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1.
J Med Virol ; 94(1): 161-172, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415583

RESUMO

Detailed information on intrahost viral evolution in SARS-CoV-2 with and without treatment is limited. Sequential viral loads and deep sequencing of SARS-CoV-2 from the upper respiratory tract of nine hospitalized children, three of whom were treated with remdesivir, revealed that remdesivir treatment suppressed viral load in one patient but not in a second infected with an identical strain without any evidence of drug resistance found. Reduced levels of subgenomic RNA during treatment of the second patient, suggest an additional effect of remdesivir on viral replication. Haplotype reconstruction uncovered persistent SARS-CoV-2 variant genotypes in four patients. These likely arose from within-host evolution, although superinfection cannot be excluded in one case. Although our dataset is small, observed sample-to-sample heterogeneity in variant frequencies across four of nine patients suggests the presence of discrete viral populations in the lung with incomplete population sampling in diagnostic swabs. Such compartmentalization could compromise the penetration of remdesivir into the lung, limiting the drugs in vivo efficacy, as has been observed in other lung infections.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/virologia , Evolução Molecular , SARS-CoV-2/genética , Monofosfato de Adenosina/uso terapêutico , Adolescente , Alanina/uso terapêutico , Criança , Pré-Escolar , Farmacorresistência Viral , Feminino , Haplótipos , Humanos , Lactente , Pulmão/virologia , Masculino , Filogenia , RNA Viral/análise , RNA Viral/genética , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Carga Viral , Replicação Viral/efeitos dos fármacos
2.
J Med Virol ; 94(1): 384-387, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34406670

RESUMO

The antiviral remdesivir has been shown to decrease the length of hospital stay in coronavirus disease 2019 (COVID-19) patients requiring supplemental oxygen. However many patients decompensate despite being treated with remdesivir. To identify potential prognostic factors in remdesivir-treated patients, we performed a retrospective cohort study of patients hospitalized at NewYork-Presbyterian Hospital/Weill Cornell Medical Center between March 23, 2020 and May 27, 2020. We identified 55 patients who were treated with remdesivir for COVID-19 and analyzed inflammatory markers and clinical outcomes. C-reactive protein (CRP), d-dimer, and lactate dehydrogenase levels were significantly higher in patients who progressed to intubation or death by 14 days compared to those who remained stable. CRP levels decreased significantly after remdesivir administration in patients who remained nonintubated over the study period. To our knowledge, this is the largest study to date examining inflammatory markers before and after remdesivir administration. Our findings support further investigation into COVID-19 treatment strategies that modify the inflammatory response.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , COVID-19/mortalidade , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/análise , COVID-19/patologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Inflamação/tratamento farmacológico , L-Lactato Desidrogenase/sangue , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , SARS-CoV-2/imunologia
3.
Farm Hosp ; 45(5): 253-257, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34806585

RESUMO

OBJECTIVE: To describe the effectiveness and safety of remdesivir in patients with SARS-CoV-2 pneumonia in real-world clinical practice  conditions. METHOD: Retrospective observational study that included all adults with  SARS-CoV-2 pneumonia admitted at the Moisès Broggi Hospital and  treated with remdesivir between July 1st and November 7th, 2020.  Efficacy outcomes were time to recovery, 28-day mortality, length of  hospital stay, and the need of mechanical ventilation after treatment. The  main safetyrelated endpoint was elevation of transaminases after  treatment. RESULTS: A total of 111 patients were included of whom 97 (87.4%) were receiving low-flow oxygen therapy. Median time to recovery was 9  days [6-14]. Seven patients (6.3%) died at 28 days' follow-up. Median  length of hospital stay was 12 days [9-22] and 15 patients (13.5%)  needed mechanical ventilation after treatment with remdesivir. Severe  hypertransaminasemia was observed in 4 patients (4%). CONCLUSIONS: Clinical outcomes of patients with SARS-CoV-2 pneumonia on low-flow oxygen therapy treated with remdesivir were  similar to those published in clinical trials, both in terms of time to  recovery and 28-day mortality.


Assuntos
COVID-19 , SARS-CoV-2 , Monofosfato de Adenosina/análogos & derivados , Adulto , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos , Resultado do Tratamento
4.
Cad Saude Publica ; 37(10): e00077721, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34787281

RESUMO

The U.S. Food and Drug Administration (FDA) has stated that the prescription of remdesivir should be cautious for patients with estimated glomerular filtration rate (eGFR) < 30 and some studies reported risk of adverse renal events. The available information on the renal safety profile for remdesivir is limited, thus we analyzed the renal and urinary adverse reactions attributed to remdesivir reported in a large open pharmacovigilance database. We obtained reports of remdesivir and other drugs used to treat COVID-19 (tocilizumab, hydroxychloroquine, lopinavir/ritonavir) registered by September 30 2020, from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed the reporting odds ratios (RORs) for reports of adverse renal and urinary events for remdesivir and other drugs. We found 2,922 reports with remdesivir registered in FAERS for COVID-19. Among these, 493 renal and urinary adverse effects (16.9%) were reported. The most frequent events were acute kidney injury (338; 11.6%), renal impairment (86; 2.9%), and renal failure (53; 1.8%). Versus hydroxychloroquine, lopinavir/ritonavir, or tocilizumab, the use of remdesivir was associated with an increased chance of reporting renal and urinary disorders regardless of gender and age of patients (2.53; 95%CI: 2.10-3.06). The ROR remained significant when we restricted the analysis to hydroxychloroquine (4.31; 95%CI: 3.25-5.71) or tocilizumab (3.92; 95%CI: 2.51-6.12). Our results reinforce this already reported signal, emphasizing that it could be extremely useful for health professionals who prescribe this new antiviral to treat COVID-19, mainly knowing its low efficacy.


Assuntos
COVID-19 , Farmacovigilância , Monofosfato de Adenosina/análogos & derivados , Sistemas de Notificação de Reações Adversas a Medicamentos , Alanina/análogos & derivados , Brasil , COVID-19/tratamento farmacológico , Humanos , Rim , SARS-CoV-2
5.
Trials ; 22(1): 831, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814933

RESUMO

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Assuntos
Fármacos Anti-HIV , Lamivudina , Monofosfato de Adenosina/análogos & derivados , Adulto , Alanina/análogos & derivados , Fármacos Anti-HIV/efeitos adversos , Sulfato de Atazanavir/efeitos adversos , Voluntários Saudáveis , Humanos , Lamivudina/efeitos adversos , Oligopeptídeos , Piridinas/efeitos adversos , Ritonavir/efeitos adversos , Tenofovir/efeitos adversos , Uganda
6.
Pak J Pharm Sci ; 34(3(Supplementary)): 1119-1126, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34602441

RESUMO

The pandemic Coronavirus (Covid-19) is continuously growing and spreading at the highest rate in all over the world. So, it is necessary to produce the new medicinal agents against this virus. The aim of the present study is to design a potent compound against COVID-19. Based on 3C-like main protease and recently developed solved structure (PDB ID: 6Y2F), a series of remdesivir analogs are designed and analyzed by employing molecular modeling against the SARS-CoV-2 by insilico approach. The molecular dynamics (MD) simulation for 500ps was performed to check the stability and orientation to inside the binding pocket for analogs R3, R9, R14 and R15. The study results exhibit that compsound R9 has strong interaction or least binding energy (-10.04kcal/mol) as compare to the other analogues due to the presences of methyl bromide and it may be useful to further investigation in vitro testing against Covid-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Peptídeo Hidrolases/metabolismo , Inibidores de Proteases/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Humanos , Simulação de Acoplamento Molecular , Pandemias/prevenção & controle , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/metabolismo
8.
Sci Rep ; 11(1): 19998, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620963

RESUMO

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Assuntos
Antivirais/metabolismo , COVID-19/tratamento farmacológico , Descoberta de Drogas , SARS-CoV-2/efeitos dos fármacos , Adenina/efeitos adversos , Adenina/análogos & derivados , Adenina/metabolismo , Adenina/farmacologia , Adenosina/efeitos adversos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacologia , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/farmacologia , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/metabolismo , Alanina/farmacologia , Amidas/efeitos adversos , Amidas/metabolismo , Amidas/farmacologia , Antivirais/efeitos adversos , Antivirais/farmacologia , COVID-19/metabolismo , Cloroquina/efeitos adversos , Cloroquina/análogos & derivados , Cloroquina/metabolismo , Cloroquina/farmacologia , Desenho de Fármacos , Humanos , Redes e Vias Metabólicas , Simulação de Acoplamento Molecular , Nitrocompostos/efeitos adversos , Nitrocompostos/metabolismo , Nitrocompostos/farmacologia , Pirazinas/efeitos adversos , Pirazinas/metabolismo , Pirazinas/farmacologia , Pirrolidinas/efeitos adversos , Pirrolidinas/metabolismo , Pirrolidinas/farmacologia , Ribavirina/efeitos adversos , Ribavirina/metabolismo , Ribavirina/farmacologia , SARS-CoV-2/metabolismo , Tiazóis/efeitos adversos , Tiazóis/metabolismo , Tiazóis/farmacologia
9.
Sci Rep ; 11(1): 19458, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593911

RESUMO

Efficacious therapeutics for Ebola virus disease are in great demand. Ebola virus infections mediated by mucosal exposure, and aerosolization in particular, present a novel challenge due to nontypical massive early infection of respiratory lymphoid tissues. We performed a randomized and blinded study to compare outcomes from vehicle-treated and remdesivir-treated rhesus monkeys in a lethal model of infection resulting from aerosolized Ebola virus exposure. Remdesivir treatment initiated 4 days after exposure was associated with a significant survival benefit, significant reduction in serum viral titer, and improvements in clinical pathology biomarker levels and lung histology compared to vehicle treatment. These observations indicate that remdesivir may have value in countering aerosol-induced Ebola virus disease.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Ebolavirus/efeitos dos fármacos , Doença pelo Vírus Ebola/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Administração Intravenosa , Aerossóis , Alanina/administração & dosagem , Alanina/farmacologia , Animais , Antivirais/administração & dosagem , Modelos Animais de Doenças , Feminino , Doença pelo Vírus Ebola/sangue , Estimativa de Kaplan-Meier , Fígado/efeitos dos fármacos , Fígado/virologia , Pulmão/patologia , Pulmão/virologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Linfonodos/virologia , Macaca mulatta , Masculino , Distribuição Aleatória , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/virologia , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico
10.
Nat Commun ; 12(1): 5809, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608167

RESUMO

SARS-CoV-2 has caused a global pandemic of COVID-19 since its emergence in December 2019. The infection causes a severe acute respiratory syndrome and may also spread to central nervous system leading to neurological sequelae. We have developed and characterized two new organotypic cultures from hamster brainstem and lung tissues that offer a unique opportunity to study the early steps of viral infection and screening antivirals. These models are not dedicated to investigate how the virus reaches the brain. However, they allow validating the early tropism of the virus in the lungs and demonstrating that SARS-CoV-2 could infect the brainstem and the cerebellum, mainly by targeting granular neurons. Viral infection induces specific interferon and innate immune responses with patterns specific to each organ, along with cell death by apoptosis, necroptosis, and pyroptosis. Overall, our data illustrate the potential of rapid modeling of complex tissue-level interactions during infection by a newly emerged virus.


Assuntos
Tronco Encefálico/virologia , Pulmão/virologia , Modelos Biológicos , SARS-CoV-2/patogenicidade , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Células Epiteliais Alveolares/virologia , Animais , Antivirais/farmacologia , Tronco Encefálico/citologia , Tronco Encefálico/imunologia , Tronco Encefálico/patologia , Cricetinae , Imunidade Inata , Inflamação , Pulmão/citologia , Pulmão/imunologia , Pulmão/patologia , Neurônios/virologia , Técnicas de Cultura de Órgãos , Morte Celular Regulada , SARS-CoV-2/efeitos dos fármacos , Tropismo Viral
11.
J Hematol Oncol ; 14(1): 163, 2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635137

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently constitutes the leading and overwhelming health issue worldwide. In comparison with adults, children present milder symptoms, with most having an asymptomatic course. We hypothesized that COVID-19 infection has a negative impact on the continuation of chemotherapy and increases nonrelapse mortality. MATERIAL AND METHODS: This study was performed to assess the course of SARS-CoV-2 among children with hematological or oncological malignancies and its impact on cancer therapy. Records of SARS-CoV-2 infection in 155 children with malignancies from 14 Polish centers for pediatric hematology and oncology were collected and analyzed. RESULTS: SARS-CoV-2 replication was observed in 155 patients. Forty-nine patients were symptomatic, with the following being the most common manifestations: fever (31 patients), gastrointestinal symptoms (10), coryza (13), cough (13) and headache (8). In children who were retested, the median time of a positive PCR result was 16 days (range 1-70 days), but 12.7% of patients were positive beyond day + 20. The length of viral PCR positivity correlated with the absolute neutrophil count at diagnosis. Seventy-six patients did not undergo further SARS-CoV-2 testing and were considered convalescents after completion of isolation. Antibiotic therapy was administered in 15 children, remdesivir in 6, convalescent plasma in 4, oxygen therapy in 3 (1-mechanical ventilation), steroids in 2, intravenous immunoglobulins in 2, and heparin in 4. Eighty patients were treated with chemotherapy within 30 days after SARS-CoV-2 infection diagnosis or were diagnosed with SARS-CoV-2 infection during 30 days of chemotherapy administration. Respiratory symptoms associated with COVID-19 and associated with oxygen therapy were present in 4 patients in the study population, and four deaths were recorded (2 due to COVID-19 and 2 due to progressive malignancy). The probability of 100-day overall survival was 97.3% (95% CI 92.9-99%). Delay in the next chemotherapy cycle occurred in 91 of 156 cases, with a median of 14 days (range 2-105 days). CONCLUSIONS: For the majority of pediatric cancer patients, SARS-CoV-2 infection does not result in a severe, life-threatening course. Our data show that interruptions in therapy are common and can result in suboptimal therapy.


Assuntos
COVID-19/complicações , COVID-19/terapia , Neoplasias Hematológicas/complicações , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Adolescente , Alanina/análogos & derivados , Alanina/uso terapêutico , Antivirais/uso terapêutico , COVID-19/diagnóstico , COVID-19/epidemiologia , Criança , Pré-Escolar , Gerenciamento Clínico , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Imunização Passiva , Lactente , Masculino , Polônia/epidemiologia , SARS-CoV-2/isolamento & purificação
12.
Enzymes ; 49: 39-62, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34696838

RESUMO

Nucleotide analogs are the cornerstone of direct acting antivirals used to control infection by RNA viruses. Here we review what is known about existing nucleotide/nucleoside analogs and the kinetics and mechanisms of RNA and DNA replication, with emphasis on the SARS-CoV-2 RNA dependent RNA polymerase (RdRp) in comparison to HIV reverse transcriptase and Hepatitis C RdRp. We demonstrate how accurate kinetic analysis reveals surprising results to explain the effectiveness of antiviral nucleoside analogs providing guidelines for the design of new inhibitors.


Assuntos
COVID-19 , Hepatite C Crônica , Monofosfato de Adenosina , Alanina , Antivirais/farmacologia , Humanos , Cinética , Nucleotídeos , RNA Viral/genética , SARS-CoV-2
13.
Elife ; 102021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34617885

RESUMO

The absence of 'shovel-ready' anti-coronavirus drugs during vaccine development has exceedingly worsened the SARS-CoV-2 pandemic. Furthermore, new vaccine-resistant variants and coronavirus outbreaks may occur in the near future, and we must be ready to face this possibility. However, efficient antiviral drugs are still lacking to this day, due to our poor understanding of the mode of incorporation and mechanism of action of nucleotides analogs that target the coronavirus polymerase to impair its essential activity. Here, we characterize the impact of remdesivir (RDV, the only FDA-approved anti-coronavirus drug) and other nucleotide analogs (NAs) on RNA synthesis by the coronavirus polymerase using a high-throughput, single-molecule, magnetic-tweezers platform. We reveal that the location of the modification in the ribose or in the base dictates the catalytic pathway(s) used for its incorporation. We show that RDV incorporation does not terminate viral RNA synthesis, but leads the polymerase into backtrack as far as 30 nt, which may appear as termination in traditional ensemble assays. SARS-CoV-2 is able to evade the endogenously synthesized product of the viperin antiviral protein, ddhCTP, though the polymerase incorporates this NA well. This experimental paradigm is essential to the discovery and development of therapeutics targeting viral polymerases.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , Nucleotídeos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Linhagem Celular , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala/métodos , Humanos , Modelos Teóricos , Nucleotídeos/metabolismo , RNA Viral , SARS-CoV-2/enzimologia , Processos Estocásticos , Replicação Viral/efeitos dos fármacos
14.
Medicine (Baltimore) ; 100(37): e27228, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34664862

RESUMO

ABSTRACT: Remdesivir is the only antiviral approved for lower respiratory tract infection produced by SARS-CoV-2. The main objective of this study was to determine the mortality rate, readmissions, mean hospital stay, need for higher levels of oxygen support, and adverse effect-induced abandonment rate in hospitalized patients diagnosed with COVID-19 and treated with remdesivir (RDSV). The secondary objective was to determine mortality-related risk factors in these patients.The study included a prospective cohort of patients admitted to a third level Spanish hospital between July 5, 2020 and February 3, 2021 for COVID-19 diagnosed by SARS-CoV-2 polymerase chain reaction and/or antigen test and treated with RDSV.Remdesivir was received by 185 patients (69.7% males) with a mean age of 62.5 years, median Charlson index of 3 (interquartile range [IQR]: 1-4), and median ambient air oxygen saturation of 91% (IQR: 90-93); 61.6% of patients had hyper-inflammatory syndrome at admission. Median time with symptoms before RDSV treatment was 5 days (IQR: 3-6) and the median hospital stay was 10 days (IQR: 7-15); 19 patients (10.3%) died after a median stay of 13.5 days (IQR: 9.7-24 days), 58 patients (12.9%) were admitted to ICU, 58 (31.4%) needed higher levels of oxygen support, 0.5% abandoned the treatment due to adverse effects, and there were no readmissions. The only mortality-related factor was the need for higher levels of oxygen support (odds ratio 12.02; 95% confidence interval 2.25-64.2).All studied patients were admitted to hospital with a diagnosis of COVID-19 and in respiratory failure, needing initial low-flow oxygen support, and all received RDSV within 1 week of symptom onset. The percent mortality was lower in these patients than was observed in all patients with severe COVID-19 admitted to our center (10.3% vs 20.3%, respectively). Despite receiving RDSV, 1 in 3 patients needed higher levels of oxygen support, the sole mortality-related factor.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/farmacologia , Alanina/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/complicações , COVID-19/mortalidade , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Estudos Retrospectivos , Espanha , Estatísticas não Paramétricas
15.
Intensive Care Med ; 47(11): 1258-1270, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34609549

RESUMO

PURPOSE: Trials of tocilizumab in patients with severe COVID-19 pneumonia have demonstrated mixed results, and the role of tocilizumab in combination with other treatments is uncertain. Here we evaluated whether tocilizumab plus remdesivir provides greater benefit than remdesivir alone in patients with severe COVID-19 pneumonia. METHODS: This randomized, double-blind, placebo-controlled, multicenter trial included patients hospitalized with severe COVID-19 pneumonia requiring > 6 L/min supplemental oxygen. Patients were randomly assigned (2:1 ratio) to receive tocilizumab 8 mg/kg or placebo intravenously plus ≤ 10 days of remdesivir. The primary outcome was time from randomization to hospital discharge or "ready for discharge" (defined as category 1, assessed by the investigator on a 7-category ordinal scale of clinical status) to day 28. Patients were followed for 60 days. RESULTS: Among 649 enrolled patients, 434 were randomly assigned to tocilizumab plus remdesivir and 215 to placebo plus remdesivir. 566 patients (88.2%) received corticosteroids during the trial to day 28. Median time from randomization to hospital discharge or "ready for discharge" was 14 (95% CI 12-15) days with tocilizumab plus remdesivir and 14 (95% CI 11-16) days with placebo plus remdesivir [log-rank P = 0.74; Cox proportional hazards ratio 0.97 (95% CI 0.78-1.19)]. Serious adverse events occurred in 128 (29.8%) tocilizumab plus remdesivir and 72 (33.8%) placebo plus remdesivir patients; 78 (18.2%) and 42 (19.7%) patients, respectively, died by day 28. CONCLUSIONS: Tocilizumab plus remdesivir did not shorten time to hospital discharge or "ready for discharge" to day 28 compared with placebo plus remdesivir in patients with severe COVID-19 pneumonia.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antimetabólitos/uso terapêutico , Antivirais , COVID-19 , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Humanos
16.
PLoS One ; 16(10): e0257648, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34662359

RESUMO

BACKGROUND: The Emergency Use Authorization (EUA) of remdesivir for coronavirus disease 2019 raised questions on transparency of applied strategy, and how to equitably allocate and prioritize eligible patients given limited supply of the medication. The absence of federal oversight highlighted the critical role by states in health policymaking during a pandemic. OBJECTIVE: To identify public state-based protocols for remdesivir allocation and clinical guidance for prioritizing remdesivir use and assess approaches and inclusion of language promoting equitable access or mitigating health disparities. METHODS: We identified remdesivir allocation strategies and clinical use guidelines for all 50 states in the U.S. and the District of Columbia accessible on state health department websites or via internet searches. Public protocols dated between May 1, 2020 and September 30, 2020 were included in the study. We reviewed strategies for allocation and clinical use, including whether protocols contained explicit language on equitable access to remdesivir or mitigating health disparities. RESULTS: A total of 38 states had a remdesivir allocation strategy, with 33 states (87%) making these public. States used diverse allocation strategies, and only 10 (30%) of the 33 states included language on equitable allocation. A total of 30 states had remdesivir clinical use guidelines, where all were publicly accessible. All guidelines referenced recommendations by federal agencies but varied in their presentation format. Of the 30 states, 12 (40%) had guidelines that included language on equitable use. Neither an allocation strategy or clinical use guideline were identified (public or non-public) for 10 states and the District of Columbia during the study period. CONCLUSIONS: The experience with the remdesivir EUA presents an opportunity for federal and state governments to develop transparent protocols promoting fair and equal access to treatments for future pandemics.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Equidade em Saúde , Disseminação de Informação , Internet , Pandemias , SARS-CoV-2 , Monofosfato de Adenosina/administração & dosagem , Alanina/administração & dosagem , Humanos , Estados Unidos/epidemiologia
17.
PLoS One ; 16(10): e0258643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34699552

RESUMO

OBJECTIVES: Remdesivir is one of the most widely recommended and used medications for COVID-19 treatment. However, different outcomes have been reported for hospitalized patients with COVID-19 treated with remdesivir. Specifically, the effect of the timing of remdesivir initiation (from patient's symptom onset) on clinical outcomes in COVID-19 patients has not been investigated. METHODS: This is a retrospective cohort study of patients hospitalized with COVID-19 and treated with or without remdisivir. The primary outcome was patient's recovery rate, defined as clinical improvement and patient's discharge by day 14 of symptom onset. The secondary outcome was the need for intensive care unit (ICU) admission, mechanical ventilation, and mortality within 28 days of patient's symptom onset. RESULTS: Out of 323 hospitalized adults with COVID-19, 107 (33.1%) received no remdesivir during their hospital stay, 107 (33.1%) received remdesivir early within 7 days of the symptom onset, and 109 (33.7%) received it at 8 days or later of symptom onset. At day 14 following symptom onset, higher proportion of patients recovered in the early remdesivir compared to the late remdesivir cohort, or patients who did not receive remdesivir (adjusted odds ratio, aOR, 2.65; 95% confidence interval [CI], 1.31 to 5.35). Moreover, early administration of remdesivir was associated with lower admission to intensive care unit (adjusted hazard ratio [aHR], 0.31; 95% CI, 0.15 to 0.64), less need for mechanical ventilation (aHR, 0.22; 95% CI, 0.10 to 0.51), and lower mortality at 28 days (aHR, 0.15; 95% CI, 0.04 to 0.53), as compared to the late remdesivir cohort or patients who did not receive remdesivir. CONCLUSION: Early administration of remdesivir within 7 days of symptom onset is associated with less need for mechanical ventilation and lower 28-days mortality.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19/tratamento farmacológico , Adulto , Hospitalização , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
19.
Int J Mol Sci ; 22(20)2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34681595

RESUMO

We report a lymphoma patient with profound B-cell deficiency after chemotherapy combined with anti-CD20 antibody successfully treated with remdesivir and convalescent plasma for prolonged SARS-CoV-2 infection. Viral clearance was likely attributed to the robust expansion and activation of TCR Vß2 CD8+ cytotoxic T cells and CD16 + CD56- NK cells. This is the first presentation of TCR-specific T cell oligoclonal response in COVID-19. Our study suggests that B-cell depleted patients may effectively respond to anti-SARS-CoV-2 treatment when NK and antigen-specific Tc cell response is induced.


Assuntos
COVID-19/terapia , Células Matadoras Naturais/imunologia , Linfócitos T Citotóxicos/imunologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Idoso , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos B/metabolismo , COVID-19/virologia , Humanos , Imunização Passiva , SARS-CoV-2/isolamento & purificação
20.
Nutrients ; 13(10)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34684530

RESUMO

In hypertensive individuals, platelet morphology and function have been discovered to be altered, and this has been linked to the development of vascular disease, including erectile dysfunction (ED). The impact of nutritional supplementation with Cyperus esculentus (tiger nut, TN) and Tetracarpidium conophorum (walnut, WN) on androgen levels, ectonucleotidases, and adenosine deaminase (ADA) activities in platelets from L-NAME (Nω-nitro-L-arginine methyl ester hydrochloride) challenged rats were investigated. We hypothesized that these nuts may show a protective effect on platelets aggregation and possibly enhance the sex hormones, thereby reverting vasoconstriction. Wistar rats (male; 250-300 g; n = 10) were grouped into seven groups as follows: basal diet control group (I); basal diet/L-NAME/Viagra (5 mg/kg/day) as positive control group (II); ED-induced group (basal diet/L-NAME) (III); diet supplemented processed TN (20%)/L-NAME (IV); diet supplemented raw TN (20%)/L-NAME (V); diet supplemented processed WN (20%)/L-NAME (VI); and diet supplemented raw WN (20%)/L-NAME (VII). The rats were given their regular diet for 2 weeks prior to actually receiving L-NAME (40 mg/kg/day) for ten days to induce hypertension. Platelet androgen levels, ectonucleotidases, and ADA were all measured. L-NAME considerably lowers testosterone levels (54.5 ± 2.2; p < 0.05). Supplementing the TN and WN diets revealed improved testosterone levels as compared to the control (306.7 ± 5.7), but luteinizing hormone levels remained unchanged. Compared to control groups, the L-NAME-treated group showed a rise in ATP (127.5%) hydrolysis and ADA (116.7%) activity, and also a decrease in ADP (76%) and AMP (45%) hydrolysis. Both TN and WN supplemented diets resulted in substantial (p < 0.05) reversal effects. Enhanced testosterone levels and modulation of the purinergic system in platelets by TN and WN could be one of the mechanisms by which they aid in vasoconstriction control.


Assuntos
Plaquetas/efeitos dos fármacos , Cyperus , Suplementos Nutricionais , Hipertensão/terapia , Juglans , NG-Nitroarginina Metil Éster/farmacologia , Adenosina Desaminase/efeitos dos fármacos , Difosfato de Adenosina/metabolismo , Monofosfato de Adenosina/metabolismo , Adenosina Trifosfatases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Dieta/métodos , Hidrólise/efeitos dos fármacos , Hipertensão/sangue , Hipertensão/induzido quimicamente , Masculino , Proteínas de Membrana/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Purinérgicos/farmacologia , Ratos , Ratos Wistar , Testosterona/sangue , Vasoconstrição/efeitos dos fármacos
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