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1.
Trials ; 21(1): 904, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129363

RESUMO

OBJECTIVES: The selected combination was based on limited evidence clinically and in vitro on the efficacy of the Favipiravir and Hydroxychloroquine in SARS-CoV-2. The two medications were listed in many guidelines as treatment options and ongoing trials assessing their efficacy and safety. Thus, we want to prove the clinical effectiveness of the combination as therapy. TRIAL DESIGN: This is an Open label, multicenter, randomized controlled clinical trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. It is a multicenter trial that will compare Favipiravir plus Hydroxychloroquine combination (experimental arm) to a control arm. PARTICIPANTS: All study procedures will be conducted in eight centres in Saudia Arabia: King Abdulaziz Medical City National Guard Health Affairs in Riyadh. King Abdulaziz Hospital - Al Ahsa, Saudi Arabia AlMadina General Hospital, Madnia, Saudi Arabia Al-Qatif Central Hospital, Saudi Arabia Imam Abdulrahman Al Faisal Hospital, Dammam, Saudi Arabia King Abdulaziz Medical City, Jeddah, Saudi Arabia King Abdulaziz Hospital, Makkah, Saudi Arabia Imam Abdulrahman Alfaisal Hospital, Riyadh, Saudi Arabia Inclusion Criteria • Should be at least 18 years of age, • Male or nonpregnant female, • Diagnosed with COVID-19 by PCR confirmed SARS-coV-2 viral infection. • Able to sign the consent form and agree to clinical samples collection (or their legal surrogates if subjects are or become unable to make informed decisions).. • Moderate or Severe COVID-19, defined as oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or significant clinical symptoms that require hospital admission. • patients had to be enrolled within 10 days of disease onset. Exclusion Criteria • Patients who are pregnant or breastfeeding. • Will be transferred to a non-study site hospital or discharged from hospital within 72 hours. • Known sensitivity/allergy to hydroxychloroquine or Favipiravir • Current use of hydroxychloroquine for another indication • Prior diagnosis of retinopathy • Prior diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency • Major comorbidities increasing the risk of study drug including: i. Hematologic malignancy, ii. Advanced (stage 4-5) chronic kidney disease or dialysis therapy, iii. Known history of ventricular arrhythmias, iv. Current use of drugs that prolong the QT interval, Severe liver damage (Child-Pugh score ≥ C, AST> 5 times the upper limit), HIV. • The investigator believes that participating in the trial is not in the best interests of the patient, or the investigator considers unsuitable for enrollment (such as unpredictable risks or subject compliance issues). • Clinical prognostic non-survival, palliative care, or in deep coma and no have response to supportive treatment within three hours of admission • Patient with irregular rhythm • Patient with a history of heart attack (myocardial infarction) • Patient with a family history of sudden death from heart attack before the age of 50 • Take other drugs that can cause prolonged QT interval • Patient who is receiving immunosuppressive therapy (cyclosporin) which cannot be switched to another agent or adjusted while using the investigational drug • Gout/history of Gout or hyperuricemia (above the ULN), hereditary xanthinuria or xanthine calculi of the urinary tract. INTERVENTION AND COMPARATOR: The treatment intervention would be for a maximum of 10 days from randomization and it would be as follows: Favipiravir for 10 days: Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10 days) Hydroxychloroquine for 5 days: (400mg) twice daily on day 1; for days 2-5 (200mg) twice daily. Reference Comparator Therapy: Standard of care is defined as: Treatment that is accepted by medical experts as a proper treatment for Covid-19 disease. Standard care comprised of, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, extracorporeal membrane oxygenation (ECMO), and antiviral therapy except Favipiravir. Also, it may include intravenous fluids and medications for symptoms relief . MAIN OUTCOMES: The primary endpoint is the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first (14 days from Randomization). RANDOMISATION: Eligible participants will be randomized in a 1:1 ratio to either the combination group (Favipiravir and Hydroxychloroquine) or a control group. The patients will be randomized utilizing Web based data entry System with a stratification based on the centre and the ICU admission. BLINDING (MASKING): This is an Open label study and only the analyst will be blinded during the study conduct. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Under the classical two arm parallel design the total effective sample sizes needed is 472 subjects (236 subjects per group). TRIAL STATUS: Protocol version 3.1 (dated 11 Aug 2020), and currently recruitment is ongoing. The date recruitment started was May 21, 2020 and the investigators anticipate the trial will finish recruiting by the end of December 2020. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04392973 , 19 May 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Pirazinas/uso terapêutico , Amidas/efeitos adversos , Antivirais/efeitos adversos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Quimioterapia Combinada , Feminino , Interações Hospedeiro-Patógeno , Humanos , Hidroxicloroquina/efeitos adversos , Pacientes Internados , Masculino , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Pirazinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Arábia Saudita , Fatores de Tempo , Resultado do Tratamento
2.
Biomedica ; 40(Supl. 2): 80-95, 2020 10 30.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-33152192

RESUMO

Introduction: Recently, researchers from China and France reported on the effectiveness of chloroquine and hydroxychloroquine for the inhibition of SARS-CoV-2 viral replication in vitro. Timely dissemination of scientific information is key in times of pandemic. A systematic review of the effect and safety of these drugs on COVID-19 is urgently needed. Objective: To map published studies until March 25, 2020, on the use of chloroquine and its derivates in patients with COVID-19. Materials and methods: We searched on PubMed, Embase, Lilacs, and 15 registries from the World Health Organization's International Clinical Trials Registry Platform for theoretical and empirical research in English, Spanish, Italian, French, or Portuguese until March 25, 2020, and made a narrative synthesis of the results. Results: We included 19 records and 24 trial registries (n=43) including 18,059 patients. China registered 66% (16/24) of the trials. Nine trials evaluate chloroquine exclusively and eight hydroxychloroquine. The records are comments (n=9), in vitro studies (n=3), narrative reviews (n=2), clinical guidelines (n=2), as well as a systematic review, an expert consensus, and a clinical trial. Conclusions: One small (n=26), non-randomized, and flawed clinical trial supports hydroxychloroquine use in patients with COVID-19. There is an urgent need for more clinical trial results to determine the effect and safety of chloroquine and hydroxychloroquine on COVID-19.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Antivirais/efeitos adversos , Antivirais/farmacologia , Betacoronavirus/fisiologia , Cloroquina/efeitos adversos , Cloroquina/farmacologia , Ensaios Clínicos como Assunto , Ensaios de Uso Compassivo , Síndrome da Liberação de Citocina/tratamento farmacológico , Reposicionamento de Medicamentos , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacologia , Estudos Multicêntricos como Assunto , Pandemias , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos
3.
Bratisl Lek Listy ; 121(11): 817-821, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33164544

RESUMO

BACKGROUND: Combination of hydroxychloroquine and azithromycin for the treatment of coronavirus disease 2019 (COVID-19) carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias. OBJECTIVE:  To characterize the ventricular repolarization indexes which are associated with malignant ventricular arrhythmias in patients treated with hydroxychloroquine and concomitant azithromycin for COVID-19. METHOD: A total of 81 patients who had hydroxychloroquine and azithromycin combination therapy because of possible or  reverse-transcription polymertase chain reaction (RT-PCR) confirmed diagnosis of COVID-19 were included in the study. Baseline and control electrocardiograms (before and after treatment) were analyzed retrospectively. Tp-e interval, Tp-e/QT and Tp-e/QTc ratios, which are ventricular repolarization indexes, were calculated. RESULTS: While there was no significant increase in QTc interval in patients receiving combination therapy, there was a significant increase in ventricular repolarization indexes. CONCLUSION: The increase in ventricular replarization indexes is associated with the risk of arrhythmia. In patients using QTc prolonging medication for COVID-19 treatment, QTc monitoring alone may not be sufficient to follow-up for arrhythmia. Even if there is no prolongation in QTc, an increase in ventricular repolarization indexes may be seen (Tab. 5, Ref. 37).


Assuntos
Azitromicina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Quimioterapia Combinada , Eletrocardiografia , Humanos , Pandemias , Estudos Retrospectivos
4.
J Med Case Rep ; 14(1): 210, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33138853

RESUMO

BACKGROUND: Since the World Health Organization declared a global pandemic due to the novel coronavirus disease2019, there have been targeted efforts to establish management modalities. Hydroxychloroquine has been suggested as a possible treatment; however, it is associated with multiple adverse reactions. We report a rare case of a patient with acute generalized exanthematous pustulosis with Stevens-Johnson syndrome due to hydroxychloroquine. Acute generalized exanthematous pustulosis is characterized by acute onset of a generalized rash that is pustular and erosive in nature, affecting limbs; trunk; face; and, less often, mucosal membranes. Although rare, it is important to be mindful of this side effect because the diagnosis is often delayed, and the disease has the potential to be life-threatening. CASE PRESENTATION: A 68-year-old American woman presented to our hospital with a painful, rapidly spreading rash. Its morphologic features included erythema multiforme-like lesions with extensive skin sloughing in various regions of the head, neck, and trunk and mucosal involvement. Her Nikolsky sign was negative, and she had no evidence of lesions on areas of skin trauma. Four weeks prior, she had been initiated on hydroxychloroquine for a presumed diagnosis of cutaneous sarcoidosis. Three punch biopsies of the head and neck area revealed subcorneal pustules consistent with acute generalized exanthematous pustulosis. Treatment began with high doses of methylprednisolone, leading to only minimal improvement of existing areas and ongoing spread to new areas. Treatment with intravenous immunoglobulin was initiated, at which point disease stability was achieved. The patient's rash ultimately resolved, as did her cutaneous pain and pruritus. CONCLUSIONS: Among many potential adverse reactions involving hydroxychloroquine, cutaneous side effects are varied and can lead to significant morbidity or even death. The drug is currently being investigated in a multitude of trials for coronavirus disease2019 treatment, prevention, and prophylaxis after exposure to severe acute respiratory syndrome coronavirus 2. Acute generalized exanthematous pustulosis is a rare side effect of hydroxychloroquine, and even fewer cases demonstrate histologic evidence of acute generalized exanthematous pustulosis while clinically presenting with Stevens-Johnson syndrome. Patients who develop Stevens-Johnson syndrome/toxic epidermal necrolysis require best supportive care with aggressive fluid and electrolyte replacement and prevention of further breakdown of the skin barrier. With the potential of widespread hydroxychloroquine use, it is important that providers be aware of its potential severe adverse drug reactions.


Assuntos
Pustulose Exantematosa Aguda Generalizada , Infecções por Coronavirus/epidemiologia , Hidroxicloroquina , Imunoglobulinas Intravenosas/administração & dosagem , Metilprednisolona/administração & dosagem , Pneumonia Viral/epidemiologia , Sarcoidose/tratamento farmacológico , Síndrome de Stevens-Johnson , Pustulose Exantematosa Aguda Generalizada/diagnóstico , Pustulose Exantematosa Aguda Generalizada/etiologia , Pustulose Exantematosa Aguda Generalizada/fisiopatologia , Pustulose Exantematosa Aguda Generalizada/terapia , Idoso , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Biópsia/métodos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Fatores Imunológicos , Pandemias , Pele/patologia , Dermatopatias/tratamento farmacológico , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/etiologia , Síndrome de Stevens-Johnson/fisiopatologia , Síndrome de Stevens-Johnson/terapia , Resultado do Tratamento
5.
Trials ; 21(1): 867, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33081817

RESUMO

BACKGROUND: There is an urgent need for treatments that can shorten hospitalization and lower the risk of secondary infection and death in patients with corona disease. The ProPac-COVID trial evaluates whether combination therapy with macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy, and pre-emptive treatment of supra-infections can shorten hospitalization duration and reduce the risk of non-invasive ventilation, treatment in the intensive care unit, and death in patients with acute hospital admission and a positive test for 2019-nCoV and symptoms of COVID-19 disease. METHODS: The ProPAC-COVID is a multi-center, randomized, placebo-controlled, double-blinded clinical trial. The primary outcome is number of days spent alive and out of hospital within 14 days from randomization. Randomization will be in blocks of unknown size, and the final allocation will be stratified for age, site of recruitment, and whether the patient has any chronic lung diseases. Data is analyzed using intention-to-treat (ITT) principles, and main analyses will also be subject to modified ITT analysis and per protocol analysis. DISCUSSION: This paper describes the detailed statistical analysis plan for the evaluation of primary and secondary endpoints of the ProPAC-COVID study. Enrolment of patients to the ProPAC-COVID study is still ongoing. The purpose of this paper is to provide primary publication of study results to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. TRIAL REGISTRATION: ClinicalTrials.gov NCT04322396 . Registered on 26 March 2020.


Assuntos
Antibacterianos/uso terapêutico , Antimaláricos/uso terapêutico , Azitromicina/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/prevenção & controle , Hidroxicloroquina/uso terapêutico , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Idoso , Antibacterianos/efeitos adversos , Antibioticoprofilaxia/métodos , Antimaláricos/efeitos adversos , Azitromicina/efeitos adversos , Betacoronavirus/genética , Estudos de Casos e Controles , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Dinamarca/epidemiologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Mortalidade Hospitalar/tendências , Hospitalização/estatística & dados numéricos , Humanos , Hidroxicloroquina/efeitos adversos , Unidades de Terapia Intensiva/estatística & dados numéricos , Análise de Intenção de Tratamento/métodos , Masculino , Ventilação não Invasiva/efeitos adversos , Placebos/administração & dosagem , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Comportamento de Redução do Risco
6.
Ann Intern Med ; 173(8): JC41, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-33075259

RESUMO

SOURCE CITATION: Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med. 2020;383:517-25. 32492293.


Assuntos
Infecções por Coronavirus , Hidroxicloroquina , Futilidade Médica , Pandemias , Pneumonia Viral , Adulto , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Humanos , Hidroxicloroquina/efeitos adversos
7.
PLoS One ; 15(10): e0240266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33007039

RESUMO

BACKGROUND: Hydroxychloroquine (HCQ) is widely used in the treatment of malaria, rheumatologic disease such as lupus, and most recently, COVID-19. These uses raise concerns about its safe use in the setting of glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially as 11% of African American men carry the G6PD A- variant. However, limited data exist regarding the safety of HCQ in this population. STUDY DESIGN AND METHODS: Recently, we created a novel "humanized" mouse model containing the G6PD deficiency A- variant (Val68Met) using CRISPR technology. We tested the effects of high-dose HCQ administration over 5 days on hemolysis in our novel G6PD A- mice. In addition to standard hematologic parameters including plasma hemoglobin, erythrocyte methemoglobin, and reticulocytes, hepatic and renal function were assessed after HCQ. RESULTS: Residual erythrocyte G6PD activity in G6PD A- mice was ~6% compared to wild-type (WT) littermates. Importantly, we found no evidence of clinically significant intravascular hemolysis, methemoglobinemia, or organ damage in response to high-dose HCQ. CONCLUSIONS: Though the effects of high doses over prolonged periods was not assessed, this study provides early, novel safety data of the use of HCQ in the setting of G6PD deficiency secondary to G6PD A-. In addition to novel safety data for HCQ, to our knowledge, we are the first to present the creation of a "humanized" murine model of G6PD deficiency.


Assuntos
Modelos Animais de Doenças , Deficiência de Glucosefosfato Desidrogenase/patologia , Hidroxicloroquina/efeitos adversos , Afro-Americanos , Animais , Infecções por Coronavirus/tratamento farmacológico , Humanos , Hidroxicloroquina/uso terapêutico , Masculino , Camundongos , Pandemias , Pneumonia Viral/tratamento farmacológico
8.
J Perinat Med ; 48(9): 1001-1007, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33055313

RESUMO

Objectives The severe acute respiratory syndrome coronavirus 2 (COVID-19) outbreak in Italy, especially in Lombardy and Bergamo city, represented probably nowadays one of the first major clusters of COVID-19 in the world. The aim of this report is to describe the activity of Bergamo Teratology Information Service (TIS) in supporting the public and health-care personnel in case of drug prescriptions in suspected/confirmed COVID-19 pregnant and lactating patients during COVID-19 outbreak in Italy. Methods All Bergamo TIS requests concerning COVID-19 pregnant and lactating women have been retrospectively evaluated from 1 March to 15 April 2020. Type of medications, drug's safety profile and compatibility with pregnancy and lactation are reported. Results Our service received information calls concerning 48 (9 pregnant, 35 lactating) patients. Among pregnant and lactating women, the requests of information were related to 16 and 60 drugs prescriptions respectively. More than half concerned drugs prescriptions during the first and second trimester (13/16) and during the first six months of lactation (37/60). Hydroxychloroquine and azithromycin were the most involved. Conclusions Hydroxychloroquine and azithromycin at dosages used for COVID-19 may be considered compatible and reasonably safe either in pregnancy and lactation. Antivirals may be considered acceptable in pregnancy. During lactation lopinavir and ritonavir probably exhibit some supportive data from literature that darunavir and cobicistat do not. Tocilizumab may be considered for COVID-19 treatment because no increased malformation rate were observed until now. However caution may be advised because human data are limited and the potential risk of embryo-fetal toxicity cannot be excluded.


Assuntos
Antivirais/efeitos adversos , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Lactação , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Complicações Infecciosas na Gravidez/virologia , Anormalidades Induzidas por Medicamentos , Adulto , Azitromicina/efeitos adversos , Anormalidades Congênitas , Prescrições de Medicamentos , Feminino , Idade Gestacional , Humanos , Hidroxicloroquina/efeitos adversos , Itália , Troca Materno-Fetal , Pessoa de Meia-Idade , Pandemias , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Teratologia
10.
Medwave ; 20(7): e8008, 2020 Aug 28.
Artigo em Espanhol | MEDLINE | ID: mdl-32877391

RESUMO

In December 2019, a new strain of the SARS-CoV-2 coronavirus was reported in Wuhan, China, which produced severe lung involvement and progressed to respiratory distress. To date, more than seventeen million confirmed cases and more than half a million died worldwide from COVID-19. Patients with cardiovascular disease are more susceptible to contracting this disease and presenting more complications. We did a literature search on the association of cardiovascular disease and COVID-19 in databases such as Scopus, PubMed/MEDLINE, and the Cochrane Library. The purpose of this review is to provide updated information for health professionals who care for patients with COVID-19 and cardiovascular disease, given that they have a high risk of complications and mortality. Treatment with angiotensin-converting enzyme inhibitors and receptor blockers is controversial, and there is no evidence not to use these medications in patients with COVID-19. Regarding treatment with hydroxychloroquine associated or not with azithromycin, there is evidence of a higher risk with its use than clinical benefit and decreased mortality. Likewise, patients with heart failure are an important risk group due to their condition per se. Patients with heart failure and COVID-19 are a diagnostic dilemma because the signs of acute heart failure could be masked. On the other hand, in patients with acute coronary syndrome, the initial therapeutic approach could change in the context of the pandemic, although only based on expert opinions. Nonetheless, many controversial issues will be the subject of future research.


Assuntos
Betacoronavirus , Doenças Cardiovasculares/complicações , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Síndrome Coronariana Aguda/etiologia , Síndrome Coronariana Aguda/terapia , Algoritmos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antivirais/efeitos adversos , Azitromicina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Quimioterapia Combinada , Eletrocardiografia/efeitos dos fármacos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Humanos , Hidroxicloroquina/efeitos adversos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Prognóstico , Sistema Renina-Angiotensina/fisiologia
11.
Int Heart J ; 61(5): 1056-1058, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921678

RESUMO

An 84-year-old woman with hypertension, Alzheimer's disease, and chronic kidney disease presented with fever and was diagnosed with corona virus disease 2019 (COVID-19). During the hospitalization, she experienced unexpected sinus bradycardia with prolonged QTc, which was thought to be closely related to the short-term use of hydroxychloroquine (HCQ), an old drug used to treat malaria and autoimmune diseases, but now used against COVID-19. The cardiac side effects of HCQ were rare, seen with short-term and low-dose use. With the COVID-19 pandemic, this case alerts clinicians to be aware of the arrhythmogenic effects of HCQ when it is used as an antiviral drug, especially in patients with preexisting cardiovascular diseases.


Assuntos
Betacoronavirus , Bradicardia/induzido quimicamente , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Pneumonia Viral/tratamento farmacológico , Idoso de 80 Anos ou mais , Feminino , Humanos , Pandemias
12.
Toxicol Appl Pharmacol ; 406: 115237, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920000

RESUMO

Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are "old", their pharmacological and toxicological profile in SARS-CoV-2 - infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6, ICAM1, CCL2, TNF, APOA1, etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2, CTSB, CXCL8, IL1B, IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders.


Assuntos
Betacoronavirus , Simulação por Computador , Mineração de Dados/métodos , Toxicogenética/métodos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Cloroquina/administração & dosagem , Cloroquina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Bases de Dados Genéticas , Quimioterapia Combinada , Redes Reguladoras de Genes/efeitos dos fármacos , Redes Reguladoras de Genes/genética , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Lopinavir/administração & dosagem , Lopinavir/efeitos adversos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos
13.
Ann Saudi Med ; 40(5): 365-372, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32954790

RESUMO

Evidence of cardiovascular complications associated with the COVID-19 global pandemic continues to evolve. These include direct and indirect myocardial injury with subsequent acute myocardial ischemia, and cardiac arrhythmia. Some results from a limited number of trials of antiviral medications, along with chloroquine/hydroxychloroquine and azithromycin, have been beneficial. However, these pharmacotherapies may cause drug-induced QT prolongation leading to ventricular arrhythmias and sudden cardiac death. Mitigation of the potential risk in these susceptible patients may prove exceptionally challenging. The Saudi Heart Rhythm Society established a task force to perform a review of this subject based on has recently published reports, and studies and recommendations from major medical organizations. The objective of this review is to identify high-risk patients, and to set clear guidelines for management of patients receiving these pharmacotherapies.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Comitês Consultivos , Antivirais/efeitos adversos , Arritmias Cardíacas/diagnóstico , Azitromicina/efeitos adversos , Betacoronavirus , Cloroquina/efeitos adversos , Inibidores do Citocromo P-450 CYP2D6/efeitos adversos , Combinação de Medicamentos , Interações Medicamentosas , Monitoramento de Medicamentos , Eletrocardiografia , Humanos , Hidroxicloroquina/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Lopinavir/efeitos adversos , Pandemias , Medição de Risco , Ritonavir/efeitos adversos , Arábia Saudita , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/diagnóstico
14.
J Interferon Cytokine Res ; 40(10): 469-471, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32881593

RESUMO

Coronavirus disease 2019 (COVID-19), which is caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has recently emerged as a global health threat. To address this health emergency, various therapeutic approaches are currently under investigation. There is limited evidence on the effectiveness of hydroxychloroquine (HCQ) and chloroquine (CQ) as COVID-19 therapies, and thus World Health Organization (WHO) mentioned that "Current data shows that this drug does not reduce deaths among hospitalized COVID-19 patients, nor help people with mild or moderate disease." CQ and HCQ are typically used for the treatment of malaria but have been recognized for certain beneficial effects in COVID-19 patients based on some clinical outcomes from the clinical treatment of COVID-19. A standard dose of HCQ has been proven effective and less toxic than CQ in COVID-19 patients; however, a comprehensive understanding of a patient's clinical condition is necessary. Based on several hospital findings, the Food and Drug Administration (FDA) has officially cancelled the emergency use authorization for HCQ and CQ for treating hospitalized COVID-19 patients on June 15, 2020. In this review, we highlight both pros and cons of the clinical use of CQ and HCQ in COVID-19 patients.


Assuntos
Anti-Infecciosos/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Cloroquina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Anti-Infecciosos/efeitos adversos , Azitromicina/uso terapêutico , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Sinergismo Farmacológico , Humanos , Hidroxicloroquina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Resultado do Tratamento
16.
Rheumatol Int ; 40(11): 1741-1751, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32880032

RESUMO

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.


Assuntos
Antirreumáticos/uso terapêutico , Betacoronavirus , Colchicina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Hidroxicloroquina/uso terapêutico , Metotrexato/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Colchicina/efeitos adversos , Hidroxicloroquina/efeitos adversos , Metotrexato/efeitos adversos , Pandemias
18.
Lancet ; 396(10256): 959-967, 2020 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-32896292

RESUMO

BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.


Assuntos
Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Idoso , Antivirais/efeitos adversos , Azitromicina/efeitos adversos , Betacoronavirus , Brasil/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Quimioterapia Combinada , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Terapia Respiratória , Padrão de Cuidado , Resultado do Tratamento
19.
Front Immunol ; 11: 2159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983179

RESUMO

The rapid spread, severity, and lack of specific treatment for COVID-19 resulted in hasty drug repurposing. Conceptually, trials of antivirals were well-accepted, but twentieth century antimalarials sparked an impassioned global debate. Notwithstanding, antiviral and immunomodulatory effects of aminoquinolines have been investigated in vitro, in vivo and in clinical trials for more than 30 years. We review the mechanisms of action of (hydroxy)chloroquine on immune cells and networks and discuss promises and pitfalls in the fight against SARS-CoV-2, the agent of the COVID-19 outbreak.


Assuntos
Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunomodulação , Pneumonia Viral/tratamento farmacológico , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Reposicionamento de Medicamentos/métodos , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacologia , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia
20.
Ann Endocrinol (Paris) ; 81(5): 507-510, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32950466

RESUMO

The World Health Organization (WHO) declared the COVID-19 epidemic to be a global pandemic in March 2020. COVID-19 is an infection caused by SARS-CoV-2, a coronavirus that utilizes the angiotensin-2 converting enzyme to penetrate thyroid and pituitary cells, and may result in a "cytokine storm". Based on the pathophysiological involvement of the pituitary-thyroid axis, the current review discusses the diagnosis of abnormal thyroid function test, and the management of patients presenting with thyrotoxicosis, thyroid-associated orbitopathy and hypothyroidism in the context of SARS-CoV-2 infection.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pandemias , Pneumonia Viral/complicações , Doenças da Glândula Tireoide/etiologia , Apoptose , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/fisiopatologia , Suscetibilidade a Doenças , Oftalmopatia de Graves/complicações , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/uso terapêutico , Hipotireoidismo/sangue , Hipotireoidismo/etiologia , Hipotireoidismo/fisiopatologia , Interleucina-6/fisiologia , Peptidil Dipeptidase A/análise , Hipófise/fisiopatologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/fisiopatologia , Receptores Virais/análise , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/fisiopatologia , Glândula Tireoide/química , Glândula Tireoide/patologia , Glândula Tireoide/fisiopatologia , Hormônios Tireóideos/sangue , Tireotoxicose/sangue , Tireotoxicose/etiologia , Tireotoxicose/fisiopatologia , Tireotropina/sangue
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