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1.
Curr Med Sci ; 41(1): 24-30, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33582901

RESUMO

The role of corticosteroids in the treatment of Coronavirus disease 2019 (COVID-19) is controversial. In the present study, we evaluated the effects of adjuvant corticosteroids treatment on the outcome of patients with COVID-19 (n=966), using Propensity Score Matching to adjust for potential differences between the corticosteroids group (n=289) and the non-corticosteroids group (n=677). Analysis of data without adjusting differences in baseline characteristics indicated that the proportion of mechanical ventilation and the mortality was higher in the corticosteroids treatment group in total or severe/critical patients. The duration of viral shedding was longer in the non-corticosteroids treatment group in total or general/mild patients. After adjusting the difference between the corticosteroids and non-corticosteroids treatment group, the analysis revealed that the use of corticosteroids had no effect on the duration of viral shedding, in-hospital mortality or 28-day mortality.


Assuntos
Corticosteroides/administração & dosagem , /fisiologia , Corticosteroides/uso terapêutico , Idoso , Quimioterapia Adjuvante , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Estudos Retrospectivos , Eliminação de Partículas Virais/efeitos dos fármacos
2.
PLoS Comput Biol ; 17(1): e1008470, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33411742

RESUMO

Finding medications or vaccines that may decrease the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could potentially reduce transmission in the broader population. We developed a computational model of the U.S. simulating the spread of SARS-CoV-2 and the potential clinical and economic impact of reducing the infectious period duration. Simulation experiments found that reducing the average infectious period duration could avert a median of 442,852 [treating 25% of symptomatic cases, reducing by 0.5 days, reproductive number (R0) 3.5, and starting treatment when 15% of the population has been exposed] to 44.4 million SARS-CoV-2 cases (treating 75% of all infected cases, reducing by 3.5 days, R0 2.0). With R0 2.5, reducing the average infectious period duration by 0.5 days for 25% of symptomatic cases averted 1.4 million cases and 99,398 hospitalizations; increasing to 75% of symptomatic cases averted 2.8 million cases. At $500/person, treating 25% of symptomatic cases saved $209.5 billion (societal perspective). Further reducing the average infectious period duration by 3.5 days averted 7.4 million cases (treating 25% of symptomatic cases). Expanding treatment to 75% of all infected cases, including asymptomatic infections (R0 2.5), averted 35.9 million cases and 4 million hospitalizations, saving $48.8 billion (societal perspective and starting treatment after 5% of the population has been exposed). Our study quantifies the potential effects of reducing the SARS-CoV-2 infectious period duration.


Assuntos
/tratamento farmacológico , Modelos Biológicos , Pandemias , /epidemiologia , Biologia Computacional , Simulação por Computador , Humanos , Pandemias/prevenção & controle , Pandemias/estatística & dados numéricos , Fatores de Tempo , Estados Unidos/epidemiologia , Eliminação de Partículas Virais/efeitos dos fármacos
3.
Nat Commun ; 12(1): 81, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33398055

RESUMO

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.


Assuntos
/imunologia , Modelos Animais de Doenças , Furões/imunologia , /imunologia , Animais , Anticorpos Antivirais/imunologia , /farmacologia , Relação Dose-Resposta a Droga , Feminino , Pulmão/imunologia , Pulmão/patologia , RNA Viral/isolamento & purificação , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologia , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/imunologia
4.
Adv Drug Deliv Rev ; 169: 100-117, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33309815

RESUMO

To address the COVID-19 pandemic, there has been an unprecedented global effort to advance potent neutralizing mAbs against SARS-CoV-2 as therapeutics. However, historical efforts to advance antiviral monoclonal antibodies (mAbs) for the treatment of other respiratory infections have been met with categorical failures in the clinic. By investigating the mechanism by which SARS-CoV-2 and similar viruses spread within the lung, along with available biodistribution data for systemically injected mAb, we highlight the challenges faced by current antiviral mAbs for COVID-19. We summarize some of the leading mAbs currently in development, and present the evidence supporting inhaled delivery of antiviral mAb as an early intervention against COVID-19 that could prevent important pulmonary morbidities associated with the infection.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Fatores Imunológicos/uso terapêutico , /efeitos dos fármacos , /antagonistas & inibidores , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Antivirais/química , Antivirais/metabolismo , /metabolismo , Humanos , Imunização Passiva , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , /metabolismo , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/fisiologia
5.
Front Immunol ; 11: 596761, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33329586

RESUMO

The disease course of COVID-19 in patients with immunodeficiencies is unclear, as well as the optimal therapeutic strategy. We report a case of a 37-year old male with common variable immunodeficiency disorder and a severe SARS-CoV-2 infection. After administration of convalescent plasma, the patient's condition improved rapidly. Despite clinical recovery, viral RNA remained detectable up to 60 days after onset of symptoms. We propose that convalescent plasma might be considered as a treatment option in patients with CVID and severe COVID-19. In addition, in patients with immunodeficiencies, a different clinical course is possible, with prolonged viral shedding.


Assuntos
Anticorpos Antivirais/administração & dosagem , Imunodeficiência de Variável Comum , RNA Viral , Eliminação de Partículas Virais , Adulto , /imunologia , Imunodeficiência de Variável Comum/sangue , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/terapia , Humanos , Imunização Passiva , Masculino , RNA Viral/sangue , RNA Viral/imunologia , /metabolismo , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/imunologia
6.
Clin Dermatol ; 38(6): 750-756, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33341209

RESUMO

Pemphigus and its variants, viz., vulgaris, foliaceous, vegetans, Ig A pemphigus, paraneoplastic pemphigus and Senear-Usher syndrome are rare autoimmune blistering diseases of the skin and/or mucous membranes. The autoantibodies involved in the pathogenesis of pemphigus against desmoglein result in the breach of the skin and mucosal barrier, which acts as the first line of defence against pathogens. In this paper we underscore the importance of the integumentary system as a shield against the acquisition as well as transmission of SARS-CoV-2 virion. We have also made an attempt to delineate the various treatment modalities available and the viral-drug dynamics involved in choosing the optimum therapeutic modality.


Assuntos
Corticosteroides/uso terapêutico , Pênfigo/tratamento farmacológico , Eliminação de Partículas Virais , Administração Oral , Corticosteroides/efeitos adversos , Fezes/virologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/virologia , Mucosa Bucal/virologia , Pênfigo/complicações , Fatores de Risco , Eliminação de Partículas Virais/efeitos dos fármacos
8.
Kidney Blood Press Res ; 45(5): 661-670, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32957112

RESUMO

BACKGROUND: The outbreak of severe acute respiratory syndrome ß-coronavirus 2 (SARS-CoV-2) has the potential to become a long-lasting global health crisis. The number of people infected with the novel coronavirus has surpassed 22 million globally, resulting in over 700,000 deaths with more than 15 million people having recovered (https://covid19.who.int). Enormous efforts are underway for rapid vaccine and treatment developments. Amongst the many ways of tackling the novel coronavirus disease 2019 (COVID-19) pandemic, extracellular vesicles (EVs) are emerging. SUMMARY: EVs are lipid bilayer-enclosed structures secreted from all types of cells, including those lining the respiratory tract. They have established roles in lung immunity and are involved in the pathogenesis of various lung diseases, including viral infection. In this review, we point out the roles and possible contribution of EVs in viral infections, as well as ongoing EV-based approaches for the treatment of COVID-19, including clinical trials. Key Messages: EVs share structural similarities to viruses and recent findings demonstrate that viruses exploit EVs for cellular exit and EVs exploit viral entry mechanisms for cargo delivery. Moreover, EV-virus interplay could be exploited for future antiviral drug and vaccine development. EV-based therapies, especially the mesenchymal stem cell-derived EVs, are being intensively studied for the treatment of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Vesículas Extracelulares/virologia , Pneumopatias/terapia , Pneumonia Viral/terapia , Antivirais/administração & dosagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Vesículas Extracelulares/metabolismo , Terapia Genética/tendências , Humanos , Pneumopatias/metabolismo , Pneumopatias/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Eliminação de Partículas Virais/efeitos dos fármacos , Eliminação de Partículas Virais/fisiologia
9.
J Zhejiang Univ Sci B ; 21(8): 628-636, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32748578

RESUMO

BACKGROUND: Currently, there are no drugs that have been proven to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Because of its broad antiviral activity, interferon (IFN) should be evaluated as a potential therapeutic agent for treatment of coronavirus disease 2019 (COVID-19), especially while COVID-19-specific therapies are still under development. METHODS: Confirmed COVID-19 patients hospitalized in the First Affiliated Hospital, School of Medicine, Zhejiang University in Hangzhou, China, from January 19 to February 19, 2020 were enrolled in a retrospective study. The patients were separated into an IFN group and a control group according to whether they received initial IFN-α2b inhalation treatment after admission. Propensity-score matching was used to balance the confounding factors. RESULTS: A total of 104 confirmed COVID-19 patients, 68 in the IFN group and 36 in the control group, were enrolled. Less hypertension (27.9% vs. 55.6%, P=0.006), dyspnea (8.8% vs. 25.0%, P=0.025), or diarrhea (4.4% vs. 19.4%, P=0.030) was observed in the IFN group. Lower levels of albumin and C-reactive protein and higher level of sodium were observed in the IFN group. Glucocorticoid dosage was lower in the IFN group (median, 40 vs. 80 mg/d, P=0.025). Compared to the control group, fewer patients in the IFN group were ventilated (13.2% vs. 33.3%, P=0.015) and admitted to intensive care unit (ICU) (16.2% vs. 44.4%, P=0.002). There were also fewer critical patients in the IFN group (7.4% vs. 25.0%, P=0.017) upon admission. Although complications during admission process were comparable between groups, the discharge rate (85.3% vs. 66.7%, P=0.027) was higher and the hospitalization time (16 vs. 21 d, P=0.015) was shorter in the IFN group. When other confounding factors were not considered, virus shedding time (10 vs. 13 d, P=0.014) was also shorter in the IFN group. However, when the influence of other factors was eliminated using propensity score matching, virus shedding time was not significantly shorter than that of the control group (12 vs. 15 d, P=0.206). CONCLUSIONS: IFN-α2b spray inhalation did not shorten virus shedding time of SARS-CoV-2 in hospitalized patients.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Interferon alfa-2/administração & dosagem , Sprays Nasais , Pneumonia Viral/tratamento farmacológico , Eliminação de Partículas Virais/efeitos dos fármacos , Albuminas/análise , Antivirais/administração & dosagem , Betacoronavirus , Proteína C-Reativa/análise , Estudos de Casos e Controles , China , Glucocorticoides/farmacologia , Hospitalização , Humanos , Pandemias , Pontuação de Propensão , Estudos Retrospectivos , Sódio/sangue
10.
Clin Respir J ; 14(11): 1067-1075, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32750201

RESUMO

INTRODUCTION: Coronavirus Disease 2019 (COVID-19) has spread worldwide, and it has reached to more than 14.5 million cases. Although Hubei province is the epicenter of China, little is known about epidemiological and clinical features of COVID-19 in other areas in Hubei province around Wuhan. In addition, the virological data, particularly the factors associated with viral shedding of COVID-19 has not been well described. OBJECTIVE: To describe the epidemiological and clinical features of patients with COVID-19 in Tianmen city, and identify risk factors associated with prolonged viral shedding of COVID-19. METHODS: Inpatients with COVID-19 admitted before February 9, 2020 were included. Characteristics were compared between patients with early and late viral RNA shedding. Multivariate cox regression model was used to investigate variables associated with prolonged viral shedding. RESULTS: One hundred and eighty-three patients were included. About 8.2% patients were categorized as critical degree of severity. All patients received antiviral therapy, with arbidol and interferon being the commonest. About 38.3% and 16.9% patients were treated with corticosteroid and immunoglobulin, respectively. Time from onset to admission (HR = 0.829, P < 0.001), and administration of corticosteroid (HR = 0.496, P = 0.002), arbidol (HR = 2.605, P = 0.008) and oseltamivir (HR = 0.416, P < 0.001) were independently associated with duration of viral shedding. CONCLUSION: Symptoms of patients from Tianmen are relatively mild. Treatment should be started as early as possible, but corticosteroid and oseltamivir should be initiated with caution. In addition, clinical trials on arbidol should be conducted to demonstrate its effectiveness.


Assuntos
Corticosteroides/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Oseltamivir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Eliminação de Partículas Virais/efeitos dos fármacos , Adulto , Betacoronavirus , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Imunoglobulinas/uso terapêutico , Indóis/uso terapêutico , Interferons/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo
11.
Trials ; 21(1): 607, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616063

RESUMO

OBJECTIVES: The primary objectives of the study are: 1. To assess the effect of hydroxychloroquine (HCQ) in reducing SARS-CoV-2 viral shedding by PCR in infected pregnant women with mild symptoms. 2. To assess the efficacy of HCQ to prevent SARS-CoV-2 infection in pregnant women in contact with an infected or suspected case. 3. To evaluate the effect of HCQ in preventing the development of the COVID-19 disease in asymptomatic SARS-CoV-2-infected pregnant women. The secondary objectives are: 1. To determine the effect of HCQ on the clinical course and duration of the COVID-19 disease in SARS-CoV-2-infected pregnant women. 2. To determine the impact of HCQ on the risk of hospitalization and mortality of SARS-CoV-2-infected pregnant women. 3. To assess the safety and tolerability of HCQ in pregnant women. 4. To describe the clinical presentation of SARS-CoV-2 infection during pregnancy. 5. To describe the effects of maternal SARS-CoV-2 infection on pregnancy and perinatal outcomes by treatment group. 6. To determine the risk of vertical transmission (intra-utero and intra-partum) of SARS-CoV-2. TRIAL DESIGN: Randomized double-blind placebo-controlled two-arm multicentre clinical trial to evaluate the safety and efficacy of HCQ to prevent and/or minimize SARS-CoV-2 infection during pregnancy. Participants will be randomized to receive a 14-day oral treatment course of HCQ or placebo, ratio 1:1. PARTICIPANTS: Study population: pregnant women undergoing routine prenatal follow up or attending emergency units at the participating hospitals who report either symptoms/signs suggestive of COVID-19 disease or close contact with a suspected or confirmed COVID-19 case. Inclusion criteria Women will be invited to participate in the trial and sign an informed consent if they meet the following inclusion criteria. • Presenting with fever (≥37.5°C) and/or one mild symptom suggestive of COVID-19 disease (cough, dyspnoea, chills, odynophagia, diarrhoea, muscle pain, anosmia, dysgeusia, headache) OR being contact* of a SARS-CoV-2 confirmed or suspected case in the past 14 days • More than 12 weeks of gestation (dated by ultrasonography) • Agreement to deliver in the study hospitals Exclusion criteria • Known hypersensitivity to HCQ or other 4-amonoquinoline compounds • History of retinopathy of any aetiology • Concomitant use of digoxin, cyclosporine, cimetidine • Known liver disease • Clinical history of cardiac pathology including known long QT syndrome • Unable to cooperate with the requirements of the study • Participating in other intervention studies • Delivery onset (characterized by painful uterine contractions and variable changes of the cervix, including some degree of effacement and slower progression of dilatation up to 5 cm for first and subsequent labours) The study participants will be stratified by clinical presentation and SARS-CoV-2 PCR results. Assignment of participants to study groups will be as follows: • SARS-CoV-2-PCR confirmed, infected pregnant women: a. symptomatic (n=100) b. asymptomatic (n=100) • SARS-CoV-2 PCR negative pregnant women in contact* with a SARS-CoV-2-infected confirmed or suspected case (n=514). *The ECDC definition of close contact will be followed. The trial will be conducted in five hospitals in Spain: Hospital Clínic of Barcelona, Hospital Sant Joan de Déu and Hospital de la Santa Creu i Sant Pau, in Barcelona, and HM Puerta del Sur and Hospital Universitario de Torrejón, in Madrid. INTERVENTION AND COMPARATOR: Participants will be randomized to HCQ (400 mg/day for three days, followed by 200 mg/day for 11 days) or placebo (2 tablets for three days, followed by one tablet for 11 days). MAIN OUTCOMES: The primary outcome is the number of PCR-confirmed infected pregnant women assessed from collected nasopharyngeal and oropharyngeal swabs at day 21 after treatment start (one week after treatment is completed). RANDOMISATION: Allocation of participants to study arms will be done centrally by the trial's Sponsor (the Barcelona Institute for Global Health, ISGlobal) by block randomization. This method will ensure balanced allocation to both arms. The electronic CRF will automatically assign a study number to each participant, depending on her study group and recruitment site. Each number will be related to a treatment number, which assigns them to one of the study arms. BLINDING (MASKING): Participants, caregivers, investigators and those assessing the outcomes will be blinded to group assignment. Study tablets (HCQ and placebo) will be identically packaged in small opaque bottles. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 200 SARS-CoV-2 infected and 514 contact pregnant women, randomised 1:1 with 100 and 227 respectively in each study arm. TRIAL STATUS: Protocol version 1.0, from May 8th, 2020. Recruitment is ongoing (first patient recruited the 19th May 2020 and recruitment end anticipated by December 2020). TRIAL REGISTRATION: EudraCT number: 2020-001587-29, registered 2 April 2020. Clinicaltrials.gov identifier: NCT04410562 , retrospectively registered 1 June 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
Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Quimioprevenção , Infecções por Coronavirus/prevenção & controle , Hidroxicloroquina/administração & dosagem , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Antivirais/efeitos adversos , Antivirais/farmacocinética , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Método Duplo-Cego , Esquema de Medicação , Feminino , Interações Hospedeiro-Patógeno , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacocinética , Estudos Multicêntricos como Assunto , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/mortalidade , Complicações Infecciosas na Gravidez/virologia , Fatores de Proteção , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Espanha , Fatores de Tempo , Resultado do Tratamento , Eliminação de Partículas Virais/efeitos dos fármacos
12.
Int J Infect Dis ; 98: 252-260, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619760

RESUMO

OBJECTIVE: The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic, but the factors influencing viral RNA shedding, which would help inform optimal control strategies, remain unclear. METHODS: The clinical course and viral RNA shedding pattern of 267 consecutive symptomatic COVID-19 patients admitted to the hospital from January 20, 2020 to March 15, 2020 were evaluated retrospectively. RESULTS: The median duration of viral RNA shedding was 12 days (interquartile range 8-16 days) after the onset of illness. Of the 267 patients included in this study, 65.2% had viral RNA clearance within 14 days, 88.8% within 21 days, and 94.4% within 28 days. Older age (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.98-1.00; p = 0.04), time lag from illness onset to hospital admission (HR 0.91, 95% CI 0.88-0.94; p < 0.001), diarrhea (HR 0.59, 95% CI 0.36-0.96; p = 0.036), corticosteroid treatment (HR 0.60, 95% CI 0.39-0.94; p = 0.024), and lopinavir/ritonavir use (HR 0.70, 95% CI 0.52-0.94; p = 0.014) were significantly and independently associated with prolonged viral RNA shedding. CONCLUSIONS: Early detection and timely hospital admission may be warranted for symptomatic COVID-19 patients, especially for older patients and patients with diarrhea. Corticosteroid treatment is associated with prolonged viral RNA shedding and should be used with caution. Lopinavir/ritonavir use may be associated with prolonged viral RNA shedding in non-severe patients; further randomized controlled trials are needed to confirm this finding.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , RNA Viral/genética , Eliminação de Partículas Virais , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Betacoronavirus/fisiologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Feminino , Hospitalização , Humanos , Lopinavir/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , RNA Viral/metabolismo , Estudos Retrospectivos , Ritonavir/uso terapêutico , Eliminação de Partículas Virais/efeitos dos fármacos
14.
Nature ; 585(7824): 273-276, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32516797

RESUMO

Effective therapies to treat coronavirus disease 2019 (COVID-19) are urgently needed. While many investigational, approved, and repurposed drugs have been suggested as potential treatments, preclinical data from animal models can guide the search for effective treatments by ruling out those that lack efficacy in vivo. Remdesivir (GS-5734) is a nucleotide analogue prodrug with broad antiviral activity1,2 that is currently being investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration3,4. In animal models, remdesivir was effective against infection with Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV)2,5,6. In vitro, remdesivir inhibited replication of SARS-CoV-27,8. Here we investigate the efficacy of remdesivir in a rhesus macaque model of SARS-CoV-2 infection9. Unlike vehicle-treated animals, macaques treated with remdesivir did not show signs of respiratory disease; they also showed reduced pulmonary infiltrates on radiographs and reduced virus titres in bronchoalveolar lavages twelve hours after the first dose. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, remdesivir-treated animals had lower lung viral loads and reduced lung damage. Thus, treatment with remdesivir initiated early during infection had a clinical benefit in rhesus macaques infected with SARS-CoV-2. Although the rhesus macaque model does not represent the severe disease observed in some patients with COVID-19, our data support the early initiation of remdesivir treatment in patients with COVID-19 to prevent progression to pneumonia.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Macaca mulatta/virologia , Pneumonia Viral/prevenção & controle , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacocinética , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Betacoronavirus/genética , Betacoronavirus/patogenicidade , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Análise Mutacional de DNA , Progressão da Doença , Farmacorresistência Viral , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Pulmão/virologia , Masculino , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Prevenção Secundária , Fatores de Tempo , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacos
15.
R I Med J (2013) ; 103(6): 39-43, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32570995

RESUMO

BACKGROUND: Dexamethasone, a synthetic glucocorticoid, has anti-inflammatory and immunosuppressive properties. There is a hyperinflammatory response involved in the clinical course of patients with pneumonia due to SARS-CoV-2. To date, there has been no definite therapy for COVID-19. We reviewed the charts of SARS-CoV-2 patients with pneumonia and moderate to severely elevated CRP and worsening hypoxemia who were treated with early, short-term dexamethasone. METHODS: We describe a series of 21 patients who tested positive for SARS-CoV-2 and were admitted to The Miriam Hospital in Providence, RI, and were treated with a short course of dexamethasone, either alone or in addition to current investigative therapies. RESULTS: CRP levels decreased significantly following the start of dexamethasone from mean initial levels of 129.52 to 40.73 mg/L at time of discharge. 71% percent of the patients were discharged home with a mean length of stay of 7.8 days. None of the patients had escalation of care, leading to mechanical ventilation. Two patients were transferred to inpatient hospice facilities on account of persistent hypoxemia, in line with their documented goals of care. CONCLUSIONS: A short course of systemic corticosteroids among inpatients with SARS-CoV-2 with hypoxic respiratory failure was well tolerated, and most patients had improved outcomes. This limited case series may not offer concrete evidence towards the benefit of corticosteroids in COVID-19. However, patients' positive response to short-term corticosteroids demonstrates that they may help blunt the severity of inflammation and prevent a severe hyperinflammatory phase, in turn reducing the length of stay, ICU admissions, and healthcare costs.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Vírus da SARS , Adulto , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Fatores de Tempo , Eliminação de Partículas Virais/efeitos dos fármacos
16.
Trials ; 21(1): 475, 2020 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493478

RESUMO

OBJECTIVES: Primary Objective • To test the efficacy of Hydroxychloroquine (HCQ) (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection Secondary objectives • To determine the safety and tolerability of HCQ as SARS-CoV-2 Post-exposure Prophylaxis (PEP) in adults • To test the efficacy of HCQ (400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days, to complete 14 days) to prevent incident SARS-CoV-2 infection 2 weeks after completing therapy, compared to ascorbic acid among contacts of persons with SARS-CoV-2 infection • To test the efficacy of HCQ to shorten the duration of SARS-CoV-2 shedding among those with SARS-CoV-2 infection in the HCQ PEP group • To test the efficacy of HCQ to prevent incident COVID-19 TRIAL DESIGN: This is a randomized, multi-center, placebo-equivalent (ascorbic acid) controlled, blinded study of HCQ PEP for the prevention of SARS-CoV-2 infection in adults exposed to the virus. PARTICIPANTS: This study will enroll up to 2000 asymptomatic adults 18 to 80 years of age (inclusive) at baseline who are close contacts of persons with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 or clinically suspected COVID-19 and a pending SARS-CoV-2 PCR test. This multisite trial will be conducted at seven sites in Seattle (UW), Los Angeles (UCLA), New Orleans (Tulane), Baltimore (UMB), New York City (NYU), Syracuse (SUNY-Upstate), and Boston (BMC). Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply: 1.Men or women 18 to 80 years of age inclusive, at the time of signing the informed consent2.Willing and able to provide informed consent3.Had a close contact of a person (index) with known PCR-confirmed SARS-CoV-2 infection or index who is currently being assessed for COVID-19 Close contact is defined as: a.Household contact (i.e., residing with the index case in the 14 days prior to index diagnosis or prolonged exposure within a residence/vehicle/enclosed space without maintaining social distance)b.Medical staff, first responders, or other care persons who cared for the index case without personal protection (mask and gloves)4.Less than 4 days since last exposure (close contact with a person with SARS-CoV-2 infection) to the index case5.Access to device and internet for Telehealth visits6.Not planning to take HCQ in addition to the study medication Exclusion criteria Participants are excluded from the study if any of the following criteria apply: 1.Known hypersensitivity to HCQ or other 4-aminoquinoline compounds2.Currently hospitalized3.Symptomatic with subjective fever, cough, or shortness of breath4.Current medications exclude concomitant use of HCQ5.Concomitant use of other anti-malarial treatment or chemoprophylaxis, including chloroquine, mefloquine, artemether, or lumefantrine.6.History of retinopathy of any etiology7.Psoriasis8.Porphyria9.Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K)10.Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen11.Known moderate or severe liver disease12.Known long QT syndrome13.Severe renal impairment14.Use of any investigational or non-registered drug or vaccine within 30 days preceding the first dose of the study drugs or planned use during the study period INTERVENTION AND COMPARATOR: Households will be randomized 1:1 (at the level of household), with close contact participants receiving one of the following therapies: •HCQ 400 mg orally daily for 3 days then 200 mg orally daily for an additional 11 days •Placebo-like control (ascorbic acid) 500 mg orally daily for 3 days then 250 mg orally daily for 11 days MAIN OUTCOMES: The primary outcome of the study is the incidence of SARS-CoV-2 infection through day 14 among participants who are SARS-CoV-2 negative at baseline by randomization group. RANDOMISATION: Participants will be randomized in a 1:1 ratio to HCQ or ascorbic acid at the level of the household (all eligible participants in 1 household will receive the same intervention). The randomization code and resulting allocation list will be generated and maintained by the Study Statistician. The list will be blocked and stratified by site and contact type (household versus healthcare worker). BLINDING (MASKING): This is a blinded study. HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be bitter and ascorbic acid will be sour. The participants will be blinded to their randomization group once assigned. Study team members, apart from the Study Pharmacist and the unblinded statistical staff, will be blinded. Laboratory staff are blinded to the group allocation. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size for the study is N=2 000 participants randomized 1:1 to either HCZ (n=1 000) and ascorbic acid (n=1 000). TRIAL STATUS: Protocol version: 1.2 05 April 2020 Recruitment is ongoing, started March 31 and anticipated end date is September 30, 2020. TRIAL REGISTRATION: ClinicalTrials.gov, Protocol Registry Number: NCT04328961 Date of registration: April 1, 2020, retrospectively registered 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
Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Hidroxicloroquina/administração & dosagem , Exposição Ocupacional/efeitos adversos , Profilaxia Pós-Exposição , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/efeitos adversos , Ácido Ascórbico/administração & dosagem , Betacoronavirus/patogenicidade , Busca de Comunicante , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Esquema de Medicação , Feminino , Humanos , Hidroxicloroquina/efeitos adversos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Saúde do Trabalhador , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia , Eliminação de Partículas Virais/efeitos dos fármacos , Adulto Jovem
17.
J Transl Med ; 18(1): 185, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32370758

RESUMO

A new human coronavirus named SARS-CoV-2 was identified in several cases of acute respiratory syndrome in Wuhan, China in December 2019. On March 11 2020, WHO declared the SARS-CoV-2 infection to be a pandemic, based on the involvement of 169 nations. Specific drugs for SARS-CoV-2 are obviously not available. Currently, drugs originally developed for other viruses or parasites are currently in clinical trials based on empiric data. In the quest of an effective antiviral drug, the most specific target for an RNA virus is the RNA-dependent RNA-polymerase (RdRp) which shows significant differences between positive-sense and negative-sense RNA viruses. An accurate evaluation of RdRps from different viruses may guide the development of new drugs or the repositioning of already approved antiviral drugs as treatment of SARS-CoV-2. This can accelerate the containment of the SARS-CoV-2 pandemic and, hopefully, of future pandemics due to other emerging zoonotic RNA viruses.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , /química , Sequência de Aminoácidos , Betacoronavirus/isolamento & purificação , Sequência Conservada , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Reposicionamento de Medicamentos , Humanos , Modelos Moleculares , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Alinhamento de Sequência , Replicação Viral/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacos
18.
PLoS Pathog ; 16(4): e1008395, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32294137

RESUMO

Influenza viruses cause seasonal outbreaks and pose a continuous pandemic threat. Although vaccines are available for influenza control, their efficacy varies each season and a vaccine for a novel pandemic virus manufactured using current technology will not be available fast enough to mitigate the effect of the first pandemic wave. Antivirals can be effective against many different influenza viruses but have not thus far been used extensively for outbreak control. Baloxavir, a recently licensed antiviral drug that targets the influenza virus endonuclease, has been shown to reduce virus shedding more effectively than oseltamivir, a widely used neuraminidase inhibitor drug. Thus it is possible that treatment with baloxavir might also interrupt onward virus transmission. To test this, we utilized the ferret model, which is the most commonly used animal model to study influenza virus transmission. We established a subcutaneous baloxavir administration method in ferrets which achieved similar pharmacokinetics to the approved human oral dose. Transmission studies were then conducted in two different locations with different experimental setups to compare the onward transmission of A(H1N1)pdm09 virus from infected ferrets treated with baloxavir, oseltamivir or placebo to naïve sentinel ferrets exposed either indirectly in adjacent cages or directly by co-housing. We found that baloxavir treatment reduced infectious viral shedding in the upper respiratory tract of ferrets compared to placebo, and reduced the frequency of transmission amongst sentinels in both experimental setups, even when treatment was delayed until 2 days post-infection. In contrast, oseltamivir treatment did not substantially affect viral shedding or transmission compared to placebo. We did not detect the emergence of baloxavir-resistant variants in treated animals or in untreated sentinels. Our results support the concept that antivirals which decrease viral shedding could also reduce influenza transmission in the community.


Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Infecções por Orthomyxoviridae/tratamento farmacológico , Oxazinas/farmacologia , Piridinas/farmacologia , Tiepinas/farmacologia , Triazinas/farmacologia , Replicação Viral/efeitos dos fármacos , Eliminação de Partículas Virais/efeitos dos fármacos , Animais , Dibenzotiepinas , Feminino , Furões , Morfolinas , Infecções por Orthomyxoviridae/transmissão , Infecções por Orthomyxoviridae/virologia , Piridonas
20.
Res Vet Sci ; 130: 222-229, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32220667

RESUMO

Feline coronavirus (FCoV) is common among cats living indoors in groups. In about 10% of infected cats, a potentially lethal disease, feline infectious peritonitis (FIP) occurs. Virus transmission is faecal-oral. Mutian® Xraphconn (Mutian X) is a product marketed to treat cats with FIP but is also being used to stop virus shedding, although no clear guidelines exist for its use for this purpose. The aim of this study was to establish the minimum dose and treatment duration required to ensure viral clearance from the faeces of asymptomatic virus-shedding cats. In five multicat households, 29 cats naturally infected with FCoV and actively shedding virus in the faeces were given Mutian X pills. Virus shedding was monitored using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) controlled for faecal inhibitors to ensure sensitivity. Mutian X given orally cleared the virus in 29 cats; although four cats required a repeated course to finally stop virus shedding. A dose of 4 mg/kg q24 h for four days was found to be the optimal treatment protocol: 2 mg/kg cleared only 80% of cats. Post-treatment using a sensitive RT-qPCR test was essential to ensure that virus clearance had been achieved, since failure to clear even one cat can result in re-infection of the others. Records of virus shedding by cats before treatment provided a retrospective control: significantly more cats stopped shedding virus after Mutian X than recovered from infection during the control period (p < .00001). This is the first report of the successful elimination of faecal FCoV shedding in chronically infected cats.


Assuntos
Antivirais/uso terapêutico , Coronavirus Felino/efeitos dos fármacos , Peritonite Infecciosa Felina/tratamento farmacológico , Eliminação de Partículas Virais/efeitos dos fármacos , Administração Oral , Animais , Gatos , Fezes/virologia , Estudos Retrospectivos
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