-312875-gn6hg6oc.txt
cache: ./cache/cord-312875-gn6hg6oc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32401405/
doi: 10.1111/1753-0407.13053
summary:
  (3) Although the exact mechanisms of action underlying the glucose-lowering properties of HCQ are still not entirely clear and may differ between patients with and without diabetes, pre-clinical and clinical data suggest that HCQ could exert multifaceted effects on glucose homeostasis, namely: improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance and intracellular insulin and insulin-receptor complex degradation, increase of adiponectin levels, reduction of systemic inflammation, and/or reduction of inflammation-induced insulin resistance in adipocytes and skeletal muscle cells. (13) More recently, a 24-week prospective randomized trial (14) and two real-world, prospective observational studies of short duration (up to 24-48 weeks) (5, 15) conducted in India have shown that the use of HCQ (400 mg/day) as an add-on treatment in patients with T2D uncontrolled on a combination of two or more oral hypoglycemic agents (including metformin, sulfonylureas, pioglitazone, DPP-4 inhibitors, SGLT2 inhibitors, and alpha-glucosidase inhibitors) was welltolerated and led to a significant improvement of glucose control (assessed by HbA1c, fasting-and postprandial blood glucose) from baseline (without occurrence of severe hypoglycemia).

title:
  Antihyperglycemic properties of hydroxychloroquine in patients with diabetes: risks and benefits at the time of COVID‐19 pandemic

abstract:
  The antimalarial drug hydroxychloroquine (HCQ) has long been used as a disease‐modifying antirheumatic drug for the treatment of several inflammatory rheumatic diseases. Over the last three decades, various studies have shown that HCQ plays also a role in the regulation of glucose homeostasis. Although the mechanisms of action underlying the glucose‐lowering properties of HCQ are still not entirely clear, evidence suggests that this drug may exert multifaceted effects on glucose regulation, including improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance and reduction of systemic inflammation. Preliminary studies have shown the safety and efficacy of HCQ (at a dose ranging from 400 to 600 mg/day) in patients with type 2 diabetes over a short‐term period. In 2014, HCQ has been approved in India as an add‐on hypoglycemic agent for patients with uncontrolled type 2 diabetes. However, large randomized controlled trials are needed to establish the safety and efficacy profile of HCQ in patients with type 2 diabetes over a long‐term period. With regard to the COVID‐19 pandemic, several medications (including HCQ) have been used as off‐label drugs due to the lack of proven effective therapies. However, emerging evidence shows limited benefit from HCQ use in COVID‐19 in general. The aim of this manuscript is to comprehensively summarize the current knowledge on the antihyperglycemic properties of HCQ and to critically evaluate the potential risks and benefits related to HCQ use in patients with diabetes, even in light of the current pandemic scenario. This article is protected by copyright. All rights reserved.


id: cord-315598-qwh72inx
author: Mendoza, Jose Luis Accini
date: 2020-10-06
txt: ./txt/cord-315598-qwh72inx.txt
cache: ./cache/cord-315598-qwh72inx.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0122726220300859?v=s5
doi: 10.1016/j.acci.2020.09.004
summary:
  De otorgarse un Consentimiento Informado amplio, éste debería ser única y exclusivamente para los procesos asociados con COVID-19".(71) AMCI ® Se recomienda considerar la transición del cuidado intensivo al cuidado paliativo en todo paciente con sospecha o diagnóstico de COVID-19 sin mejoría a pesar de las intervenciones óptimas, con empeoramiento progresivo de su pronóstico vital y ante un evidente deterioro; aplicando medidas generales en control de síntomas ( Manejo de secreciones -Tratamiento del dolor -Tratamiento de la disnea -Sedación paliativa), así como apoyo espiritual, siempre acompañando al paciente y nunca abandonarlo en el final de la vida. En cuanto hace referencia a la situación actual de pandemia por SARS-CoV-2 y compromiso pulmonar; Wu y cols, en Marzo de 2.020 realizaron un estudio retrospectivo de 201 pacientes con COVID-19 en China; para aquellos pacientes que desarrollaron SDRA, el tratamiento con metilprednisolona estuvo asociado con una disminución del riesgo de muerte (23/50 [46%] con esteroides vs 21/34 [62%] sin esteroides; HR, 0.38 [IC 95%, 0.20-0.72]), con las limitaciones de los estudios retrospectivo, de un solo centro, con un limitado número de pacientes (400).

title:
  ACTUALIZACION DE LA DECLARACIÓN DE CONSENSO EN MEDICINA CRITICA PARA LA ATENCIÓN MULTIDISCIPLINARIA DEL PACIENTE CON SOSPECHA O CONFIRMACIÓN DIAGNÓSTICA DE COVID-19

abstract:
  Antecedentes y objetivos: La enfermedad por coronavirus de 2019 (COVID-19) es una enfermedad ocasionada por el nuevo coronavirus del síndrome respiratorio agudo grave (SARS-CoV-2). Se identificó por primera vez en diciembre de 2019 en la ciudad de Wuhan, en los meses siguientes se expandió rápidamente a todos los continentes y la Organización Mundial de la Salud (OMS), la reconoció como una pandemia global el 11 de marzo de 2020. La mayoría de los individuos son asintomáticos pero una baja proporción ingresan a cuidados intensivos con una alta morbilidad y mortalidad. Este consenso tiene como objetivo actualizar la declaratoria inicial emitida por la Asociación Colombiana de Medicina Crítica (AMCI) para el manejo del paciente críticamente enfermo con COVID-19 dentro de las áreas críticas de las instituciones de salud. Métodos: Este estudio utilizó dos técnicas de consenso formal para construir las recomendaciones finales: Delphi modificada y grupos nominales. Se construyeron preguntas por la estrategia PICO. 10 grupos nominales desarrollaron recomendaciones para cada unidad temática. El producto del consenso fue evaluado y calificado en una ronda Delphi y se discutió de forma virtual por los relatores de cada núcleo y los representantes de sociedades médicas científicas afines al manejo del paciente con COID-19. Resultados: 80 expertos nacionales participaron en la actualización del consenso AMCI, especialistas en Medicina Critica y Cuidados Intensivos, Nefrología, Neurología, Neumología, bioeticistas, Medicina interna, Anestesia, Cirugía General, Cirugía de cabeza y cuello, Cuidados Paliativos, Enfermeras Especialistas en Medicina crítica, Terapeutas respiratorias especialistas en medicina crítica y Fisioterapia, con experiencia clínica en la atención del paciente críticamente enfermo. La declaratoria emite recomendaciones en los ámbitos más relevantes para la atención en salud de los casos de COVID-19 al interior de las unidades de cuidados intensivos en el contexto nacional de Colombia. Conclusiones: un grupo significativo multidisciplinario de profesionales expertos en medicina crítica emiten mediante técnicas de consenso formal recomendaciones sobre la mejor práctica para la atención del paciente críticamente enfermo con COVID-19. Las recomendaciones deben ser adaptadas a las condiciones específicas, administrativas y estructurales de las distintas unidades de cuidados intensivos del país. Background and objectives: The 2019 coronavirus disease (COVID-19) is caused by the new severe acute respiratory syndrome coronavirus (SARS-CoV-2). It was first identified in December 2019 in Wuhan, China. In the following months it spread quickly to all continents and was recognised as a global pandemic by the World Health Organization (WHO) on March 11th, 2020. Most cases of infection remain asymptomatic, while a low proportion require intensive care, experiencing high morbidity and mortality. This consensus aims to update the initial statement issued by the Colombian Association of Critical Medicine (AMCI) for the management of the critically ill patient with COVID-19 within the critical areas of health institutions. Methods: This study used two formal consensus techniques to construct the final recommendations: modified Delphi and nominal groups. Questions were constructed using the PICO strategy. Recommendations for each thematic unit were developed by 10 nominal groups. The consensus product was evaluated and qualified in a Delphi round, and was discussed virtually by the speaker of each nucleus, as well as the representatives of scientific medical societies related to the management of the patient with COVID-19. Results: A total of 80 national experts participated in the update of the AMCI consensus, all specialists in Critical and Intensive Care Medicine, Nephrologists, Neurologists, Chest physician, bioethicists, Internal medicine specialists, Anaesthetists, General Surgeons, head and neck surgery, palliative care, Nurses Specialised in Critical Medicine, Respiratory therapists specialised in critical medicine and Physiotherapy, with clinical experience in the care of critically ill patients. This update issues recommendations in the most relevant areas for health care of COVID-19 patients within the intensive care units, contextualised for Colombia. Conclusions: A significant multidisciplinary group of professionals, who are experts in critical medicine, reviewed and issued recommendations on best practice for the care of critically ill patients with COVID-19 through formal consensus techniques. Recommendations must be adapted to the specific, administrative, and structural conditions of the different intensive care units in the country.


id: cord-315864-zadogqiu
author: Davido, Benjamin
date: 2020-08-02
url: https://doi.org/10.1016/j.ijantimicag.2020.106129
doi: 10.1016/j.ijantimicag.2020.106129
title:
  nImpact of medical care including anti-infective agents use on the prognosis of COVID-19 hospitalized patients over time

abstract:
  INTRODUCTION: Interest of anti-infective agents in COVD-19 showed discrepant results. However, there is no evaluation about the impact in changes of practices on the prognosis over time. METHODS: Single center, retrospective study, conducted from March 5(th) to April 25(th) 2020, in adults hospitalized in a medicine ward for a COVID-19. Patient characteristics were compared between 2 periods (before/after March 19(th)) considering French guidelines issued by learned societies. Aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission in intensive care unit (ICU) and/or death. RESULTS: One hundred thirty-two patients were admitted, mean age was 59.0 ± 16.3 years, mean CRP level was 84.0±71.1 mg/L, 46% had a lymphocyte count<1000/mm(3). When prescribed, anti-infective agents were lopinavir-ritonavir (n=12), azithromycin (AZI) (n=28) and AZI combined with hydroxychloroquine (HCQ) (n=52). Between the 2 periods we noted a significant decrease of ICU admission, from 43% to 12% (p<0.0001). Delays until transfer in ICU were similar between periods (p=0.86). Pulmonary CT-scan were significantly more performed (from 50% to 90%, p<0.0001), as oxygen-dependency (53% vs 80%, p=0.001) and prescription of AZI±HCQ (from 25% to 76%, p<0.0001) were greater over time. Multivariate analyses showed a reduction of unfavorable outcome in patients receiving AZI±HCQ (HR=0.45, 95%IC [0.21-0.97], p=0.04), especially among an identified category of individuals (lymphocyte≥1000/mm(3) or CRP≥100 mg/L). CONCLUSION: The present study revealed a significant decrease of admission in ICU over time probably related to multiple factors, including a better indication of pulmonary CT-scan, of oxygen therapy, and a suitable prescription of anti-infective agents.


id: cord-316992-fe5u2oi0
title: Hydroxychloroquine in rheumatic autoimmune disorders and beyond
author: Nirk, Eliise Laura
date: 2020-07-26
txt: ./txt/cord-316992-fe5u2oi0.txt
cache: ./cache/cord-316992-fe5u2oi0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.15252/emmm.202012476
doi: 10.15252/emmm.202012476
summary:
  These effects are achieved through the modulation of the autoimmune response by (i) impairing functions of the endolysosomal system through its lysosomotropic effects (Ziegler & Unanue, 1982; Kaufmann & Krise, 2007; Yoon et al, 2010) , (ii) decreasing the levels of circulating pro-inflammatory cytokines (Sperber et al, 1993; Van Den Borne et al, 1997) , (iii) inhibiting T-cell proliferation (Landewe et al, 1995; Costedoat-Chalumeau et al, 2014) , (iv) blocking Tolllike receptors (TLRs) (Kyburz et al, 2006) and (v) autophagy inhibition (An et al, 2017c) . Activation of TLRs, especially in macrophages, monocytes and T helper cells, but also in neutrophils and endothelial cells, induces the production and secretion of pro-inflammatory cytokines, a hallmark of RADs (Beutler & Cerami, 1989 (A) CQ and HCQ are weak bases that accumulate inside acidic subcellular compartments, e.g. endosomes and lysosomes.

abstract:
  Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases. Due to its cost‐effectiveness, safety and efficacy, HCQ is especially used in rheumatic autoimmune disorders (RADs), such as systemic lupus erythematosus, primary Sjögren's syndrome and rheumatoid arthritis. Despite this widespread use in the clinic, HCQ molecular modes of action are still not completely understood. By influencing several cellular pathways through different mechanisms, CQ and HCQ inhibit multiple endolysosomal functions, including autophagy, as well as endosomal Toll‐like receptor activation and calcium signalling. These effects alter several aspects of the immune system with the synergistic consequence of reducing pro‐inflammatory cytokine production and release, one of the most marked symptoms of RADs. Here, we review the current knowledge on the molecular modes of action of these drugs and the circumstances under which they trigger side effects. This is of particular importance as the therapeutic use of HCQ is expanding beyond the treatment of malaria and RADs.


id: cord-317561-ewo6vvlr
title: HCQ prophylaxis in COVID-19 did not show any QTc prolongation in Healthcare workers
author: Jha, Sujeet
date: 2020-11-10
url: https://www.sciencedirect.com/science/article/pii/S0019483220302716?v=s5
doi: 10.1016/j.ihj.2020.11.005
abstract:
  BACKGROUND: HCQ is a commonly recommended drug for the prophylaxis of COVID-19. One of its rare side-effect includes QTc prolongation. METHODS: This was a prospective, cross sectional and observational study conducted on Hydroxychloroquine (HCQ) among Healthcare Workers (HCWs) at Max Super Speciality Hospital, Saket, New Delhi, India. A 3-lead ECG (only limb leads, it does not require chest leads) was performed. The QTc cut offs were pre decided, QTC < 470ms for males and < 480ms for females was considered within the normal limits and anything above this was regarded as QTc prolongation. RESULTS: There were 274 HCWs enrolled into the study, including 175 males and 99 females. Majority of the HCWs were young and had a mean age of 32.19±9.29 years. Out of these, 218 were taking HCQ as per the Indian Council of Medical Research (ICMR) guidelines. The median cumulative dose being taken was 1600mg and the median QTc of these participants was 390ms in males and 391.5ms in females. Subsequently, 33 participants were followed-up and found to have a median QTc of 389ms and a cumulative dose of HCQ as 2000mg. CONCLUSION: In conclusion, ours is a first study in the middle of the pandemic which showed that HCQ prophylaxis in young HCWs without comorbidities did not show any QTc prolongation.


id: cord-317624-qdzhncs0
author: Choi, Min Joo
date: 2020-10-27
txt: ./txt/cord-317624-qdzhncs0.txt
cache: ./cache/cord-317624-qdzhncs0.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1201971220322669?v=s5
doi: 10.1016/j.ijid.2020.10.062
summary:
  METHODS: Nationwide retrospective case-control study was conducted to compare the effect of HCQ and LPV/r on viral shedding duration among patients with mild-to-moderate COVID-19 using the reimbursement data of National Health Insurance Service. This study aimed to compare the effect of HCQ and LPV/r on the viral shedding duration among patients with mild-to-moderate COVID-19 cases using South Korea''s National Health J o u r n a l P r e -p r o o f Insurance Service (NHIS) database. Among these, only mild-to-moderate grade 1 patients were included in the analysis, and the effect of LPV/r or HCQ use on viral shedding duration was evaluated ( Figure 1 ). In the previous studies including mild COVID-19 patients in CTCs, the mean viral shedding duration from symptom onset was 21-24.5 days, which is longer than the results of our control group , Noh et al., 2020 .

title:
  Comparison of antiviral effect for mild-to-moderate COVID-19 cases between lopinavir/ritonavir versus hydroxychloroquine: A nationwide propensity score-matched cohort study

abstract:
  OBJECTIVES: We aimed to compare the antiviral effect of hydroxychloroquine (HCQ) and lopinavir/ritonavir (LPV/r) in patients with COVID-19. METHODS: Nationwide retrospective case-control study was conducted to compare the effect of HCQ and LPV/r on viral shedding duration among patients with mild-to-moderate COVID-19 using the reimbursement data of National Health Insurance Service. After propensity score matching (PSM), multivariate analysis was conducted to determine statistically significant risk factors associated with prolonged viral shedding. RESULTS: Overall, 4,197 patients with mild-to-moderate COVID-19 were included. Patients were categorized into three groups: LPV/r (n = 1,268), HCQ (n = 801), and standard care without HCQ or LPV/r (controls, n = 2128). The median viral shedding duration was 23 (IQR 17–32), 23 (IQR 16–32), and 18 (IQR 12–25) days in the LPV/r, HCQ, and control groups, respectively. Even after PSM, the viral shedding duration was not significantly different between LPV/r and HCQ groups: 23 (IQR, 17–32) days versus 23 (IQR, 16–32) days. On multivariate analysis, old age, malignancy, steroid use, and concomitant pneumonia were statistically significant risk factors for prolonged viral shedding. CONCLUSION: The viral shedding duration was similar between HCQ and LPV/r treatment groups. There was no benefit in improving viral clearance compared to the control group.


id: cord-317761-tkqmu1va
title: Chloroquine and hydroxychloroquine in the context of COVID-19
author: Shukla, Ashutosh M
date: 2020-04-28
url: https://doi.org/10.7573/dic.2020-4-5
doi: 10.7573/dic.2020-4-5
abstract:
  Chloroquine and closely related structural analogs, employed initially for the treatment of malaria, are now gaining worldwide attention due to the rapidly spreading pandemic caused by severe acute respiratory syndrome-coronavirus-2, named coronavirus disease (COVID) of 2019 (COVID-19). Although much of this attention has a mechanistic basis, the hard efficacy data for chloroquine/hydroxychloroquine in the management of the clinical syndrome of COVID-19 have been limited thus far. This review aims to present the available in vitro and clinical data for the role of chloroquine/hydroxychloroquine in COVID-19 and attempts to put them into perspective, especially in relation to the different risks/benefits particular to each patient who may require treatment.


id: cord-318092-errwp80i
author: Ren, L.
date: 2020-05-08
txt: ./txt/cord-318092-errwp80i.txt
cache: ./cache/cord-318092-errwp80i.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.05.02.20088872v1?rss=1
doi: 10.1101/2020.05.02.20088872
summary:
  Methods: We systematically searched PubMed, MEDLINE, Cochrane, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before March 31, 2020. Our objective was to identify all randomized clinical trials (RCTs) that compared the safety profiles of chloroquine or hydroxychloroquine with placebo or other active agents. This review was not restricted to studies conducted in the English language; it includes reports from any countries that compared CQ or HCQ with placebo or other active agents, since there is a wealth of information in RCTs from many different countries. Together, these stratified data provide ample information regarding the percentage of participants who experienced specific AEs. Subgroup meta-analysis for CQ and HCQ with respect to age, duration, and dosage. For HCQ, there was no evidence that age, duration of trial, or dosage affected total AEs. Further meta-regression analyses can be found in Supplementary Figure 1 .

title:
  Assessment of Hydroxychloroquine and Chloroquine Safety Profiles: A Systematic Review and Meta-Analysis

abstract:
  Background: Recently, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) have emerged as potential antiviral and immunomodulatory options for the treatment of 2019 coronavirus disease (COVID-19). To examine the safety profiles of these medications, we systematically evaluated the adverse events (AEs) of these medications from published randomized controlled trials (RCTs). Methods: We systematically searched PubMed, MEDLINE, Cochrane, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and the ClinicalTrials.gov for all the RCTs comparing CQ or HCQ with placebo or other active agents, published before March 31, 2020. The random-effects or fixed-effects models were used to pool the risk estimates relative ratio (RR) with 95% confidence interval (CI) for the outcomes. Results: The literature search yielded 23 and 17 studies for CQ and HCQ, respectively, that satisfied our inclusion criteria. Of these studies, we performed meta-analysis on the ones that were placebo-controlled, which included 6 studies for CQ and 14 studies for HCQ. We did not limit our analysis to published reports involving viral treatment alone; data also included the usage of either CQ or HCQ for the treatment of other diseases. The trials for the CQ consisted of a total of 2,137 participants (n=1,077 CQ, n=1,060 placebo), while the trials for HCQ involved 1,096 participants (n=558 HCQ and n=538 placebo). The overall mild or total AEs were statistically higher comparing CQ or HCQ to placebo. The AEs were further categorized into four groups and analyses revealed that neurologic, gastrointestinal, dermatologic, and ophthalmic AEs were higher in participants taking CQ compared to placebo. Although this was not evident in HCQ treated groups, further analyses suggested that there were more AEs attributed to other organ system that were not included in the categorized meta-analyses. Additionally, meta-regression analyses revealed that total AEs was affected by dosage for the CQ group. Conclusions: Taken together, we found that participants taking either CQ or HCQ have more AEs than participants taking placebo. Precautionary measures should be taken when using these drugs to treat COVID-19.


id: cord-319571-fspmgg4s
author: Sehailia, Moussa
date: 2020-07-22
txt: ./txt/cord-319571-fspmgg4s.txt
cache: ./cache/cord-319571-fspmgg4s.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32696720/
doi: 10.1080/07391102.2020.1796809
summary:
  Although, functional importance of different targets has been linked to the viral replication and maturation of coronaviruses'' family such as Chymotrypsin-like protease(3CLpro) or known as Mpro (Khan et al., 2020; Muralidharan et al., 2020) or Envelope protein (E) (Gupta et al., 2020; Boopathi et al., 2020) but it has been confirmed that the binding of the viral trimeric surface spike glycoprotein (SProtein) of SARS-CoV-2 to the human receptor angiotensin-converting enzyme 2 (hACE2) is the first step in host infection . Therefore, it is very likely that selective interaction of HCQ with the surface of SARS-CoV-2 SProtein through the formation of an inclined tape over the hydrophobic pocket responsible for hosting the Lys353 hotspot (the OH group in this case is acting like a hook by forming a hydrogen bond with Asn501), can be responsible for the prevention of tighter binding with hACE2 protein via restricting penetration of Lys353 into its finally assigned destination on the SProtein RBD (Figure 2 ).

title:
  Antimalarial-agent artemisinin and derivatives portray more potent binding to Lys353 and Lys31-binding hotspots of SARS-CoV-2 spike protein than hydroxychloroquine: potential repurposing of artenimol for COVID-19

abstract:
  Medicinal herbs have proved along history to be a source of multiple cures. In this paper, we demonstrate how hydroxychloroquine can act as a good inhibitor of SARS-CoV-2 Spike protein receptor-binding-domain using molecular docking studies. We also unveil how hydroxychloroquine can interfere in the prevention of Lys353 in hACE2 from interacting with the corresponding binding hotspot present on the Spike protein. Further screening of artemisinin & derived compounds produced better Vina docking score than hydroxychloroquine (-7.1 kcal mol(−1) for artelinic acid vs. −5.5 kcal mol(−1) for hydroxychloroquine). Artesunate, artemisinin and artenimol, showed two mode of interactions with Lys353 and Lys31 binding hotspots of the Spike protein. Molecular dynamics analysis confirmed that the formed complexes are able to interact and remain stable in the active site of their respective targets. Given that these molecules are effective antivirals with excellent safety track records in humans against various ailment, we recommend their potential repurposing for the treatment of SARS-CoV-2 patients after successful clinical studies. In addition, an extraction protocol for artemisinin from Artemisia annua L. is proposed in order to cope with the potential urgent global demand. Communicated by Ramaswamy H. Sarma


id: cord-320499-76o2zj0v
title: Hydroxychloroquine-induced Stevens–Johnson syndrome in COVID-19: a rare case report
author: Davoodi, Lotfollah
date: 2020-06-25
url: https://doi.org/10.1093/omcr/omaa042
doi: 10.1093/omcr/omaa042
abstract:
  The international outbreak of respiratory illness termed coronavirus disease 2019 (COVID-19) began in December 2019 that has affected >0.8 million individuals. Self-limiting respiratory tract involvement, severe pneumonia, multiorgan failure and death are the spectrum of COVID-19. To date, there are no especial therapeutic agents for COVID-19 infections. One such medication includes the antimalarial hydroxychloroquine (HCQ), which recently reported as a possible therapy for shortening the duration of COVID-19 symptoms, reducing inflammatory reactions to infection, impairing the exacerbation of pneumonia and boosting lung imaging findings. Like all medications, HCQ has side effects and may occur in COVID-19 patients. Here, we report on the case of a 42-year-old woman, presented with fever and dry cough, who had COVID-19 and 2 days later presented with a pruritic erythematous maculopapular rash, which started from the distal of upper extremities and rapidly, involved the entire body.


id: cord-321337-tg8kfiot
author: Hulme, Oliver J
date: 2020-04-03
txt: ./txt/cord-321337-tg8kfiot.txt
cache: ./cache/cord-321337-tg8kfiot.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.03.31.20048777
doi: 10.1101/2020.03.31.20048777
summary:
  Statistical evidence for the positive effect model ranged from strong for the original data (BF ~11), to moderate when including patients who deteriorated (BF ~4.35), to anecdotal when excluding untested patients (BF ~2), and to anecdotal negative evidence if untested patients were assumed positive (BF ~0.6). Here we perform the test HCQ mono versus comparison group, and assess its sensitivity to the variants of the data under different assumptions regarding deteriorated and untested patients. As is evident from this, the strength of the evidence for the positive effect of HCQ mono over the comparison group is highly sensitive to the assumptions regarding what to do with the deteriorated or untested patients. Performing a Bayesian A/B test, we found that for the original data, there was strong statistical evidence for the positive effect of HCQ mono improving the chances of viral reduction when compared to the comparison group.

title:
  A Bayesian reanalysis of the effects of hydroxychloroquine and azithromycin on viral carriage in patients with COVID-19

abstract:
  Gautret and colleagues reported results of a non-randomised open-label case series which examined the effects of hydroxychloroquine and azithromycin on viral load in the upper respiratory tract of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients. The authors report that hydroxychloroquine (HCQ) had significant virus reducing effects, and that dual treatment of both HCQ and azithromycin further enhanced virus reduction. This data has triggered speculation whether these drugs should be considered as candidates for the treatment of severe COVID-19. However, questions have been raised regarding the study's data integrity, statistical analyses, and experimental design. We therefore reanalysed the original data to interrogate the main claims of the paper. Here we apply Bayesian statistics to assess the robustness of the original papers claims by testing four variants of the data: 1) The original data; 2) Data including patients who deteriorated; 3) Data including patients who deteriorated with exclusion of untested patients in the comparison group; 4) Data that includes patients who deteriorated with the assumption that untested patients were negative. To ask if HCQ monotherapy is effective, we performed an A/B test for a model which assumes a positive effect, compared to a model of no effect. We find that the statistical evidence is highly sensitive to these data variants. Statistical evidence for the positive effect model ranged from strong for the original data (BF ~11), to moderate when including patients who deteriorated (BF ~4.35), to anecdotal when excluding untested patients (BF ~2), and to anecdotal negative evidence if untested patients were assumed positive (BF ~0.6). To assess whether HCQ is more effective when combined with AZ, we performed the same tests, and found only anecdotal evidence for the positive effect model for the original data (BF ~2.8), and moderate evidence for all other variants of the data (BF ~5.6). Our analyses only explore the effects of different assumptions about excluded and untested patients. These assumptions are not adequately reported, nor are they justified in the original paper, and we find that varying them causes substantive changes to the evidential support for the main claims of the original paper. This statistical uncertainty is exacerbated by the fact that the treatments were not randomised, and subject to several confounding variables including the patients' consent to treatment, different care centres, and clinical decision-making. Furthermore, while the viral load measurements were noisy, showing multiple reversals between test outcomes, there is greater certainty around other clinical outcomes such as the 4 patients who seriously deteriorated. The fact that all of these belonged to the HCQ monotherapy group should be assigned greater weight when evaluating the potential clinical efficacy of HCQ. Randomised controlled trials are currently underway, and will be critical in resolving this uncertainty as to whether HCQ and AZ are effective as a treatment for COVID-19.


id: cord-323647-q67fa0m3
author: Misra, Durga Prasanna
date: 2020-09-02
url: https://doi.org/10.1007/s00296-020-04694-2
doi: 10.1007/s00296-020-04694-2
title:
  Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates

abstract:
  Repurposing of antirheumatic drugs has garnered global attention. The aim of this article is to overview available evidence on the use of widely used antirheumatic drugs hydroxychloroquine, methotrexate and colchicine for additional indications. Hydroxychloroquine has endothelial stabilizing and anti-thrombotic effects. Its use has been explored as an adjunctive therapy in refractory thrombosis in antiphospholipid syndrome. It may also prevent recurrent pregnancy losses in the absence of antiphospholipid antibodies. Hydroxychloroquine favourably modulates atherogenic lipid and glycaemic profiles. Methotrexate has been tried for modulation of cardiovascular events in non-rheumatic clinical conditions, although a large clinical trial failed to demonstrate a benefit. Colchicine has been shown to successfully reduce the risk of recurrent cardiovascular events in a large multicentric trial. Potential antifibrotic effects of colchicine require further exploration. Hydroxychloroquine, methotrexate and colchicine are also being tried at different stages of the ongoing Coronavirus Disease 19 (COVID-19) pandemic for prophylaxis and treatment. While the use of these agents is being diversified, their adverse effects should be timely diagnosed and prevented. Hydroxychloroquine can cause retinopathy and rarely cardiac and auditory toxicity, retinopathy being dose and time dependent. Methotrexate can cause transaminitis, cytopenias and renal failure, particularly in acute overdoses. Colchicine can rarely cause myopathies, cardiomyopathy, cytopenias and transaminitis. Strong evidence is warranted to keep balance between benefits of repurposing these old antirheumatic drugs and risk of their adverse effects.


id: cord-324166-6ydn2bvy
author: Kumar, Neeraj
date: 2020-08-20
txt: ./txt/cord-324166-6ydn2bvy.txt
cache: ./cache/cord-324166-6ydn2bvy.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1080/07391102.2020.1808072
doi: 10.1080/07391102.2020.1808072
summary:
  We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Similar binding sites were employed for performing the molecular docking of the noscapine conjugations with the target Mpro of coronavirus using the Hex 8.0 and SwissDock servers. With these significant results, it can be attributed that Nos-Hcq conjugate has a high potential to bind the target Mpro enzyme and further can be used as effective therapeutics for SARS-CoV-2. We report the efficient combinatorial therapy by conjugating the noscapine (antitussive drug) with potential hydroxychloroquine (Nos-Hcq) against the SARS-CoV-2, through the computational assays with insights into the experimental results.

title:
  Antitussive noscapine and antiviral drug conjugates as arsenal against COVID-19: a comprehensive chemoinformatics analysis

abstract:
  Coronavirus pandemic has caused a vast number of deaths worldwide. Thus creating an urgent need to develop effective counteragents against novel coronavirus disease (COVID-19). Many antiviral drugs have been repurposed for treatment but implicated minimal recovery, which further advanced the need for clearer insights and innovation to derive effective therapeutics. Strategically, Noscapine, an approved antitussive drug with positive effects on lung linings may show favorable outcomes synergistically with antiviral drugs in trials. Hence, we have theoretically examined the combinatorial drug therapy by culminating the existing experimental results with in silico analyses. We employed the antitussive noscapine in conjugation with antiviral drugs (Chloroquine, Umifenovir, Hydroxychloroquine, Favlplravir and Galidesivir). We found that Noscapine-Hydroxychloroquine (Nos-Hcq) conjugate has strong binding affinity for the main protease (Mpro) of SARS-CoV-2, which performs key biological function in virus infection and progression. Nos-Hcq was analyzed through molecular dynamics simulation. The MD simulation for 100 ns affirmed the stable binding of conjugation unprecedentedly through RMSD and radius of gyration plots along with critical reaction coordinate binding free energy profile. Also, dynamical residue cross-correlation map with principal component analysis depicted the stable binding of Nos-Hcq conjugate to Mpro domains with optimal secondary structure statistics of complex dynamics. Also, we reveal the drugs with stable binding to major domains of Mpro can significantly improve the work profile of reaction coordinates, drug accession and inhibitory regulation of Mpro. The designed combinatorial therapy paves way for further prioritized in vitro and in vivo investigations for drug with robust binding against Mpro of SARS-CoV-2.


id: cord-324707-9ld73wv1
title: Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial
author: Mitjà, Oriol
date: 2020-07-16
txt: ./txt/cord-324707-9ld73wv1.txt
cache: ./cache/cord-324707-9ld73wv1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/cid/ciaa1009
doi: 10.1093/cid/ciaa1009
summary:
  Study outcomes were the reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment start, patient disease progression using the WHO scale up to 28 days, and time to complete resolution of symptoms. Adult patients aged 18 years or more were eligible if they had mild symptoms of Covid-19 (i.e., fever, acute cough, shortness of breath, sudden olfactory or gustatory loss, or influenza-like-illness) for less than five days before enrollment, were non-hospitalized, and had a positive PCR test for SARS-CoV-2 in the baseline nasopharyngeal swab. We estimated that a sample size of 280 patients would provide the trial with 80% power to detect a difference of 0.5 log 10 in the mean reduction of SARS-CoV-2 viral load at a two-sided significance level of α = 0.05, assuming an expected standard deviation of 1.5 [23] .

abstract:
  BACKGROUND: No therapeutics have yet been proven effective for the treatment of mild-illness caused by SARS-CoV-2. We aimed to determine whether early treatment with hydroxychloroquine (HCQ) would be more efficacious than no-treatment for outpatients with mild Covid-19. METHODS: We conducted a multicenter, open label, randomized controlled trial in Catalonia (Spain) between March 17, and May 26, 2020. Eligible Covid-19 cases were non-hospitalized adult patients with recently confirmed SARS-CoV-2 infection and less than five days of symptoms. Patients were assigned to receive HCQ (800 mg on day 1, followed by 400 mg once daily for 6 days) or no antiviral treatment (not-placebo controlled). Study outcomes were the reduction of viral RNA load in nasopharyngeal swabs up to 7 days after treatment start, patient disease progression using the WHO scale up to 28 days, and time to complete resolution of symptoms. Adverse events were assessed up to 28 days. RESULTS: A total of 293 patients were eligible for intention-to-treat analysis: 157 in the control arm and 136 in the intervention arm. The mean age was 41.6 years (SD 12.6), mean viral load at baseline was 7.90 (SD 1.82) Log(10) copies/mL, and median time from symptom onset to randomization was 3 days. No significant differences were found in the mean reduction of viral load at day 3 (-1.41 vs. -1.41 Log(10) copies/mL in the control and intervention arm, respectively; difference 0.01 [95% CI -0.28;0.29]) or at day 7 (-3.37 vs. -3.44; d –0.07 [-0.44;0.29]). This treatment regimen did not reduce risk of hospitalization (7.1%, control vs. 5.9%, intervention; RR 0.75 [0.32;1.77]) nor shortened the time to complete resolution of symptoms (12 days, control vs. 10 days, intervention; p = 0.38). No relevant treatment-related AEs were reported. CONCLUSIONS: In patients with mild Covid-19, no benefit was observed with HCQ beyond the usual care.


id: cord-326154-01es0zv4
title: Cardiovascular Safety of Potential Drugs for the Treatment of Coronavirus Disease 2019
author: Aggarwal, Gaurav
date: 2020-05-16
url: https://www.ncbi.nlm.nih.gov/pubmed/32425199/
doi: 10.1016/j.amjcard.2020.04.054
abstract:
  Coronavirus disease 2019 (COVID-19) has become a global pandemic. It is still uncontrolled in most countries and no therapies are currently available. Various drugs are under investigation for its treatment. The disease is known to have worse outcomes in patients who have underlying cardiovascular disease. Chloroquine/hydroxychloroquine, azithromycin, remdesivir and lopinavir/ritonavir are currently being studied in trials and show some promise. Conduction disorders, heart failure and mortality have been reported with the use of these drugs. It is important to have a knowledge of potential cardiotoxic effects of these drugs before using them for COVID-19 patients for better allocation of healthcare resources and improvement in clinical outcomes.


id: cord-327006-m847xdzk
author: Di Castelnuovo, A.
date: 2020-11-04
url: http://medrxiv.org/cgi/content/short/2020.11.01.20223958v1?rss=1
doi: 10.1101/2020.11.01.20223958
title:
  Low dose hydroxychloroquine is associated with lower mortality in COVID-19: a meta-analysis of 26 studies and 44,521 patients

abstract:
  Background: Hydroxychloroquine (HCQ) was proposed as potential treatment for COVID-19, but its association with mortality is not well characterized. We conducted two meta-analyses to evaluate the association between HCQ (with or without azithromycin (AZM)) and total mortality in COVID-19 patients. Methods: Articles were retrieved until October 20th, 2020 by searching in seven databases. Data were combined using the general variance-based method on relative risk estimates. Results: A total of 26 articles were found (N=44,521 COVID-19 patients, including N=7,324 from 4 randomized clinical trials (RCTs)); 10 studies were valuable for analysing the association of HCQ+AZM. Overall, the use of HCQ was associated with 21% lower mortality risk (pooled risk ratio: 0.79, 95%CI: 0.67 to 0.93; high level of heterogeneity: I2=82%, random effects). This association vanished (1.10, 95%CI: 0.99 to 1.23 and 1.10, 95%CI: 0.99 to 1.23) when daily dose >400 mg or total dose >4,400 mg were used, respectively). HCQ+AZM was also associated with 25% lower mortality risk, but uncertainty was large (95%CI: 0.50 to 1.13; P=0.17). No association was apparent when only pooling the 4 RCTs (13.8% of the overall weight; pooled risk ratio: 1.11, 95%CI: 0.99 to 1.24). Conclusions: HCQ use was not associated with either increased or decreased mortality in COVID-19 patients when 4 RCTs only were evaluated, while a 7% to 33% reduced mortality was observed when observational studies were also included. The association was mainly apparent when pooling studies using lower doses of HCQ. These findings can help disentangling the debate on HCQ use in COVID-19.


id: cord-327360-4qpk99x9
author: Elsawah, Hozaifa Khalil
date: 2020-08-18
url: https://www.ncbi.nlm.nih.gov/pubmed/32808712/
doi: 10.1002/jmv.26442
title:
  Hydroxychloroquine for treatment of non‐severe COVID‐19 patients; systematic review and meta‐analysis of controlled clinical trials

abstract:
  BACKGROUND: Being a pandemic and having a high global case fatality rate directed us to assess the evidence strength of hydroxychloroquine efficacy in treating COVID‐19 arising from clinical trials and to update the practice with the most reliable clinical evidence. METHODS: A comprehensive search was started in June up to July‐18, 2020 in many databases, including PubMed, Embase and others. Of 432 studies found, only six studies fulfilled the inclusion criteria which includes: clinical trials, age>12 years with non‐severe COVID‐19, PCR‐confirmed COVID‐19, hydroxychloroquine is the intervention beyond the usual care. Data extraction and bias risk assessment were done by two independent authors. Both fixed‐effect and random‐effect models were utilized for pooling data using risk difference as a summary measure. The primary outcomes are clinical and radiological COVID‐19 progression, SARS‐CoV‐2 clearance in the pharyngeal swab, and mortality. The secondary outcomes are the adverse effects of hydroxychloroquine. RESULTS: Among 609 COVID‐19 confirmed patients obtained from pooling 6 studies, 294 patients received Hydroxychloroquine and 315 patients served as a control. Hydroxychloroquine significantly prevent early radiological progression relative to control with risk difference and 95% confidence interval of ‐0.2 (‐0.36 to ‐0.03). On the other hand, hydroxychloroquine did not prevent clinical COVID‐19 progression, reduce 5‐days mortality, or enhance viral clearance on days 5, 6, 7. Moreover, many adverse effects were reported with hydroxychloroquine therapy. CONCLUSIONS: Failure of hydroxychloroquine to show viral clearance or clinical benefits with additional adverse effects outweigh its protective effect from radiological progression in non‐severe COVID‐19 patients. Benefit‐risk balance should guide hydroxychloroquine use in COVID‐19. This article is protected by copyright. All rights reserved.


id: cord-327575-5pcnuqgy
author: Morrisette, Taylor
date: 2020-08-01
url: https://www.ncbi.nlm.nih.gov/pubmed/32740858/
doi: 10.1007/s40121-020-00325-2
title:
  The Pharmacokinetic and Pharmacodynamic Properties of Hydroxychloroquine and Dose Selection for COVID-19: Putting the Cart Before the Horse

abstract:
  Coronavirus disease 2019 (COVID-19), caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a global pandemic. To date, only remdesivir and dexamethasone have demonstrated a positive response in a prospective, randomized trial for the treatment of patients with COVID-19. Hydroxychloroquine (HCQ) is an agent available in an oral formulation with in vitro activity against SARS-CoV-2 that has been suggested as a potential agent. Unfortunately, results of randomized trials evaluating HCQ as treatment against a control group are lacking, and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) profile against SARS-CoV-2. The objective of this review was to describe the current understanding of the PK/PD and dose selection of HCQ against SARS-CoV-2, discuss knowledge gaps, and identify future studies that are needed to optimize the efficacy and safety of treatments against COVID-19.


id: cord-328257-kl4wh2zg
author: Xu, H
date: 2020-09-28
url: https://doi.org/10.1101/2020.09.27.316158
doi: 10.1101/2020.09.27.316158
title:
  Hydroxychloroquine increased psychiatric-like behaviors and disrupted the expression of related genes in the mouse brain

abstract:
  Hydroxychloroquine (HCQ), which has been proposed as a therapeutic or prophylactic drug for SARS-COV-2, has been administered to thousands of individuals with varying efficacy; however, our understanding of its adverse effects is insufficient. It was reported that HCQ induced psychiatric symptoms in a few patients with autoimmune diseases, but it is still uncertain whether HCQ poses a risk to mental health. Therefore, in this study, we treated healthy mice with two different doses of HCQ that are comparable to clinically administered doses for 7 days. Psychiatric-like behaviors and the expression of related molecules in the brain were evaluated at two time points, i.e., 24 h and 10 days after drug administration. We found that HCQ increased anxiety behavior at both 24 h and 10 days and enhanced depressive behavior at 24 h. Furthermore, HCQ decreased the mRNA expression of interleukin-1beta and corticotropin-releasing hormone (Crh) in the hippocampus and decreased the mRNA expression of brain-derived neurotrophic factor (Bdnf) in both the hippocampus and amygdala. Most of these behavioral and molecular changes were sustained beyond 10 days after drug administration, and some of them were dose-dependent. Although this animal study does not prove that HCQ has a similar effect in humans, it indicates that HCQ poses a significant risk to mental health and suggests that further clinical investigation is essential. According to our data, we recommend that HCQ be carefully used as a prophylactic drug in people who are susceptible to mental disorders.


id: cord-328714-jg562twk
author: Oscanoa, Teodoro J.
date: 2020-10-24
url: https://www.ncbi.nlm.nih.gov/pubmed/33164789/
doi: 10.1016/j.ijantimicag.2020.106212
title:
  Frequency of Long QT in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine: a Meta-analysis

abstract:
  INTRODUCTION: Hydroxychloroquine (HCQ) has been proposed as SARS-CoV-2 treatment but the frequency of Long QT (LQT) during use is unknown. OBJECTIVE: Conduct a meta-analysis of the frequency of LQT in patients with SARS-CoV-2 infection treated with HCQ. DATA SOURCES: We searched PubMed, EMBASE, Google Scholar, the Cochrane Database of Systematic Reviews and preprint servers (medRxiv, Research Square) for studies published between December 2019 and June 30, 2020. METHODS: Effect statistics were pooled using random effects. The quality of observational studies and randomized controlled trials was appraised with STROBE and the Cochrane Risk of Bias Assessment tools, respectively. OUTCOMES: Critical LQT was defined as: (1) maximum QT corrected (QTc)≥500 ms (if QRS<120 ms) or QTc≥550 ms (if QRS≥120 ms), and (2) QTc increase of ≥60 ms. RESULTS: In the 28 studies included (n=9124), the frequency of LQT during HCQ treatment was 6.7% (95% CI: 3.7-10.2%). In 20 studies (n=7825), patients were also taking other QT-prolonging drugs; the frequency of LQT in the other 8 studies (n=1299) was 1.7% (95% CI:0.3-3.9%). 20 studies (n=6869) reported HCQ discontinuation due to LQT, with a frequency of 3.7% (95% CI: 1.5-.6%). The frequency of ventricular arrhythmias during HCQ treatment was 1.68% (127/7539) and that of arrhythmogenic death 0.69% (39/5648). Torsades de Pointes occurred in 0.06% (3/5066). The group with highest risk of HCQ-associated LQT were those older than 60 years (p<0.001). CONCLUSIONS: HCQ-associated cardiotoxicity in SARS-CoV-2 patients is uncommon but requires ECG monitoring especially in those older than 60 years and/or taking other QT-prolonging drugs.


id: cord-329920-s928u6g3
title: Chloroquine, but not hydroxychlorquine, prolongs the QT interval in a primary care population
author: Isaksen, J. L.
date: 2020-06-20
url: http://medrxiv.org/cgi/content/short/2020.06.19.20135475v1?rss=1
doi: 10.1101/2020.06.19.20135475
abstract:
  Background: Chloroquine (CQ) and Hydroxychloroquine (HCQ) have recently been suggested as treatment for the current Corona Virus Disease 2019 (COVID-19) pandemic. However, despite their long-term use and only few case reports on adverse effects, CQ and HCQ are listed as a known risk of the lethal ventricular arrhythmia Torsade de Pointes and their cardiac safety profile is being questioned. Thus, we aimed to investigate the electrocardiographic and mortality effects of CQ and HCQ in a primary care population. Methods: We used Danish health care registers and electrocardiograms (ECGs) from primary care to define three studies. 1) A paired study of subjects with ECGs before and during use of CQ/HCQ, 2) a matched ECG study of subjects taking CQ/HCQ compared to controls, and 3) a mortality study on people taking HCQ matched to control. In both matched studies, we adjusted for connective tissue diseases, use of QT-prolonging drugs, and cardiac disease. We used the QTc interval as the marker for electrocardiographic safety. In the mortality study, cases were followed from first claimed prescription until 300 days after estimated completion of the last prescription. 95% confidence intervals follow estimates in parenthesis. Results: Use of CQ was associated with a 5.5 (0.7;10) ms increase in QTc in the paired study (n=10). In the matched study (n=28, controls=280), QTc was insignificantly increased in subjects taking CQ by 4.7 (-3.4;13) ms. With a {Delta}QTc of 1.0 (-5.6;7.5), use of HCQ was not associated with an increased QTc in the paired study (n=32). In the matched study (n=172, controls=1,720), QTc also was not different between groups (p=0.5). In the mortality study (n=3,368), use of HCQ was associated with a hazard ratio of 0.67 (0.43;1.05). Conclusions: In subjects free of COVID-19, we found a small increase in QTc associated with use of chloroquine, but not hydroxychloroquine. We found no increased mortality associated with use of hydroxychloroquine.


id: cord-332654-nav15g8k
author: Paniri, Alireza
date: 2020-08-04
txt: ./txt/cord-332654-nav15g8k.txt
cache: ./cache/cord-332654-nav15g8k.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S001429992030546X
doi: 10.1016/j.ejphar.2020.173454
summary:
  The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy. Furthermore, growing body of evidence demonstrated that several factors including CYP450 single nucleotide polymorphisms (SNPs), and epigenetic molecules such as non-coding RNAs (ncRNAs), DNA methylation and histone acetylation influenced the expression levels of CYP450, and consequently might influence HCQ metabolism. The major purpose of this review is to discuss the pharmacokinetic and pharmacodynamic characteristics of CQ and HCQ that may be influenced by epigenetic mechanisms including ncRNAs and CYP2D6 SNPs, and thereby cause several side effects such as cardiotoxicity, prolonged QT interval, gastrointestinal problems (like dyspepsia and abdominal cramps), central nervous system or skin disorders, and especially retinopathy.

title:
  Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations

abstract:
  Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.


id: cord-333144-gyuh2fvl
author: Siddiqui, Arif Jamal
date: 2020-08-05
txt: ./txt/cord-333144-gyuh2fvl.txt
cache: ./cache/cord-333144-gyuh2fvl.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1080/07391102.2020.1802345
doi: 10.1080/07391102.2020.1802345
summary:
  Therefore, this review focuses on the current use of various drugs as single agents (hydroxychloroquine, ivermectin, azithromycin, favipiravir, remdesivir, umifenovir, teicoplanin, nitazoxanide, doxycycline, and dexamethasone) or in combinations with immunomodulators additionally. While some drugs have shown therapeutic effect against COVID-19 infection such as hydroxychloroquine (Al-Kofahi et al., 2020; Choudhary & Sharma 2020; Liu et al., 2020; Sinha & Balayla 2020) , azithromycin, (Andreani et al., 2020a; Choudhary & Sharma 2020) ivermectin (Caly et al., 2020; Chaccour et al., 2020; Choudhary & Sharma 2020) and some other antivirals (Asai et al., 2020; Boopathi et al., 2020; Lian et al., 2020) . Consequently, this review will provide an insight and comprehensive view on different therapeutic approaches including combining of different known anti-parasitic drugs, as well as proposing novel suggestions of chemoprophylaxis drug therapy, which can be used in the current treatment and vaccine development strategies against COVID-19 disease.

title:
  Current status and strategic possibilities on potential use of combinational drug therapy against COVID-19 caused by SARS-CoV-2

abstract:
  The spread of new coronavirus infection starting December 2019 as novel SARS-CoV-2, identified as the causing agent of COVID-19, has affected all over the world and been declared as pandemic. Approximately, more than 8,807,398 confirmed cases of COVID-19 infection and 464,483 deaths have been reported globally till the end of 21 June 2020. Until now, there is no specific drug therapy or vaccine available for the treatment of COVID-19. However, some potential antimalarial drugs like hydroxychloroquine and azithromycin, antifilarial drug ivermectin and antiviral drugs have been tested by many research groups worldwide for their possible effect against the COVID-19. Hydroxychloroquine and ivermectin have been identified to act by creating the acidic condition in cells and inhibiting the importin (IMPα/β1) mediated viral import. There is a possibility that some other antimalarial drugs/antibiotics in combination with immunomodulators may help in combatting this pandemic disease. Therefore, this review focuses on the current use of various drugs as single agents (hydroxychloroquine, ivermectin, azithromycin, favipiravir, remdesivir, umifenovir, teicoplanin, nitazoxanide, doxycycline, and dexamethasone) or in combinations with immunomodulators additionally. Furthermore, possible mode of action, efficacy and current stage of clinical trials of various drug combinations against COVID-19 disease has also been discussed in detail. Communicated by Ramaswamy H. Sarma


id: cord-336572-n6juf8tw
author: Kalligeros, Markos
date: 2020-08-05
url: https://api.elsevier.com/content/article/pii/S2213716520301934
doi: 10.1016/j.jgar.2020.07.018
title:
  Hydroxychloroquine use in Hospitalized Patients with COVID-19: An observational matched cohort study

abstract:
  • The efficacy of HCQ in patients with COVID-19 is currently evaluated. • In our center the use of HCQ did not decrease the risk of in-hospital death. • HCQ use did not decrease the time to clinical improvement and the hospitalization length. • ASPs can allow for the safe evaluation of agents and treatments against COVID-19.


id: cord-337198-4sors3bg
author: Clementi, Nicola
date: 2020-07-10
txt: ./txt/cord-337198-4sors3bg.txt
cache: ./cache/cord-337198-4sors3bg.txt
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url: https://www.ncbi.nlm.nih.gov/pubmed/32754147/
doi: 10.3389/fmicb.2020.01704
summary:
  In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 and Caco-2 cells. In this study, we tested HCQ against a SARS-CoV-2 Italian clinical isolate, by using different protocols of drug administration corresponding to its possible prophylactic, therapeutic, and prophylactic/therapeutic use in patients. A clinical isolate hCoV-19/Italy/UniSR1/2020 (GISAID accession ID: EPI_ISL_413489) was isolated and propagated in Vero E6 cells, and viral titer was determined by 50% tissue culture infective dose (TCID 50 ) and plaque assay for confirming the obtained titer. HCQ EC 50 against SARS-CoV-2 was obtained by both CPE and RT-PCR analysis on results from full-time experimental setting on Vero E6 cells. Different concentrations of HCQ were tested on Vero E6 to determine the effective concentration of the drug against SARS-CoV-2 in vitro infection (Figure 1) .

title:
  Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro

abstract:
  While the SARS-CoV-2 pandemic is heavily hitting the world, it is of extreme importance that significant in vitro observations guide the quick set up of clinical trials. In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 and Caco-2 cells. This suggests that only a combined prophylactic and therapeutic use of hydroxychloroquine may be effective in limiting viral replication in patients.


id: cord-339669-p61j2caf
title: QTc evaluation in COVID‐19 patients treated with chloroquine/hydroxychloroquine
author: Monzani, Alice
date: 2020-05-18
url: https://www.ncbi.nlm.nih.gov/pubmed/32356580/
doi: 10.1111/eci.13258
abstract:
  In late December 2019, a cluster of pneumonia cases caused by a novel coronavirus occurred in Wuhan, China and has spread rapidly initially throughout Europe and later USA (1). The pathogen was originally called 2019 novel coronavirus (2019-nCoV) and later named severe acute respiratory syndrome coronavirus 2 (SARS-nCoV-2) by the World Health Organization (WHO).


id: cord-339717-2a8zv9xl
title: Hydroxychloroquine/Azithromycin Therapy and QT Prolongation in Hospitalized Patients with COVID-19
author: O’Connell, Thomas F.
date: 2020-08-05
url: https://api.elsevier.com/content/article/pii/S2405500X20306939
doi: 10.1016/j.jacep.2020.07.016
abstract:
  ABSTRACT Background Hydroxychloroquine and azithromycin (HCQ/AZM) are being widely used to treat COVID-19 despite the known risk of QT interval prolongation and unknown risk of arrhythmogenesis in this population. Objective The study aimed to characterize corrected QT (QTc) prolongation in a cohort of hospitalized COVID-19 patients treated with combination HCQ/AZM. Methods A retrospective cohort of COVID-19 hospitalized patients treated with HCQ/AZM was reviewed. The QTc interval was calculated prior to drug administration and for the first 5 days following initiation. The primary end point was the magnitude of QTc prolongation, and factors associated with QTc prolongation. Secondary endpoints were incidences of sustained ventricular tachycardia or ventricular fibrillation and all-cause mortality. Results Among 415 patients receiving concomitant HCQ/AZM, the mean QTc increased from 443±25 msec to a maximum of 473±40 msec (87 (21%) had a QTc ≥500 msec). Factors associated with QTc prolongation ≥500 msec were age (p < 0.001), body mass index <30 kg/m2 (p = 0.005), heart failure (p < 0.001), elevated creatinine (p = 0.005), and peak troponin (p < 0.001). The change in QTc was not associated with death over the short period of the study in a population where mortality was already high (hazard ratio, 0.998, p = 0.607). No primary high-grade ventricular arrhythmias were observed. Conclusions An increase in QTc was seen in hospitalized COVID-19 patients treated with HCQ/AZM. Several clinical factors were associated with greater QTc prolongation. Changes in QTc were not associated with increased risk of death.


id: cord-339737-7qdjea6f
author: Sbidian, E.
date: 2020-06-19
txt: ./txt/cord-339737-7qdjea6f.txt
cache: ./cache/cord-339737-7qdjea6f.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.06.16.20132597
doi: 10.1101/2020.06.16.20132597
summary:
  -Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ on 28-day mortality -Our results suggest an excess risk of mortality in patients treated by a combination of HCQ and AZI, but not with HCQ alone -Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies . Results from competing risks multivariable analyses for 28-day mortality and hospital discharge are displayed in Table 3 , showing both raw unadjusted estimates for the average treatment effect of ''HCQ alone ''or ''HCQ plus AZI'', and AIPTW results from double robust estimation accounting for confounders for the outcome and the treatment allocation.

title:
  Hydroxychloroquine with or without azithromycin and in-hospital mortality or discharge in patients hospitalized for COVID-19 infection: a cohort study of 4,642 in-patients in France

abstract:
  Objective To assess the clinical effectiveness of oral hydroxychloroquine (HCQ) with or without azithromycin (AZI) in preventing death or leading to hospital discharge. Design Retrospective cohort study. Setting An analysis of data from electronic medical records and administrative claim data from the French Assistance Publique - Hopitaux de Paris (AP-HP) data warehouse, in 39 public hospitals, Ile-de-France, France. Participants All adult inpatients with at least one PCR-documented SARS-CoV-2 RNA from a nasopharyngeal sample between February 1st, 2020 and April 6th, 2020 were eligible for analysis. The study population was restricted to patients who did not receive COVID-19 treatments assessed in ongoing trials, including antivirals and immunosuppressive drugs. End of follow-up was defined as the date of death, discharge home, day 28 after admission, whichever occurred first, or administrative censoring on May 4, 2020. Intervention Patients were further classified into 3 groups: (i) receiving HCQ alone, (ii) receiving HCQ together with AZI, and (iii) receiving neither HCQ nor AZI. Exposure to a HCQ/AZI combination was defined as a simultaneous prescription of the 2 treatments (more or less one day). Main outcome measures The primary outcome was all-cause 28-day mortality as a time-to-event endpoint under a competing risks survival analysis framework. The secondary outcome was 28-day discharge home. Augmented inverse probability of treatment weighted (AIPTW) estimates of the average treatment effect (ATE) were computed to account for confounding. Results A total of 4,642 patients (mean age: 66.1 +/- 18; males: 2,738 (59%)) were included, of whom 623 (13.4%) received HCQ alone, 227 (5.9%) received HCQ plus AZI, and 3,792 (81.7%) neither drug. Patients receiving "HCQ alone" or "HCQ plus AZI" were more likely younger, males, current smokers and overall presented with slightly more co-morbidities (obesity, diabetes, any chronic pulmonary diseases, liver diseases), while no major difference was apparent in biological parameters. After accounting for confounding, no statistically significant difference was observed between the "HCQ" and "Neither drug" groups for 28-day mortality: AIPTW absolute difference in ATE was +1.24% (-5.63 to 8.12), ratio in ATE 1.05 (0.77 to 1.33). 28-day discharge rates were statistically significantly higher in the "HCQ" group: AIPTW absolute difference in ATE (+11.1% [3.30 to 18.9]), ratio in ATE (1.25 [1.07 to 1.42]). As for the "HCQ+AZI" vs neither drug, trends for significant differences and ratios in AIPTW ATE were found suggesting higher mortality rates in the former group (difference in ATE +9.83% [-0.51 to 20.17], ratio in ATE 1.40 [0.98 to 1.81];p=0.062). Conclusions Using a large non-selected population of inpatients hospitalized for COVID-19 infection in 39 hospitals in France and robust methodological approaches, we found no evidence for efficacy of HCQ or HCQ combined with AZI on 28-day mortality. Our results suggested a possible excess risk of mortality associated with HCQ combined with AZI, but not with HCQ alone. Significantly higher rates of discharge home were observed in patients treated by HCQ, a novel finding warranting further confirmation in replicative studies. Altogether, our findings further support the need to complete currently undergoing randomized clinical trials.


id: cord-339838-8okrjbfn
title: Pharmacist''s perspective on HCQ treatment of COVID‐19
author: Wang, Ya‐Ling
date: 2020-06-12
txt: ./txt/cord-339838-8okrjbfn.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32533592/
doi: 10.1002/kjm2.12249
abstract: nan
summary:
  key: cord-339838-8okrjbfn authors: Wang, Ya‐Ling; Wang, Shih‐Han; Yang, Ai‐Yu After oral absorption, HCQ is widely distributed in various tissues in the body. 1 This finding is similar to another in-vitro study on Although HCQ is safer and more effective than Chloroquine, special attention should be paid to the interaction and side effects when it is used with Azithromycin. 4 There''s no guidance for the treatment of COVID-19 has indicated that the dose of HCQ can be calculated according to body weight and adjusted according to different races. All authors declare no conflict of interest. Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection Observational study of hydroxychloroquine in hospitalized patients with COVID-19


id: cord-340090-dqhdws5k
author: Behera, P.
date: 2020-11-03
url: http://medrxiv.org/cgi/content/short/2020.10.29.20222661v1?rss=1
doi: 10.1101/2020.10.29.20222661
title:
  Role of ivermectin in the prevention of COVID-19 infection among healthcare workers in India: A matched case-control study

abstract:
  Background: Ivermectin is one among several potential drugs explored for its therapeutic and preventive role in COVID-19 infection. The study was aimed to explore the association between ivermectin prophylaxis and development of COVID-19 infection among healthcare workers. Methods: A hospital-based matched case-control study was conducted among healthcare workers of AIIMS Bhubaneswar, India, from September to October 2020. Profession, gender, age and date of diagnosis were matched for 186 case-control pairs. Cases and controls were healthcare workers who tested positive and negative, respectively, for COVID-19 by RT-PCR. Exposure was defined as the intake of ivermectin and/or hydroxychloroquine and/or vitamin-C and/or other prophylaxis for COVID-19. Data collection and entry was done in Epicollect5, and analysis was performed using STATA version 13. Conditional logistic regression models were used to describe the associated factors for COVID-19 infection. Results: Ivermectin prophylaxis was taken by 77 controls and 38 cases. Two-dose ivermectin prophylaxis (0.27, 95% CI, 0.15-0.51) was associated with 73% reduction of COVID-19 infection among healthcare workers for the following one month, those who were involved in physical activity (3.06 95% CI, 1.18-7.93) for more than an hour/day were more likely to contract COVID-19 infection. Type of household, COVID duty, single-dose ivermectin prophylaxis, vitamin-C prophylaxis and hydroxychloroquine prophylaxis were not associated with COVID-19 infection. Conclusion: Two-dose ivermectin prophylaxis at a dose of 300 g/kg with a gap of 72 hours was associated 73% reduction of COVID-19 infection among healthcare workers for the following one-month. Further research is required before its large scale use. Keywords: COVID-19, Ivermectin, Chemoprophylaxis, Healthcare workers, India


id: cord-341101-5yvjbr5q
author: Hashem, Anwar M.
date: 2020-05-06
txt: ./txt/cord-341101-5yvjbr5q.txt
cache: ./cache/cord-341101-5yvjbr5q.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32387694/
doi: 10.1016/j.tmaid.2020.101735
summary:
  While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. In general, studies showed no significant effect of CQ on CoVs including SARS-CoV and feline infectious peritonitis virus (FIPV) replication or clinical scores in mice and cats, respectively [105, 110] . There are very limited published clinical trials that studied the possible antiviral effect of CQ or HCQ in CoV and non-CoV infected patients (Table 5 ). Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

title:
  Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review

abstract:
  The rapidly spreading Coronavirus Disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), represents an unprecedented serious challenge to the global public health community. The extremely rapid international spread of the disease with significant morbidity and mortality made finding possible therapeutic interventions a global priority. While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. Recent publications have re-examined the use of Chloroquine (CQ) and/or Hydroxychloroquine (HCQ) as a potential therapeutic option for these patients. In an attempt to explore the evidence that supports their use in COVID-19 patients, we comprehensively reviewed the previous studies which used CQ or HCQ as an antiviral treatment. Both CQ and HCQ demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. While few clinical trials have suggested some beneficial effects of CQ and HCQ in COVID-19 patients, most of the reported data are still preliminary. Given the current uncertainty, it is worth being mindful of the potential risks and strictly rational the use of these drugs in COVID-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of COVID-19.


id: cord-341377-mjdg84ny
author: Cohen, I. V.
date: 2020-05-26
url: http://medrxiv.org/cgi/content/short/2020.05.19.20107227v1?rss=1
doi: 10.1101/2020.05.19.20107227
title:
  Determinants of cardiac adverse events of chloroquine and hydroxychloroquine in 20 years of drug safety surveillance reports

abstract:
  Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization's List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to the risk of drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.


id: cord-342746-2hbcbvt6
author: Lane, J. C. E.
date: 2020-04-10
url: http://medrxiv.org/cgi/content/short/2020.04.08.20054551v1?rss=1
doi: 10.1101/2020.04.08.20054551
title:
  Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study

abstract:
  Background: Hydroxychloroquine has recently received Emergency Use Authorization by the FDA and is currently prescribed in combination with azithromycin for COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin. Methods: New user cohort studies were conducted including 16 severe adverse events (SAEs). Rheumatoid arthritis patients aged 18+ and initiating hydroxychloroquine were compared to those initiating sulfasalazine and followed up over 30 days. Self-controlled case series (SCCS) were conducted to further establish safety in wider populations. Separately, SAEs associated with hydroxychloroquine-azithromycin (compared to hydroxychloroquine-amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, Netherlands, Spain, UK, and USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (CalHRs) according to drug use. Estimates were pooled where I2<40%. Results: Overall, 956,374 and 310,350 users of hydroxychloroquine and sulfasalazine, and 323,122 and 351,956 users of hydroxychloroquine-azithromycin and hydroxychloroquine-amoxicillin were included. No excess risk of SAEs was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. SCCS confirmed these findings. However, when azithromycin was added to hydroxychloroquine, we observed an increased risk of 30-day cardiovascular mortality (CalHR2.19 [1.22-3.94]), chest pain/angina (CalHR 1.15 [95% CI 1.05-1.26]), and heart failure (CalHR 1.22 [95% CI 1.02-1.45]) Conclusions: Short-term hydroxychloroquine treatment is safe, but addition of azithromycin may induce heart failure and cardiovascular mortality, potentially due to synergistic effects on QT length. We call for caution if such combination is to be used in the management of Covid-19.


id: cord-344120-7t5ce2hb
title: SARS-CoV-2 pharmacologic therapies and their safety/effectiveness according to level of evidence
author: Baroutjian, Amanda
date: 2020-09-01
txt: ./txt/cord-344120-7t5ce2hb.txt
cache: ./cache/cord-344120-7t5ce2hb.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0735675720307853
doi: 10.1016/j.ajem.2020.08.091
summary:
  CONCLUSION: According to level 1 evidence reviewed here, the most effective SARS-Co-V-2 pharmacologic treatments include remdesivir for mild to severe disease, and a triple regimen therapy consisting of lopinavir-ritonavir, ribavirin and interferon beta-1b for mild to moderate disease. 20 Another randomized controlled open-label trial in 199 hospitalized patients with confirmed SARS-CoV-2 with severe COVID-19 was done to compare the clinical effectiveness of lopinavir-ritonavir to standard care alone. According to the level 1 evidence reviewed here, the most effective treatments against SARS-CoV-2, measured by time to negative RT-PCR and time to clinical improvement, are remdesivir therapy and a triple medication regimen (lopinavir-ritonavir, ribavirin, and interferon beta-1b). First, in patients with severe COVID-19, treatment with lopinavir-ritonavir showed no significant difference in time to clinical improvement, mortality at day 28, or detectable viral load compared to standard care alone.

abstract:
  INTRODUCTION: There is a pressing need for COVID-19 transmission control and effective treatments. We aim to evaluate the safety and effectiveness of SARS-CoV-2 pharmacologic therapies as of August 2, 2020 according to study level of evidence. METHODS: PubMed, ScienceDirect, Cochrane Library, JAMA Network and PNAS were searched. The following keywords were used: ((COVID-19) OR (SARS-CoV-2)) AND ((((((therapeutics) OR (treatment)) OR (vaccine)) OR (hydroxychloroquine)) OR (antiviral)) OR (prognosis)). Results included peer-reviewed studies published in English. RESULTS: 15 peer-reviewed articles met study inclusion criteria, of which 14 were RCTs and one was a systematic review with meta-analysis. The following pharmacologic therapies were evaluated: chloroquine (CQ), hydroxychloroquine (HCQ), antivirals therapies, plasma therapy, anti-inflammatories, and a vaccine. CONCLUSION: According to level 1 evidence reviewed here, the most effective SARS-Co-V-2 pharmacologic treatments include remdesivir for mild to severe disease, and a triple regimen therapy consisting of lopinavir-ritonavir, ribavirin and interferon beta-1b for mild to moderate disease. Also, dexamethasone significantly reduced mortality in those requiring respiratory support. However, there is still a great need for detailed level 1 evidence on pharmacologic therapies.


id: cord-347186-tbtmqmpr
title: Chloroquine and hydroxychloroquine as a repurposed agent against COVID-19: a narrative review
author: Acharya, Yogesh
date: 2020-08-04
url: https://doi.org/10.1177/2049936120947517
doi: 10.1177/2049936120947517
abstract:
  The predicament arising from the coronavirus disease 2019 (COVID-19) pandemic has become one of the most significant modern public health challenges. Despite uncertainties in the viral determinants and pathogenesis, it is crucial to accurately inspect all available evidence to construct accurate clinical guidelines for optimised patient care. This study aims to discuss the available evidence for the use of chloroquine (CQ) and hydroxychloroquine (HCQ) against COVID-19. Early in vitro studies of CQ/HCQ against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are convincing. But contradictory evidence exists on the clinical use of CQ/HCQ, either alone or in combination with azithromycin. As of now, there is no compelling clinical evidence on CQ, HCQ, and azithromycin in COVID-19 and the available evidence is limited to methodologically inferior non-randomised studies. Studies have also shown detrimental drug reactions to CQ and ‘HCQ plus azithromycin’, mainly cardiac side effects in hospitalised patients with coexisting cardiovascular comorbidities. Therefore, we recommend that physicians avoid high doses and exercise extreme caution in the compassionate use of CQ/HCQ, either alone or in combination with other antiviral drugs.


id: cord-347731-eqxn6auk
author: Garcia‐Cremades, Maria
date: 2020-05-12
url: https://doi.org/10.1002/cpt.1856
doi: 10.1002/cpt.1856
title:
  Optimizing Hydroxychloroquine Dosing for Patients With COVID‐19: An Integrative Modeling Approach for Effective Drug Repurposing

abstract:
  Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus disease of 2019 (COVID‐19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID‐19 treatment. The data sources included were (i) longitudinal clinical, pharmacokinetic (PK), and virologic data from patients with severe acute respiratory syndrome‐2 (SARS‐CoV‐2) infection who received HCQ with or without azithromycin (n = 116), (ii) in vitro viral replication data and SARS‐CoV‐2 viral load inhibition by HCQ, (iii) a population PK model of HCQ, and (iv) a model relating chloroquine PKs to corrected QT (QTc) prolongation. A mechanistic PK/virologic/QTc model for HCQ was developed and externally validated to predict SARS‐CoV‐2 rate of viral decline and QTc prolongation. SARS‐CoV‐2 viral decline was associated with HCQ PKs (P < 0.001). The extrapolated patient half‐maximal effective concentration (EC(50)) was 4.7 µM, comparable to the reported in vitro EC(50s). HCQ doses > 400 mg b.i.d. for ≥5 days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS‐CoV‐2 infection, and shorten treatment courses, compared with lower dose (≤ 400 mg daily) regimens. However, HCQ doses > 600 mg b.i.d. were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID‐19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy.


id: cord-347775-hidb8q1u
author: Karatza, Eleni
date: 2020-09-30
txt: ./txt/cord-347775-hidb8q1u.txt
cache: ./cache/cord-347775-hidb8q1u.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32933365/
doi: 10.1080/00498254.2020.1824301
summary:
  Model-based simulations of HCQ concentrations revealed that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects. 4. Based on the results from simulations performed and the currently published knowledge regarding HCQ in COVID-19 treatment, this study provides evidence that a high loading dose followed by sparse doses could offer significant benefits to the patients. Dosing schemes were designed in order to achieve a fast onset of "high" concentrations during the initial phase of the disease, since an initial higher viral load is anticipated, especially for patients with severe COVID-19, and then keep HCQ blood levels below 2250 ng/ml and over 500 ng/ml, at all times.

title:
  Optimization of hydroxychloroquine dosing scheme based on COVID-19 patients’ characteristics: a review of the literature and simulations

abstract:
  1. During the recent COVID-19 outbreak hydroxychloroquine (HCQ) has been proposed as a safe and effective therapeutic option. However, a wide variety of dosing schemes has been applied in the clinical practice and tested in clinical studies. 2. An extended literature survey was performed investigating the pharmacokinetics, the efficacy and safety of HCQ in COVID-19 treatment. Population pharmacokinetic models were retrieved from the literature and after evaluation and assessment one was selected in order to perform simulations. 3. The most commonly applied dosing schemes were explored for patients with different weights and different levels of HCQ clearance impairment. Model-based simulations of HCQ concentrations revealed that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects. For instance, the dosing scheme proposed for a 70 kg adult with moderate COVID-19 symptoms would be 600 mg upon diagnosis, 400 mg after 12 h, 300 mg after 24 h, 200 mg after 36 h, followed by 200 mg BID for 4 d, followed by 200 mg OD for 5 d. 4. Based on the results from simulations performed and the currently published knowledge regarding HCQ in COVID-19 treatment, this study provides evidence that a high loading dose followed by sparse doses could offer significant benefits to the patients.


id: cord-348987-3jpdvy7n
title: Chloroquine and hydroxychloroquine for COVID‐19: A word of caution
author: Annangi, Srinadh
date: 2020-05-11
txt: ./txt/cord-348987-3jpdvy7n.txt
cache: ./cache/cord-348987-3jpdvy7n.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32394513/
doi: 10.1111/resp.13845
abstract: nan
summary:
  1 Prior research including with human immunodeficiency virus (HIV) and SARS-CoV-1 has shown that in vitro antiviral activity of CQ and HCQ does not necessarily translate to in vivo clinical efficacy. 3 It is unclear how the differences in the EC 50 values will impact the in vivo prophylactic antiviral efficacy at their recommended doses of HCQ 400 mg twice daily (bd) on day 1 and then 200 mg bd for 5 days. Until then, CQ and HCQ should only be used in the setting of clinical trials with a clear understanding among physicians and patients of uncertain efficacy and potentially harmful side effects. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial


id: cord-349868-lb2jcl8m
author: Patel, Jay
date: 2020-07-12
txt: ./txt/cord-349868-lb2jcl8m.txt
cache: ./cache/cord-349868-lb2jcl8m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32789088/
doi: 10.7759/cureus.9151
summary:
  We present the cases of two COVID-19-positive patients treated with HCQ at our institution, which showed adverse effects of the medication. Hydroxychloroquine (HCQ), a common antimalarial and lupus drug, has been shown to potentially reduce viral carriage and the number of symptomatic days in COVID-19 patients according to an open-label non-randomized French case study of 36 patients [2] . The purpose of this case series was to highlight some of the cardiovascular complications related to HCQ and to engage in a risk-benefit analysis of its use in mild/moderate presentations of COVID-19. We believe these are among the first few cases illustrating adverse cardiovascular effects of the experimental five-day HCQ therapy in mild/moderate presentations of COVID-19. Case 2, considered as low risk, demonstrated how HCQ therapy initiated in an outpatient resulted in an adverse outcome that led to hospital admission.

title:
  Cardiovascular Considerations of Experimental Hydroxychloroquine Therapy on Patients Diagnosed With COVID-19: A Case Series Review

abstract:
  The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and its high virulence along with its variable presentation have generated a significant amount of interest within the medical community. The heterogeneous nature of the symptoms of the disease caused by SARS-CoV-2, coronavirus disease 2019 (COVID-19), ranging from being asymptomatic to severe acute respiratory distress syndrome (ARDS), has created significant interest in potential therapeutics. Given the lack of randomized controlled trials, most medications are experimental, and only anecdotal evidence is available so far regarding their efficacy. One medication that emerged as an early frontrunner as a promising therapeutic was hydroxychloroquine (HCQ), a common antimalarial and lupus drug. The adverse side effects that could result from its use did not gain much attention initially. We present the cases of two COVID-19-positive patients treated with HCQ at our institution, which showed adverse effects of the medication. While HCQ may have some therapeutic effect, it should be borne in mind that patients may experience more harm than benefit from its use.


id: cord-350992-l6l24pco
author: Roldan, Eugenia Quiros
date: 2020-05-13
txt: ./txt/cord-350992-l6l24pco.txt
cache: ./cache/cord-350992-l6l24pco.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1043661820312123?v=s5
doi: 10.1016/j.phrs.2020.104904
summary:
  Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. We also propose a different insight into some of CQ and HCQ effects, suggesting a potential role of iron homeostasis in Sars-Cov-2 disease (COVID-19), similarly to several other human viral infections [2] [3] [4] . The search strategy was to use different search terms alone and in any combination, such as "Sars-Cov-2 disease", "COVID-19", "Sars-Cov-2", "coronavirus", "clinical trial", "treatment", "drug", "chloroquine", "hydroxychloroquine", "iron", "virus", "viral entry", "viral spread", "anti-viral activity", "infection", "inflammation", "immunity", "innate immunity", "cytokine", "IL-6", "TNF-", "IL-1", "adaptive immunity", "thrombosis", "in vitro".

title:
  The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis?

abstract:
  The anti-malarial drugs chloroquine (CQ) and primarily the less toxic hydroxychloroquine (HCQ) are currently used to treat autoimmune diseases for their immunomodulatory and anti-thrombotic properties. They have also been proposed for the treatment of several viral infections, due to their anti-viral effects in cell cultures and animal models, and, currently, for the treatment of coronavirus disease 2019 (COVID-19), the pandemic severe acute respiratory syndrome caused by coronavirus 2 (Sars-Cov-2) infection that is spreading all over the world. Although in some recent studies a clinical improvement in COVID-19 patients has been observed, the clinical efficacy of CQ and HCQ in COVID-19 has yet to be proven with randomized controlled studies, many of which are currently ongoing, also considering pharmacokinetics, optimal dosing regimen, therapeutic level and duration of treatment and taking into account patients with different severity degrees of disease. Here we review what is currently known on the mechanisms of action of CQ and HCQ as anti-viral, anti-inflammatory and anti-thrombotic drugs and discuss the up-to-date experimental evidence on the potential mechanisms of action of CQ/HCQ in Sars-Cov2 infection and the current clinical knowledge on their efficacy in the treatment of COVID-19 patients. Given the role of iron in several human viral infections, we also propose a different insight into a number of CQ and HCQ pharmacological effects, suggesting a potential involvement of iron homeostasis in Sars-Cov-2 infection and COVID-19 clinical course.


id: cord-351510-8m4930bc
author: Aquino, Yves S J
date: 2020-07-09
url: https://www.ncbi.nlm.nih.gov/pubmed/32647045/
doi: 10.1136/medethics-2020-106306
title:
  Hydroxychloroquine and COVID-19: critiquing the impact of disease public profile on policy and clinical decision-making

abstract:
  The controversy surrounding the use of hydroxychloroquine (HCQ), an antimalarial drug, for COVID-19 has raised numerous ethical and policy problems. Since the suggestion that HCQ has potential for COVID-19, there have been varying responses from clinicians and healthcare institutions, ranging from adoption of protocols using HCQ for routine care to the conduct of randomised controlled trials to an effective system-wide prohibition on its use for COVID-19. In this article, we argue that the concept of ‘disease public profile’ has become a prominent, if not the sole, determinant in decision-making across various healthcare responses to the pandemic. In the case of COVID-19, the disease’s public profile is based on clinical and non-clinical factors that include contagiousness, clinical presentation and media coverage. In particular, we briefly examine the dangers of a heightened public profile in magnifying the inequality of diseases and undermining three key ethical concepts, namely (1) evidence-based practice, (2) sustainable allocation and (3) meaningful consent.


id: cord-352557-l7sahv5t
author: Takla, Michael
date: 2020-11-13
url: https://api.elsevier.com/content/article/pii/S1319016420302644
doi: 10.1016/j.jsps.2020.11.003
title:
  Chloroquine, hydroxychloroquine, and COVID-19: systematic review and narrative synthesis of efficacy and safety

abstract:
  The COVID-19 pandemic has required clinicians to urgently identify new treatment options or the re-purposing of existing drugs. Of particular interest are chloroquine (CQ) and hydroxychloroquine (HCQ). The aims of this systematic review are to systematically identify and collate 24 studies describing the use of CQ and HCQ in human clinical trials and to provide a detailed synthesis of evidence of its efficacy and safety. Of clinical trials, 100% showed no significant difference in the probability of viral transmission or clearance in prophylaxis or therapy, respectively, compared to the control group. Among observational studies employing an endpoint specific to efficacy, 58% concurred with the finding of no significant difference in the attainment of outcomes. Three-fifths of clinical trials and half of observational studies examining an indicator unique to drug safety discovered a higher probability of adverse events in those treated patients suspected of, and diagnosed with, COVID-19. Of the total papers focusing on cardiac side-effects, 44% found a greater incidence of QTc prolongation and/or arrhythmias, 44% found no evidence of a significant difference, and 11% mixed results. The strongest available evidence points towards the inefficacy of CQ and HCQ in prophylaxis or in the treatment of hospitalised COVID-19 patients.


id: cord-353749-2vlc11rx
title: Flattening the Risk: Pre-Exposure Prophylaxis for COVID-19
author: Stricker, Raphael B
date: 2020-10-19
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url: https://doi.org/10.2147/idr.s264831
doi: 10.2147/idr.s264831
summary:
  24 In one uncontrolled study, HCQ prophylaxis in a hospital setting with a known SARS-CoV-2 exposure prevented dissemination of viral infection. 40 The second case-control study of HCWs found that four or more weekly doses of HCQ resulted in significantly less infection with SARS-CoV-2 (adjusted odds ratio 0.44, p<0.001). 45 In a retrospective cohort study of 32,109 rheumatic disease patients from the US Veterans Health Administration, the incidence of SARS-CoV-2 infection was equivalent regardless of chronic HCQ use (0.3% in users versus 0.4% in non-users), but mortality was significantly decreased in patients taking HCQ (odds ratio 0.70, p=0.0031). SARS-CoV-2 infection in a patient on chronic hydroxychloroquine therapy: implications for prophylaxis Long-term hydroxychloroquine use in patients with rheumatic conditions and development of SARS-CoV-2 infection: a retrospective cohort study Hydroxychloroquine in the COVID-19 pandemic era: in pursuit of a rational use for prophylaxis of SARS-CoV-2 infection

abstract:
  To date, more than 35 million people worldwide have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent of coronavirus disease 2019 (COVID-19), and more than one million have died in the COVID-19 pandemic. International economies are stalled and social isolation based on palpable fear of death remains the order of the day. The United States and other countries are moving toward resuming work activities and social interaction to boost economic recovery. While this makes financial sense, from a medical perspective our population has already suffered and will continue to suffer severe losses in the absence of a viable aggressive prophylaxis strategy for SARS-CoV-2. Herein, we present a plan to address this problem.


id: cord-354653-m0717ywt
author: Leung, Alexander KC
date: 2020-07-20
url: https://www.ncbi.nlm.nih.gov/pubmed/32742294/
doi: 10.7573/dic.2020-5-8
title:
  Hydroxychloroquine-induced hyperpigmentation in a 14-year-old female with systemic lupus erythematosus

abstract:
  Hydroxychloroquine (HCQ)-induced hyperpigmentation is uncommon but is increasingly recognized. To our knowledge, HCQ-induced hyperpigmentation has not been reported in the pediatric age group. Herein, we present the case of a 14-year-old girl with systemic lupus erythematosus, who developed hyperpigmentation on her shins and dorsum of the left foot, approximately 3 years after initiating treatment with HCQ. Physicians who treat children with HCQ for reasons such as rheumatologic disorders, dermatologic disorders and, more recently, coronavirus disease-19 should be aware of this less-known side effect of HCQ.


