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1.
Acta Pharm ; 71(2): 163-174, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33151166

RESUMO

The current outbreak of novel coronavirus (COVID-19) infections urges the need to identify potential therapeutic agents. Therefore, the repurposing of FDA-approved drugs against today's diseases involves the use of de-risked compounds with potentially lower costs and shorter development timelines. In this study, the recently resolved X-ray crystallographic structure of COVID-19 main protease (Mpro) was used to generate a pharmacophore model and to conduct a docking study to capture antiviral drugs as new promising COVID-19 main protease inhibitors. The developed pharmacophore successfully captured five FDA-approved antiviral drugs (lopinavir, remdesivir, ritonavir, saquinavir and raltegravir). The five drugs were successfully docked into the binding site of COVID-19 Mpro and showed several specific binding interactions that were comparable to those tying the co-crystallized inhibitor X77 inside the binding site of COVID-19 Mpro. Three of the captured drugs namely, remdesivir, lopinavir and ritonavir, were reported to have promising results in COVID-19 treatment and therefore increases the confidence in our results. Our findings suggest an additional possible mechanism of action for remdesivir as an antiviral drug inhibiting COVID-19 Mpro. Additionally, a combination of structure-based pharmacophore modeling with a docking study is expected to facilitate the discovery of novel COVID-19 Mpro inhibitors.


Assuntos
Infecções por Coronavirus/enzimologia , Pneumonia Viral/enzimologia , Inibidores de Proteases/farmacologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/química , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Cristalografia por Raios X , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , Humanos , Modelos Químicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/química , Relação Estrutura-Atividade
2.
BMC Pulm Med ; 20(1): 301, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33198751

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly reached pandemic proportions. Given that the main target of SARS-CoV-2 are lungs leading to severe pneumonia with hyperactivation of the inflammatory cascade, we conducted a prospective study to assess alveolar inflammatory status in patients with moderate to severe COVID-19. METHODS: Diagnostic bronchoalveolar lavage (BAL) was performed in 33 adult patients with SARS-CoV-2 infection by real-time PCR on nasopharyngeal swab admitted to the Intensive care unit (ICU) (n = 28) and to the Intermediate Medicine Ward (IMW) (n = 5). We analyze the differential cell count, ultrastructure of cells and Interleukin (IL)6, 8 and 10 levels. RESULTS: ICU patients showed a marked increase in neutrophils (1.24 × 105 ml- 1, 0.85-2.07), lower lymphocyte (0.97 × 105 ml- 1, 0.024-0.34) and macrophages fractions (0.43 × 105 ml- 1, 0.34-1.62) compared to IMW patients (0.095 × 105 ml- 1, 0.05-0.73; 0.47 × 105 ml- 1, 0.28-1.01 and 2.14 × 105 ml- 1, 1.17-3.01, respectively) (p < 0.01). Study of ICU patients BAL by electron transmission microscopy showed viral particles inside mononuclear cells confirmed by immunostaining with anti-viral capsid and spike antibodies. IL6 and IL8 were significantly higher in ICU patients than in IMW (IL6 p < 0.01, IL8 p < 0.0001), and also in patients who did not survive (IL6 p < 0.05, IL8 p = 0.05 vs. survivors). IL10 did not show a significant variation between groups. Dividing patients by treatment received, lower BAL concentrations of IL6 were found in patients treated with steroids as compared to those treated with tocilizumab (p < 0.1) or antivirals (p < 0.05). CONCLUSIONS: Alveolitis, associated with COVID-19, is mainly sustained by innate effectors which showed features of extensive activation. The burden of pro-inflammatory cytokines IL6 and IL8 in the broncho-alveolar environment is associated with clinical outcome.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Inflamação/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Leucócitos/imunologia , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia Viral/imunologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Corticosteroides/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/terapia , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Unidades de Terapia Intensiva , Interleucina-10/imunologia , Itália , Leucócitos Mononucleares/virologia , Lopinavir/uso terapêutico , Pulmão/citologia , Pulmão/virologia , Linfócitos/imunologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neutrófilos/imunologia , Pandemias , Pneumonia Viral/terapia , Prognóstico , Estudos Prospectivos , Respiração Artificial/métodos , Ritonavir/uso terapêutico , Glicoproteína da Espícula de Coronavírus/metabolismo , Taxa de Sobrevida , Vírion/metabolismo , Vírion/ultraestrutura
3.
BMJ Case Rep ; 13(10)2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33130588

RESUMO

An 82-year-old man with an extensive medical history presented to the emergency room with complaints of generalised weakness and cough. He tested positive for COVID-19 10 days prior to presenting to the emergency room. Although his symptoms started a week prior to diagnosis, his weakness increased, warranting emergency response. A comprehensive metabolic panel was drawn from the patient on admission, indicating markedly high liver function tests (LFTs) ≥20 times above the upper limit of normal. On day 1 of admission, the decision was still made to start remdesivir (5-day course) due to decompensated acute respiratory failure as well as dexamethasone. The patient's LFTs significantly improved throughout his hospital stay. The patient made a full recovery and was discharged on day 10 of hospitalisation.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Hepatopatias/diagnóstico , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Insuficiência Respiratória/diagnóstico , Monofosfato de Adenosina/administração & dosagem , Idoso de 80 Anos ou mais , Alanina/administração & dosagem , Dexametasona/administração & dosagem , Serviço Hospitalar de Emergência , Humanos , Tempo de Internação , Hepatopatias/complicações , Testes de Função Hepática , Masculino , Pandemias/prevenção & controle , Pandemias/estatística & dados numéricos , Alta do Paciente , Insuficiência Respiratória/terapia , Índice de Gravidade de Doença , Resultado do Tratamento
5.
SAR QSAR Environ Res ; 31(11): 857-867, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33100032

RESUMO

A novel coronavirus recently identified in Wuhan, China (2019-nCoV) has resulted in an increasing number of patients globally, and has become a highly lethal pathogenic member of the coronavirus family affecting humans. 2019-nCoV has established itself as one of the most threatening pandemics that human beings have faced, and therefore analysis and evaluation of all possible responses against infection is required. One such strategy includes utilizing the knowledge gained from the SARS and MERS outbreaks regarding existing antivirals. Indicating a potential for success, one of the drugs, remdesivir, under repurposing studies, has shown positive results in initial clinical studies. Therefore, in the current work, the authors have attempted to utilize the remdesivir-RdRp complex - RdRp (RNA-dependent RNA polymerase) being the putative target for remdesivir - to screen a library of the already reported RdRp inhibitor database. Further clustering on the basis of structural features and scoring refinement was performed to filter out false positive hits. Finally, molecular dynamics simulation was carried out to validate the identification of hits as RdRp inhibitors against novel coronavirus 2019-nCoV. The results yielded two putative hits which can inhibit RdRp with better potency than remdesivir, subject to further biological evaluation.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Simulação de Acoplamento Molecular , RNA Replicase/antagonistas & inibidores , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/química , Alanina/farmacologia , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/enzimologia , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral , Relação Quantitativa Estrutura-Atividade , Proteínas Virais/efeitos dos fármacos
6.
Front Immunol ; 11: 570927, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123144

RESUMO

The emergence and rapid spread of SARS-CoV-2 in December 2019 has brought the world to a standstill. While less pathogenic than the 2002-2003 SARS-CoV, this novel betacoronavirus presents a global threat due to its high transmission rate, ability to invade multiple tissues, and ability to trigger immunological hyperactivation. The identification of the animal reservoir and intermediate host were important steps toward slowing the spread of disease, and its genetic similarity to SARS-CoV has helped to determine pathogenesis and direct treatment strategies. The exponential increase in cases has necessitated fast and reliable testing procedures. Although RT-PCR remains the gold standard, it is a time-consuming procedure, paving the way for newer techniques such as serologic tests and enzyme immunoassays. Various clinical trials using broad antiviral agents in addition to novel medications have produced controversial results; however, the advancement of immunotherapy, particularly monoclonal antibodies and immune modulators is showing great promise in clinical trials. Non-orthodox medications such as anti-malarials have been tested in multiple institutions but definitive conclusions are yet to be made. Adjuvant therapies have also proven to be effective in decreasing mortality in the disease course. While no formal guidelines have been established, the multitude of ongoing clinical trials as a result of unprecedented access to research data brings us closer to halting the SARS-CoV-2 pandemic.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Betacoronavirus/genética , Betacoronavirus/imunologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Reservatórios de Doenças/virologia , Reposicionamento de Medicamentos/métodos , Humanos , Técnicas Imunoenzimáticas , Imunoterapia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/diagnóstico , Pneumonia Viral/patologia , Pneumonia Viral/terapia , Receptores Virais/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Testes Sorológicos/métodos , Glicoproteína da Espícula de Coronavírus/metabolismo
7.
Int J Occup Environ Med ; 11(4): 157-178, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33098401

RESUMO

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and has created a worldwide pandemic. Many patients with this infection have an asymptomatic or mild illness, but a small percentage of patients require hospitalization and intensive care. Patients with respiratory tract involvement have a spectrum of presentations that range from scattered ground-glass infiltrates to diffuse infiltrates with consolidation. Patients with the latter radiographic presentation have severe hypoxemia and usually require mechanical ventilation. In addition, some patients develop multiorgan failure, deep venous thrombi with pulmonary emboli, and cytokine storm syndrome. The respiratory management of these patients should focus on using low tidal volume ventilation with low intrathoracic pressures. Some patients have significant recruitable lung and may benefit from higher positive end-expiratory pressure (PEEP) levels and/or prone positioning. There is no well-established anti-viral treatment for this infection; the United States Food and Drug Administration (FDA) has provided emergency use authorization for convalescent plasma and remdesivir for the treatment of patients with COVID-19. In addition, randomized trials have demonstrated that dexamethasone improves outcomes in patients on mechanical ventilators or on oxygen. There are ongoing trials of other drugs which have the potential to moderate the acute inflammatory state seen in some of these patients. These patients often need prolonged high-level intensive care. Hospitals are confronted with significant challenges in patient management, supply management, health care worker safety, and health care worker burnout.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/virologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Humanos , Imunização Passiva/métodos , Pulmão/virologia , Pandemias , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Respiração com Pressão Positiva/métodos , Síndrome do Desconforto Respiratório do Adulto/terapia , Estados Unidos
8.
J Drugs Dermatol ; 19(9): 889-892, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026746

RESUMO

Early December 2019 witnessed an international outbreak of a novel coronavirus (COVID 19) designated severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2). Since then, a number of therapeutic molecules have been explored to have potential efficacy against the SARS-Cov-2 per se or its sequelae. There are no Food and Drug Administration specific therapies approved so far; however, numerous drugs based on varying levels of evidence, in vitro studies and compassionate drug trials are being established as therapeutic agents, especially drugs approved for previous emergence of the severe acute respiratory syndrome (SARS-CoV-1) and Middle east respiratory syndrome coronavirus (MERS-Cov). Numerous active clinical trials for COVID-19 with more than 150 drugs and products are under study. Needless to say, many dermatological drugs are being employed to mitigate this pandemic threat. We aim to review drugs with potential against SARS-Cov-2 widely used in dermatology practice. Additionally, rampant and overzealous use of these drugs as well as introduction of new molecules might lead to emergence of adverse effects associated with these agents. Dermatologists must be on lookout for any cutaneous adverse effects of these drugs. J Drugs Dermatol. 2020;19(9):889-892. doi:10.36849/JDD.2020.5323.


Assuntos
Antivirais/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Fármacos Dermatológicos/efeitos adversos , Erupção por Droga/etiologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/análogos & derivados , Antivirais/uso terapêutico , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Erupção por Droga/epidemiologia , Erupção por Droga/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Incidência , Masculino , Pandemias , Prognóstico , Medição de Risco , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/epidemiologia
9.
Eur Rev Med Pharmacol Sci ; 24(18): 9739-9743, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33015819

RESUMO

OBJECTIVE: Remdesivir is a nucleotide analogue prodrug that inhibits viral RNA polymerases. It has been recognized recently as a promising antiviral drug against a wide array of RNA viruses (including SARS/MERS-CoV5). We aimed at determining which drugs used in dentistry interact with Remdesivir in order to avoid adverse reactions that may worsen the condition of patients with COVID-19. MATERIALS AND METHODS: A literature review was conducted to identify potential drug interactions between remdesivir (used in the treatment of COVID-19) and drugs prescribed in dentistry. The search was made in the databases PubMed and MEDLINE and official websites using key terms remdesivir, drug interactions and dentistry for articles published up to 31st July 2020. RESULTS: According to the articles reviewed, a total of 279 drugs interact with Remdesivir. Two major interactions have been reported, 277 moderate drug interactions, and one with alcohol/food. The drug interactions involving drugs prescribed in dentistry are all moderate drug interactions and are (according to drug group): (1) antibiotics: azithromycin, clavulanate, doxycycline, erythromycin, levofloxacin; (2) antifungals: clotrimazole, fluconazole, itraconazole, ketoconazole; (3) non-steroidal anti-inflammatories (NAIDS): celecoxib diclofenac, etodolac, flurbiprofen, ibuprofen, ketoprofen, ketorolac, mefenamic acid, naproxen, piroxicam. CONCLUSIONS: It is clinically necessary for oral health professionals to be aware of possible drug interactions that may occur between remdesivir and drugs commonly prescribed in dentistry in order to prevent adverse reactions that may even endanger the life of a patient with COVID-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Infecções por Coronavirus , Odontologia , Interações Medicamentosas , Pandemias , Pneumonia Viral , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Humanos , Pneumonia Viral/tratamento farmacológico
10.
Folia Med (Plovdiv) ; 62(3): 592-596, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33009760

RESUMO

INTRODUCTION: Despite clinical trials, there are still no approved specific therapies or any vaccine against COVID-19. The only option available is using investigational drugs for compassionate use. The update of the existing regulation regarding compassionate use is to ensure the effective and sustainable development of health policies and technologies over the COVID-19 pandemic and beyond. AIM: The present short communication aimed to highlight the need for early and expanded access to investigational drugs for compassionate use as well as a call for an update of the existing regulation in Bulgaria concerning compassionate use in the era of COVID-19. MATERIALS AND METHODS: In EU and Bulgaria as well, the legal framework for compassionate use was introduced by Article 83 (1) of Regulation (EC) No 726/2004 of the European Parliament and of the Council; in principle, Regulations of the European Parliament and of the Council are mandatory for all Member States. Remdesivir appears to have a favorable clinical and safety profile, as reported in a case involving patients with severe COVID-19 through a compassionate use programme. RESULTS: The overall probability of clinical improvement observed in 36 of 53 COVID-19 patients received intravenous remdesivir as part of a compassionate use programme was 68% (95% CI 40% to 80%). Thirty two patients (60%) demonstrated at least one adverse event, twelve 12 patients (23%) experienced serious adverse events and seven patients (13%) died. CONCLUSION: The global pandemic mandates Bulgarian Drug Agency for a reasonable update of the existing national regulation concerning compassionate use and off-label therapies. In the era of COVID-19, it is important for Bulgarian patients to have early and expanded access to investigational drugs for compassionate use.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Ensaios de Uso Compassivo/legislação & jurisprudência , Infecções por Coronavirus/tratamento farmacológico , Política de Saúde/legislação & jurisprudência , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Betacoronavirus , Bulgária , Drogas em Investigação , Humanos , Pandemias
12.
Sci Rep ; 10(1): 16200, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004837

RESUMO

The current coronavirus (COVID-19) pandemic is exacerbated by the absence of effective therapeutic agents. Notably, patients with COVID-19 and comorbidities such as hypertension and cardiac diseases have a higher mortality rate. An efficient strategy in response to this issue is repurposing drugs with antiviral activity for therapeutic effect. Digoxin (DIG) and ouabain (OUA) are FDA drugs for heart diseases that have antiviral activity against several coronaviruses. Thus, we aimed to assess antiviral activity of DIG and OUA against SARS-CoV-2 infection. The half-maximal inhibitory concentrations (IC50) of DIG and OUA were determined at a nanomolar concentration. Progeny virus titers of single-dose treatment of DIG, OUA and remdesivir were approximately 103-, 104- and 103-fold lower (> 99% inhibition), respectively, than that of non-treated control or chloroquine at 48 h post-infection (hpi). Furthermore, therapeutic treatment with DIG and OUA inhibited over 99% of SARS-CoV-2 replication, leading to viral inhibition at the post entry stage of the viral life cycle. Collectively, these results suggest that DIG and OUA may be an alternative treatment for COVID-19, with potential additional therapeutic effects for patients with cardiovascular disease.


Assuntos
Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Digoxina/farmacologia , Ouabaína/farmacologia , Replicação Viral , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Betacoronavirus/fisiologia , Chlorocebus aethiops , Cloroquina/farmacologia , Concentração Inibidora 50 , Células Vero
13.
Clin Microbiol Rev ; 34(1)2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33055231

RESUMO

Patients and physicians worldwide are facing tremendous health care hazards that are caused by the ongoing severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) pandemic. Remdesivir (GS-5734) is the first approved treatment for severe coronavirus disease 2019 (COVID-19). It is a novel nucleoside analog with a broad antiviral activity spectrum among RNA viruses, including ebolavirus (EBOV) and the respiratory pathogens Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2. First described in 2016, the drug was derived from an antiviral library of small molecules intended to target emerging pathogenic RNA viruses. In vivo, remdesivir showed therapeutic and prophylactic effects in animal models of EBOV, MERS-CoV, SARS-CoV, and SARS-CoV-2 infection. However, the substance failed in a clinical trial on ebolavirus disease (EVD), where it was inferior to investigational monoclonal antibodies in an interim analysis. As there was no placebo control in this study, no conclusions on its efficacy in EVD can be made. In contrast, data from a placebo-controlled trial show beneficial effects for patients with COVID-19. Remdesivir reduces the time to recovery of hospitalized patients who require supplemental oxygen and may have a positive impact on mortality outcomes while having a favorable safety profile. Although this is an important milestone in the fight against COVID-19, approval of this drug will not be sufficient to solve the public health issues caused by the ongoing pandemic. Further scientific efforts are needed to evaluate the full potential of nucleoside analogs as treatment or prophylaxis of viral respiratory infections and to develop effective antivirals that are orally bioavailable.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Doença pelo Vírus Ebola/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/farmacologia , Alanina/farmacocinética , Alanina/farmacologia , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Ensaios Clínicos como Assunto , Ensaios de Uso Compassivo/métodos , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Esquema de Medicação , Ebolavirus/efeitos dos fármacos , Ebolavirus/crescimento & desenvolvimento , Ebolavirus/patogenicidade , Doença pelo Vírus Ebola/mortalidade , Doença pelo Vírus Ebola/patologia , Doença pelo Vírus Ebola/virologia , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/crescimento & desenvolvimento , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Pandemias , Segurança do Paciente , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/crescimento & desenvolvimento , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/mortalidade , Síndrome Respiratória Aguda Grave/patologia , Síndrome Respiratória Aguda Grave/virologia , Análise de Sobrevida , Resultado do Tratamento
14.
Sci Rep ; 10(1): 16577, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024223

RESUMO

SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Exonucleases/metabolismo , Pneumonia Viral/tratamento farmacológico , Pró-Fármacos/farmacologia , RNA Viral/efeitos dos fármacos , Sofosbuvir/farmacologia , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/química , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/enzimologia , Infecções por Coronavirus/virologia , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Pandemias , Pneumonia Viral/virologia , Pró-Fármacos/uso terapêutico , RNA Replicase/antagonistas & inibidores , RNA Replicase/metabolismo , RNA Viral/química , RNA Viral/metabolismo , Sofosbuvir/química , Sofosbuvir/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
16.
Monaldi Arch Chest Dis ; 90(4)2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33059413

RESUMO

Knowledge of treatment regimens and outcomes for novel coronavirus disease 2019 (COVID-19) is evolving. Recent studies have reported mortality rates ranging from 39-50% among hospitalized patients with COVID-19. We report our experience ofmanagement and outcomes of hospitalized patients with COVID-19 at a large tertiary-care center in Midwestern United States. Of 658 patients presenting to our tertiary care center, 217 needed hospitalization, majority (77%) of whom were severely sick requiring admission to the intensive care unit (ICU). All received corticosteroids, and 78% of the patients received tocilizumab. More than two-thirds of the patients received anticoagulation and 80% of patients in the ICU had prone-positioning. The median duration of hospitalization was 12 days (interquartile range, 8 to16), median duration of intensive care unit stay was 7 days (interquartile range, 5 to 9) and requirement of mechanical ventilation was 6 days (interquartile range, 5 to 8) in our cohort. Of the 217 patients, 27 died (12% mortality). The majority of our patients received corticosteroids, tocilizumab, anticoagulation and prone positioning. While higher mortality rates of >30% have been reported in various studies among hospitalized patients with COVID-19, the majority of hospitalized patients in our cohort survived with a low mortality rate. The majority of our patients received corticosteroids, tocilizumab, anticoagulation and prone positioning. While higher mortality rates of >30% have been reported in various studies among hospitalized patients with COVID-19, the majority of hospitalized patients in our cohort survived with a low mortality rate.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Cuidados Críticos , Hospitalização , Pneumonia Viral/terapia , Atenção Terciária à Saúde , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Imunização Passiva , Meio-Oeste dos Estados Unidos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Respiração Artificial , Estudos Retrospectivos , Centros de Atenção Terciária
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