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1.
Rev Med Suisse ; 17(720-1): 80-84, 2021 Jan 13.
Artigo em Francês | MEDLINE | ID: mdl-33443836

RESUMO

The main pharmacovigilance updates in 2020 are reviewed. Remdesivir in COVID-19: relatively safe but turns out to be less effective than expected. Hydroxychloroquine in COVID-19 : lack of efficacy and risk of arrhythmias. Cytokines storm in COVID-19: may impact pharmacokinetics. VEGF inhibitors: risk of aneurysm and artery dissection. Tofacitinib: dose-dependant risk of venous thromboembolic events. Ondansetron in the first trimester of pregnancy : a highly debated risk of orofacial cleft defects. Fingolimod : contraindicated during pregnancy due to suspected risk of congenital malformations. Ranitidine: global market withdrawal due to contamination with nitrosamines. Ulipristal for uterine fibroids : market withdrawal due to risk of severe liver injury. Ingenol mebutate : market withdrawal due to paradoxical risk of skin cancers.


Assuntos
Farmacovigilância , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Fenda Labial/prevenção & controle , Contraindicações de Medicamentos , Síndrome da Liberação de Citocina/virologia , Feminino , Cloridrato de Fingolimode/efeitos adversos , Humanos , Hidroxicloroquina/efeitos adversos , Leiomioma/tratamento farmacológico , Norpregnadienos/uso terapêutico , Farmacocinética , Gravidez , Ranitidina/efeitos adversos , Retirada de Medicamento Baseada em Segurança , Neoplasias Cutâneas/induzido quimicamente
2.
Theranostics ; 11(3): 1207-1231, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391531

RESUMO

Rationale: Coronavirus disease 2019 (COVID-19) has spread worldwide and poses a threat to humanity. However, no specific therapy has been established for this disease yet. We conducted a systematic review to highlight therapeutic agents that might be effective in treating COVID-19. Methods: We searched Medline, Medrxiv.org, and reference lists of relevant publications to identify articles of in vitro, in vivo, and clinical studies on treatments for severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19 published in English until the last update on October 11, 2020. Results: We included 36 studies on SARS, 30 studies on MERS, and 10 meta-analyses on SARS and MERS in this study. Through 12,200 title and 830 full-text screenings for COVID-19, eight in vitro studies, 46 randomized controlled trials (RCTs) on 6,886 patients, and 29 meta-analyses were obtained and investigated. There was no therapeutic agent that consistently resulted in positive outcomes across SARS, MERS, and COVID-19. Remdesivir showed a therapeutic effect for COVID-19 in two RCTs involving the largest number of total participants (n = 1,461). Other therapies that showed an effect in at least two RCTs for COVID-19 were sofosbuvir/daclatasvir (n = 114), colchicine (n = 140), IFN-ß1b (n = 193), and convalescent plasma therapy (n = 126). Conclusions: This review provides information to help establish treatment and research directions for COVID-19 based on currently available evidence. Further RCTs are required.


Assuntos
Antivirais/uso terapêutico , Infecções por Coronavirus/terapia , Síndrome Respiratória Aguda Grave/terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Animais , Carbamatos/uso terapêutico , Infecções por Coronavirus/mortalidade , Modelos Animais de Doenças , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada/métodos , Humanos , Imidazóis/uso terapêutico , Imunização Passiva/métodos , Pirrolidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome Respiratória Aguda Grave/mortalidade , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Valina/análogos & derivados , Valina/uso terapêutico
4.
J Infect Dis ; 223(1): 23-27, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33089317

RESUMO

We describe a case of chronic coronavirus disease 2019 (COVID-19) in a patient with lymphoma and associated B-cell immunodeficiency. Viral cultures and sequence analysis demonstrate ongoing replication of infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for at least 119 days. The patient had 3 admissions related to COVID-19 over a 4-month period and was treated twice with remdesivir and convalescent plasma with resolution of symptoms. The patient's lack of seroconversion and prolonged course illustrate the importance of humoral immunity in resolving SARS-CoV-2 infection. This case highlights challenges in managing immunocompromised hosts, who may act as persistent shedders and sources of transmission.


Assuntos
/virologia , Replicação Viral , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Antivirais/sangue , Hospitalização , Humanos , Imunidade Humoral , Hospedeiro Imunocomprometido , Linfoma de Célula do Manto/complicações , Masculino , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária/complicações , Soroconversão
5.
Eur J Pharmacol ; 890: 173642, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33065096

RESUMO

A methodology for the exploration of clinical suitability of Remdesivir drug to SARS-CoV-2 main protease based on the computational, theoretical analysis pertinent to Gibb's free energy computed from the Molecular Dynamic simulations with OPLS-AA force field at 300 K/atmospheric pressure and the variation of thermodynamic potentials over the entire simulation run of 100 ns. This study emphasized the suitability of Remdesivir drug to SARS-CoV-2 protein and the same is emphasized by the results of global clinical trials. This methodology can be applied for future design, development of more specific repurposed inhibitors for the treatment of SARS-CoV-2 infection.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , /tratamento farmacológico , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Animais , Antivirais/farmacologia , Humanos , Simulação de Dinâmica Molecular
6.
Mol Inform ; 40(1): e2000144, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830452

RESUMO

The analysis of B-factor profiles from X-ray protein structures can be utilized for structure-based drug design since protein mobility changes have been associated with the quality of protein-ligand interactions. With the BANΔIT (B'-factor analysis and ΔB' interpretation toolkit), we have developed a JavaScript-based browser application that provides a graphical user interface for the normalization and analysis of B'-factor profiles. To emphasize the usability for rational drug design applications, we have analyzed a selection of crystallographic protein-ligand complexes and have given exemplary conclusions for further drug optimization including the development of a B'-factor-supported pharmacophore model for SARS CoV-2 main protease inhibitors. BANΔIT is available online at https://bandit.uni-mainz.de. The source code can be downloaded from https://github.com/FBarthels/BANDIT.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Desenho de Fármacos , Inibidores de Proteases/química , Navegador , Monofosfato de Adenosina/química , Monofosfato de Adenosina/uso terapêutico , Biologia Computacional , Humanos , Inibidores de Proteases/uso terapêutico
7.
Biochem Pharmacol ; 183: 114296, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33191206

RESUMO

The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause human disease. As of September 2020, SARS-CoV-2 has been reported in 213 countries and more than 31 million cases have been confirmed, with an estimated mortality rate of ∼3%. Unfortunately, a drug or vaccine is yet to be discovered to treat COVID-19. Thus, repurposing of existing cancer drugs will be a novel approach in treating COVID-19 patients. These drugs target viral replication cycle, viral entry and translocation to the nucleus. Some can enhance innate antiviral immune response as well. Hence this review focuses on comprehensive list of 22 drugs that work against COVID-19 infection. These drugs include fingolimod, colchicine, N4-hydroxycytidine, remdesivir, methylprednisone, oseltamivir, icatibant, perphanizine, viracept, emetine, homoharringtonine, aloxistatin, ribavirin, valrubicin, famotidine, almitrine, amprenavir, hesperidin, biorobin, cromolyn sodium, and antibodies- tocilzumab and sarilumab. Also, we provide a list of 31 drugs that are predicted to function against SARS-CoV-2 infection. In summary, we provide succinct overview of various therapeutic modalities. Among these 53 drugs, based on various clinical trials and literature, remdesivir, nelfinavir, methylpredinosolone, colchicine, famotidine and emetine may be used for COVID-19. SIGNIFICANCE: It is of utmost important priority to develop novel therapies for COVID-19. Since the effect of SARS-CoV-2 is so severe, slowing the spread of diseases will help the health care system, especially the number of visits to Intensive Care Unit (ICU) of any country. Several clinical trials are in works around the globe. Moreover, NCI developed a recent and robust response to COVID-19 pandemic. One of the NCI's goals is to screen cancer related drugs for identification of new therapies for COVID-19. https://www.cancer.gov/news-events/cancer-currents-blog/2020/covid-19-cancer-nci-response?cid=eb_govdel.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Antivirais/uso terapêutico , Reposicionamento de Medicamentos/métodos , /efeitos dos fármacos , 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 , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Antivirais/química , Antivirais/farmacologia , Reposicionamento de Medicamentos/tendências , Humanos , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
8.
Life Sci ; 264: 118663, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33121991

RESUMO

AIMS: COVID-19 outbreak has created a public health catastrophe all over the world. Here, we have aimed to conduct a systematic review and meta-analysis on remdesivir use for COVID-19. MAIN METHODS: We searched Pubmed, Scopus, Embase, and preprint sites and identified ten studies for qualitative and four studies for quantitative analysis using PRISMA guidelines. The quantitative synthesis was performed using fixed and random effect models in RevMan 5.4. Heterogeneity was assessed using the I-squared (I2) test. KEY FINDINGS: Comparing 10-day remdesivir group with placebo or standard of care (SOC) group, remdesivir reduced 14 days mortality (OR 0.61, CI 0.41-0.91), need for mechanical ventilation (OR 0.73, CI 0.54-0.97), and severe adverse effects (OR 0.69, 95% CI 0.54 to 0.88). Clinical improvement on day 28 (OR 1.59, CI 1.06-2.39), day 14 clinical recovery (OR 1.48, CI 1.19-1.84), and day 14 discharge rate (OR 1.41, CI 1.15-1.73) were better among remdesivir group. Earlier clinical improvement (MD -2.51, CI -4.16 to -0.85); and clinical recovery (MD -4.69, CI -5.11 to -4.28) were seen among the remdesivir group. Longer course (10 days) of remdesivir showed a higher discharge rate at day 14 (OR 2.11, CI 1.50-2.97), but there were significantly higher rates of serious adverse effects, and drug discontinuation than the 5-day course. SIGNIFICANCE: Remdesivir showed a better 14 days mortality profile, clinical recovery, and discharge rate. Overall clinical improvement and clinical recovery were earlier among the remdesivir group. 10-day remdesivir showed more adverse outcome than 5-day course with no significant benefits.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , /tratamento farmacológico , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Humanos
10.
J Med Virol ; 93(2): 1171-1174, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32813283

RESUMO

Several randomized clinical trials (RCTs) that investigated the effectiveness of remdesivir for the treatment of coronavirus disease-2019 (COVID-19) have generated inconsistent evidence. The present study aimed to synthesize available RCT evidence using network meta-analyses (NMAs). Both blinded and open-label RCTs in PubMed database from inception to 7 June 2020 that contained "remdesivir", "Covid-19", and "trial" in the abstracts conducted on hospitalized COVID-19 persons were identified and screened. The studies must have at least one remdesivir arm and evaluated one of the pre-specified outcomes. The outcomes were clinical improvement between days 10 to 15 after randomization and clinical recovery during the follow-up period. The identified literature was supplemented with relatively recent studies that were known to the researchers if not already included. Frequentist NMAs with random effects were conducted. Both 10-day and 5-day remdesivir regimens were associated with higher odds of clinical improvement (odds ratio [OR] of 10-day regimen: 1.35, 95% confidence interval [CI], 1.09-1.67); OR of 5-day regimen: 1.81, 95% CI, 1.32-2.45, and higher probabilities of clinical recovery (relative risk [RR] of 10-day regimen: 1.24, 95% CI, 1.07-1.43; RR of 5-day regimen: 1.47, 95% CI, 1.16-1.87 compared with placebo. Remdesivir may have clinical benefits among hospitalized COVID-19 persons.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Metanálise em Rede , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Resultado do Tratamento
11.
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
12.
Mod Rheumatol Case Rep ; 5(1): 101-107, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019894

RESUMO

Anti-melanoma differentiation-associated gene 5 juvenile dermatomyositis (anti-MDA5 JDM) is associated with high risk of developing rapidly progressive interstitial lung disease (RP-ILD). Here we report an 11-year-old girl with anti-MDA5 JDM and RP-ILD which led to a fatal outcome, further aggravated by SARS-CoV-2 infection. She was referred to our hospital after being diagnosed with anti-MDA5 JDM and respiratory failure due to RP-ILD. On admission, fibrobronchoscopy with bronchoalveolar lavage (BAL) revealed Pneumocystis jirovecii infection so treatment with intravenous trimethoprim-sulfamethoxazole was initiated. Due to RP-ILD worsening, immunosuppressive therapy was intensified using methylprednisolone pulses, cyclophosphamide, tofacitinib and intravenous immunoglobulin without response. She developed severe hypoxemic respiratory failure, pneumomediastinum and pneumothorax, further complicated with severe RP-ILD and cervical subcutaneous emphysema. Three real-time RT-PCR for SARS-CoV-2 were made with a negative result. In addition, she was complicated with a secondary hemophagocytic lymphohistiocytosis and a fourth real-time PCR for SARS-CoV-2 performed in BAS sample was positive. Despite aggressive treatment of RP-ILD due to anti-MDA5 JDM, there was no improvement of respiratory failure in the following days and patient developed refractory septic shock and died. Anti-MDA5 JDM patients with RP-ILD have a poor prognosis with a high mortality rate. For this reason, intensive immunosuppressive therapy is essential including the use of promising drugs such as tofacitinib. COVID-19 in children with underlying health conditions like anti-MDA5 JDM may still be at risk for disease and severe complications.


Assuntos
/complicações , Dermatomiosite/complicações , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Pneumonia por Pneumocystis/complicações , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , Autoanticorpos/imunologia , Broncoscopia , Criança , Ciclofosfamida/uso terapêutico , Dermatomiosite/tratamento farmacológico , Dermatomiosite/imunologia , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Hospedeiro Imunocomprometido , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Helicase IFIH1 Induzida por Interferon/imunologia , Pulmão/diagnóstico por imagem , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/terapia , Linfo-Histiocitose Hemofagocítica/imunologia , Enfisema Mediastínico/etiologia , Metilprednisolona/uso terapêutico , Piperidinas/uso terapêutico , Pneumonia por Pneumocystis/imunologia , Pneumotórax/etiologia , Pirimidinas/uso terapêutico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Choque Séptico/etiologia , Enfisema Subcutâneo/etiologia , Tomografia Computadorizada por Raios X , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico
13.
PLoS Med ; 17(12): e1003501, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33378357

RESUMO

BACKGROUND: Numerous clinical trials and observational studies have investigated various pharmacological agents as potential treatment for Coronavirus Disease 2019 (COVID-19), but the results are heterogeneous and sometimes even contradictory to one another, making it difficult for clinicians to determine which treatments are truly effective. METHODS AND FINDINGS: We carried out a systematic review and network meta-analysis (NMA) to systematically evaluate the comparative efficacy and safety of pharmacological interventions and the level of evidence behind each treatment regimen in different clinical settings. Both published and unpublished randomized controlled trials (RCTs) and confounding-adjusted observational studies which met our predefined eligibility criteria were collected. We included studies investigating the effect of pharmacological management of patients hospitalized for COVID-19 management. Mild patients who do not require hospitalization or have self-limiting disease courses were not eligible for our NMA. A total of 110 studies (40 RCTs and 70 observational studies) were included. PubMed, Google Scholar, MEDLINE, the Cochrane Library, medRxiv, SSRN, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched from the beginning of 2020 to August 24, 2020. Studies from Asia (41 countries, 37.2%), Europe (28 countries, 25.4%), North America (24 countries, 21.8%), South America (5 countries, 4.5%), and Middle East (6 countries, 5.4%), and additional 6 multinational studies (5.4%) were included in our analyses. The outcomes of interest were mortality, progression to severe disease (severe pneumonia, admission to intensive care unit (ICU), and/or mechanical ventilation), viral clearance rate, QT prolongation, fatal cardiac complications, and noncardiac serious adverse events. Based on RCTs, the risk of progression to severe course and mortality was significantly reduced with corticosteroids (odds ratio (OR) 0.23, 95% confidence interval (CI) 0.06 to 0.86, p = 0.032, and OR 0.78, 95% CI 0.66 to 0.91, p = 0.002, respectively) and remdesivir (OR 0.29, 95% CI 0.17 to 0.50, p < 0.001, and OR 0.62, 95% CI 0.39 to 0.98, p = 0.041, respectively) compared to standard care for moderate to severe COVID-19 patients in non-ICU; corticosteroids were also shown to reduce mortality rate (OR 0.54, 95% CI 0.40 to 0.73, p < 0.001) for critically ill patients in ICU. In analyses including observational studies, interferon-alpha (OR 0.05, 95% CI 0.01 to 0.39, p = 0.004), itolizumab (OR 0.10, 95% CI 0.01 to 0.92, p = 0.042), sofosbuvir plus daclatasvir (OR 0.26, 95% CI 0.07 to 0.88, p = 0.030), anakinra (OR 0.30, 95% CI 0.11 to 0.82, p = 0.019), tocilizumab (OR 0.43, 95% CI 0.30 to 0.60, p < 0.001), and convalescent plasma (OR 0.48, 95% CI 0.24 to 0.96, p = 0.038) were associated with reduced mortality rate in non-ICU setting, while high-dose intravenous immunoglobulin (IVIG) (OR 0.13, 95% CI 0.03 to 0.49, p = 0.003), ivermectin (OR 0.15, 95% CI 0.04 to 0.57, p = 0.005), and tocilizumab (OR 0.62, 95% CI 0.42 to 0.90, p = 0.012) were associated with reduced mortality rate in critically ill patients. Convalescent plasma was the only treatment option that was associated with improved viral clearance rate at 2 weeks compared to standard care (OR 11.39, 95% CI 3.91 to 33.18, p < 0.001). The combination of hydroxychloroquine and azithromycin was shown to be associated with increased QT prolongation incidence (OR 2.01, 95% CI 1.26 to 3.20, p = 0.003) and fatal cardiac complications in cardiac-impaired populations (OR 2.23, 95% CI 1.24 to 4.00, p = 0.007). No drug was significantly associated with increased noncardiac serious adverse events compared to standard care. The quality of evidence of collective outcomes were estimated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The major limitation of the present study is the overall low level of evidence that reduces the certainty of recommendations. Besides, the risk of bias (RoB) measured by RoB2 and ROBINS-I framework for individual studies was generally low to moderate. The outcomes deducted from observational studies could not infer causality and can only imply associations. The study protocol is publicly available on PROSPERO (CRD42020186527). CONCLUSIONS: In this NMA, we found that anti-inflammatory agents (corticosteroids, tocilizumab, anakinra, and IVIG), convalescent plasma, and remdesivir were associated with improved outcomes of hospitalized COVID-19 patients. Hydroxychloroquine did not provide clinical benefits while posing cardiac safety risks when combined with azithromycin, especially in the vulnerable population. Only 29% of current evidence on pharmacological management of COVID-19 is supported by moderate or high certainty and can be translated to practice and policy; the remaining 71% are of low or very low certainty and warrant further studies to establish firm conclusions.


Assuntos
Anti-Inflamatórios/uso terapêutico , Hidroxicloroquina/efeitos adversos , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/efeitos adversos , Alanina/análogos & derivados , Alanina/uso terapêutico , Anti-Inflamatórios/efeitos adversos , Azitromicina/efeitos adversos , Azitromicina/uso terapêutico , /terapia , Estado Terminal , Hospitalização , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Metanálise em Rede , Estudos Observacionais como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Ned Tijdschr Geneeskd ; 1642020 11 12.
Artigo em Holandês | MEDLINE | ID: mdl-33331727

RESUMO

Much has changed in the medical treatment of COVID-19 after the first patient with an infection with SARS-CoV-2 in the Netherlands was diagnosed in February 2020. On the basis of limited data, at first only off-label use of (hydroxy)chloroquine seemed to be a treatment option. However, now based on the findings of several randomized studies, other medicines have been included in the Dutch guidelines about the treatment of COVID-19. In this article, we will briefly discuss the current state of affairs with regard to the drugs (hydroxy) chloroquine, remdesivir and corticosteroids. Again, it appears that only well-executed randomized clinical trials can determine the status of various supposedly effective drugs.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Reposicionamento de Medicamentos , Glucocorticoides , Hidroxicloroquina , /efeitos dos fármacos , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , /epidemiologia , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/normas , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Países Baixos/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
15.
PLoS One ; 15(12): e0243705, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33301514

RESUMO

BACKGROUND: Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19. METHODS: Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed. RESULTS: We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed. CONCLUSIONS: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , /efeitos dos fármacos , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
16.
Adv Chronic Kidney Dis ; 27(5): 434-441, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33308510

RESUMO

Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Insuficiência Renal Crônica/metabolismo , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , /prevenção & controle , /uso terapêutico , Cloroquina/uso terapêutico , Creatinina/metabolismo , Citidina/análogos & derivados , Citidina/uso terapêutico , Dexametasona/uso terapêutico , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Hidroxicloroquina/uso terapêutico , Hidroxilaminas/uso terapêutico , Imunização Passiva , Interferons/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Lopinavir/uso terapêutico , Pirazinas/uso terapêutico , Eliminação Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Terapia de Substituição Renal , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico
17.
Medwave ; 20(11): e8080, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33361753

RESUMO

Objective: Provide a timely, rigorous and continuously updated summary of the evidence on the role of remdesivir in the treatment of patients with COVID-19. Methods: Eligible studies were randomized trials evaluating the effect of remdesivir versus placebo or no treatment. We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in databases, trial registries, preprint servers and websites relevant to COVID-19. All the searches covered the period until 25 August 2020. No date or language restrictions were applied. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria, and extracted data on study characteristics, methods, outcomes, and risk of bias, using a predesigned, standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. Results: Our search strategy yielded 574 references. Finally, we included three randomized trials evaluating remdesivir in addition to standard care versus standard care alone. The evidence is very uncertain about the effect of remdesivir on mortality (RR 0.7, 95% CI 0.46 to 1.05; very low certainty evidence) and the need for invasive mechanical ventilation (RR 0.69, 95% CI 0.39 to 1.24; very low certainty evidence). On the other hand, remdesivir likely results in a large increase in the incidence of adverse effects in patients with COVID-19 (RR 1.29, 95% CI 0.58 to 2.84; moderate certainty evidence). Conclusions: The evidence is insufficient for the outcomes critical for making decisions on the role of remdesivir in the treatment of patients with COVID-19, so it is impossible to balance potential benefits, if there are any, with the adverse effects and costs. PROSPERO registration number: CRD42020183384.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , /tratamento farmacológico , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial/estatística & dados numéricos , Resultado do Tratamento
18.
J Comp Eff Res ; 9(18): 1243-1246, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33274643

RESUMO

The race to find an effective treatment for coronavirus disease 2019 (COVID-19) is still on, with only two treatment options currently authorized for emergency use and/or recommended for patients hospitalized with severe respiratory symptoms: low-dose dexamethasone and remdesivir. The USA decision to stockpile the latter has resulted in widespread condemnation and in similar action being taken by some other countries. In this commentary we discuss whether stockpiling remdesivir is justified in light of the currently available evidence.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Cooperação Internacional , Internacionalidade , Estoque Estratégico/métodos , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , Humanos , Estados Unidos
19.
Indian J Med Ethics ; V(3): 202-207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33295289

RESUMO

The world is going through an unprecedented medical emergency with no effective remedy for the SARS-CoV2 virus causing Covid-19. Two drugs used for other indications in the past, hydroxychloroquine (HCQ) and remdesivir (RDV), are sought to be repurposed to treat Covid-19. Both these drugs have received emergency use authorisation by the US Food and Drug Administration. In this review, we critically analyse the identification of and subsequent events concerning these two drugs as potential treatment options for Covid-19, and conclude by raising some ethical issues that require serious thought from the global scientific community concerned with using these two drugs against Covid-19.

Key Words: Covid-19, hydroxychloroquine, remdesivir, USFDA, emergency use authorisation

.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Emergências , Ética , Hidroxicloroquina/uso terapêutico , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Alanina/efeitos adversos , Alanina/uso terapêutico , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Humanos , Hidroxicloroquina/efeitos adversos , Uso Off-Label , Pandemias , Segurança do Paciente , Resultado do Tratamento
20.
Eur Rev Med Pharmacol Sci ; 24(23): 12593-12608, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336780

RESUMO

The coronavirus disease 2019 (COVID-19) is declared as an international emergency in 2020. Its prevalence and fatality rate are rapidly increasing but the medication options are still limited for this perilous disease. The emergent outbreak of COVID-19 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps propagating globally. The present scenario has emphasized the requirement for therapeutic opportunities to relive and overcome this latest pandemic. Despite the fact, the deteriorating developments of COVID-19, there is no drug certified to have considerable effects in the medical treatment for COVID-19 patients. The COVID-19 pandemic requests for the rapid testing of new treatment approaches. Based on the evidence, hydroxychloroquine is the first medicine opted for the treatment of disease. Umifenovir, remdesivir, and fevipiravir are deemed the most hopeful antiviral agent by improving the health of infected patients. The dexamethasone is a first known steroid medicine that can save the lives of seriously ill patients, and it is shown in a randomized clinical trial by the United Kingdom that it reduced the death rate in COVID-19 patients. The current review recapitulates the existing evidence of possible therapeutic drugs, peptides, humanized antibodies, convulsant plasma, and vaccination that has revealed potential in fighting COVID-19 infections. Many randomized and controlled clinical trials are taking place to further validate these agent's safety and effectiveness in curing COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , /tratamento farmacológico , /terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Antiparasitários/uso terapêutico , Canabinoides/uso terapêutico , Cloroquina/uso terapêutico , Inativadores do Complemento/uso terapêutico , Dexametasona/uso terapêutico , Combinação de Medicamentos , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Indóis/uso terapêutico , Interferons/uso terapêutico , Ivermectina/uso terapêutico , Lopinavir/uso terapêutico , Pirazinas/uso terapêutico , Ritonavir/uso terapêutico , Teicoplanina/uso terapêutico , Tetraciclinas/uso terapêutico , Tiazóis/uso terapêutico
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