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1.
Br J Hosp Med (Lond) ; 82(3): 1-9, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33792391

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread and have grave health and socioeconomic consequences worldwide. Researchers have raced to understand the pathophysiological mechanisms underpinning the disease caused by SARS-CoV-2 so that effective therapeutic targets can be discovered. This review summarises the key pharmacotherapies that are being investigated for treatment of COVID-19, including antiviral, immunomodulator and anticoagulation strategies.


Assuntos
Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Glucocorticoides/uso terapêutico , Fatores Imunológicos/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/uso terapêutico , Colchicina/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Imunização Passiva , Ivermectina/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico
3.
Inflamm Res ; 70(4): 407-428, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33640999

RESUMO

BACKGROUND: The aim of this review is to explore whether patients with autoimmune diseases (AIDs) were at high risk of infection during the COVID-19 epidemic and how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic affected immune system. METHODS: A systematic literature search was performed using the foreign databases (NCBI, web of science, EBSCO, ELSEVIER ScienceDirect) and Chinese databases (WanFang, CNKI (China National Knowledge Infrastructure), VIP, CBM) to locate all relevant publications (up to January 10, 2021). The search strategies used Medical Search Headings (MeSH) headings and keywords for "COVID-19" or "SARS-CoV-2" or "coronavirus" and "autoimmune disease". RESULTS: This review evaluates the effect of SARS-CoV-2 on the immune system through ACE-2 receptor binding as the main pathway for cell attachment and invasion. It is speculated that SARS-COV-2 infection can activate lymphocytes and inflammatory response, which may play a role in the clinical onset of AIDs and also patients were treated with immunomodulatory drugs during COVID-19 outbreak. Preliminary studies suggested that the risk of developing severe forms of COVID-19 in patients with AIDs treated with immunomodulators or biologics might not increase. A large number of samples are needed for further verification, leading to an excessive immune response to external stimuli. CONCLUSION: The relationship between autoimmune diseases and SARS-CoV-2 infection is complex. During the COVID-19 epidemic, individualized interventions for AIDs should be provided such as Internet-based service.


Assuntos
Doenças Autoimunes/complicações , Doenças Autoimunes/epidemiologia , /epidemiologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Azetidinas/uso terapêutico , /terapia , Células Dendríticas/virologia , Humanos , Sistema Imunitário , Imunidade Inata , Imunização Passiva/tendências , Doenças Inflamatórias Intestinais/imunologia , Células Matadoras Naturais/virologia , Lúpus Eritematoso Sistêmico/imunologia , Monócitos/virologia , Esclerose Múltipla/imunologia , Purinas/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico
5.
Theranostics ; 11(1): 316-329, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33391477

RESUMO

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Síndrome da Liberação de Citocina/imunologia , Citocinas/metabolismo , Imunossupressores/uso terapêutico , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , /imunologia , Ensaios Clínicos como Assunto , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Imunossupressores/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Purinas/farmacologia , Purinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Resultado do Tratamento
6.
Anal Chem ; 93(5): 2767-2775, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33474935

RESUMO

Clinical tissue specimens are often unscreened, and preparation of tissue sections for analysis by mass spectrometry imaging (MSI) can cause aerosolization of particles potentially carrying an infectious load. We here present a decontamination approach based on ultraviolet-C (UV-C) light to inactivate clinically relevant pathogens such as herpesviridae, papovaviridae human immunodeficiency virus, or SARS-CoV-2, which may be present in human tissue samples while preserving the biodistributions of analytes within the tissue. High doses of UV-C required for high-level disinfection were found to cause oxidation and photodegradation of endogenous species. Lower UV-C doses maintaining inactivation of clinically relevant pathogens to a level of increased operator safety were found to be less destructive to the tissue metabolome and xenobiotics. These doses caused less alterations of the tissue metabolome and allowed elucidation of the biodistribution of the endogenous metabolites. Additionally, we were able to determine the spatially integrated abundances of the ATR inhibitor ceralasertib from decontaminated human biopsies using desorption electrospray ionization-MSI (DESI-MSI).


Assuntos
Descontaminação/métodos , Raios Ultravioleta , Animais , Azetidinas/análise , Azetidinas/uso terapêutico , /virologia , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Metaboloma , Naftalenos/análise , Naftalenos/uso terapêutico , Fotólise/efeitos da radiação , Ratos , Ratos Wistar , /efeitos da radiação , Espectrometria de Massas por Ionização por Electrospray/métodos , Terfenadina/química , Inativação de Vírus/efeitos da radiação
7.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33440983

RESUMO

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Assuntos
Antivirais/uso terapêutico , /terapia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Cloroquina/farmacologia , Cloroquina/uso terapêutico , Combinação de Medicamentos , Humanos , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Imunização Passiva , Indóis/farmacologia , Indóis/uso terapêutico , Interferons/farmacologia , Interferons/uso terapêutico , Ivermectina/farmacologia , Ivermectina/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ribavirina/farmacologia , Ribavirina/uso terapêutico , Ritonavir/farmacologia , Ritonavir/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico
8.
Neurology ; 96(3): e376-e386, 2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33328324

RESUMO

OBJECTIVE: To investigate the effects of siponimod on cognitive processing speed in patients with secondary progressive (SP) multiple sclerosis (MS), by means of a predefined exploratory and post hoc analysis of the Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND) study, a randomized controlled trial comparing siponimod and placebo. METHODS: EXPAND was a double-blind, placebo-controlled phase 3 trial involving 1,651 patients with SPMS randomized (2:1) to either siponimod 2 mg/d or placebo. Cognitive function was assessed with the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT), and Brief Visuospatial Memory Test-Revised (BVMT-R) administered at baseline, 6-month intervals, and end of treatment. RESULTS: Between-group differences in mean change from baseline in SDMT scores were significantly better in siponimod- vs placebo-treated patients at month 12 (difference 1.08 [95% confidence interval 0.23-1.94]; p = 0.0132), month 18 (1.23 [0.25-2.21); p = 0.0135), and month 24 (2.30 [1.11-3.50]; p = 0.0002). Siponimod-treated patients were at significantly lower risk for having a 4-point sustained decrease in SDMT score (hazard ratio [HR] 0.79 [0.65-0.96]; p = 0.0157), while their chance for having a 4-point sustained increase in SDMT score was higher (HR 1.28 [1.05-1.55]; p = 0.0131). PASAT and BVMT-R scores did not differ significantly between the 2 treatment groups (all p > 0.28). CONCLUSION: Siponimod had a significant benefit on SDMT in patients with SPMS. Siponimod-treated patients were at significantly lower risk for having a ≥4-point decrease in SDMT score and had a significantly higher chance for having a ≥4-point increase in SDMT score, a magnitude of change accepted as clinically meaningful. CLINICALTRIALSGOV IDENTIFIER: NCT01665144. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for patients with SPMS, siponimod had a significant benefit on cognitive processing speed.


Assuntos
Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Cognição/efeitos dos fármacos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Adulto , Azetidinas/farmacologia , Compostos de Benzil/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/psicologia , Testes Neuropsicológicos , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia
9.
Eur Rev Med Pharmacol Sci ; 24(23): 12527-12535, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33336773

RESUMO

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/imunologia , Miocardite/imunologia , /metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Antioxidantes/uso terapêutico , Apoptose , Fator Natriurético Atrial/uso terapêutico , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Glucocorticoides/uso terapêutico , Glicoproteínas/uso terapêutico , Humanos , Hipóxia/metabolismo , Hipóxia/terapia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Isquemia Miocárdica/metabolismo , Miocardite/metabolismo , Miocardite/terapia , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Oxigenoterapia , Respiração Artificial , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Inibidores da Tripsina/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , alfa-Metiltirosina/uso terapêutico
12.
Nat Rev Immunol ; 20(10): 585-586, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32788708
13.
Mult Scler Relat Disord ; 45: 102437, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763844

RESUMO

We encourage studies on the effectiveness of multiple sclerosis drugs for the treatment of ARDS in COVID-19 infection. These drugs, through the inhibition of the RhoA/actin-dependent expression of virus receptors in the macrophages and macrophage recruitment to the lungs, have the potential to inhibit cytokine storm of lung macrophages, reduce or eliminate ARDS and improve the outcome of COVID-19 infection.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/complicações , Cloridrato de Fingolimode/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Pandemias , Pneumonia Viral/complicações , /virologia
14.
Int Immunopharmacol ; 86: 106749, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32645632

RESUMO

In December 2019, a novel coronavirus pneumonia (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suddenly broke out in China and rapidly spread all over the world. Recently, a cell surface protein, known as angiotensin-converting enzyme II (ACE2), has been identified to be involved in receptor-mediated endocytosis for SARS-CoV-2 entry to the cells. Many studies have reported the clinical characteristics of COVID-19: sudden deterioration of disease around 1-2 weeks after onset; much lower level of lymphocytes, especially natural killer (NK) cells in peripheral blood; extremely high pro-inflammatory cytokines and C reactive protein (CRP). About 15.7% of patients develop severe pneumonia, and cytokine storm is an important factor leading to rapid disease progression. Currently, there are no specific drugs for COVID-19 and the cytokine storm it causes. Baricitinib intracellularly inhibits the proinflammatory signal of several cytokines by suppressing Janus kinase (JAK) JAK1/JAK2. It has been demonstrated clinical benefits for the patients with rheumatoid arthritis (RA), active systemic lupus erythematosus and atopic dermatitis with good efficacy and safety records. Baricitinib is expected to interrupt the passage and intracellular assembly of SARS-CoV-2 into the target cells mediated by ACE2 receptor, and treat cytokine storm caused by COVID-19. Several clinical trials are currently investigating the drug, and one of which has been completed with encouraging results. In this paper, we will elaborate the role of cytokine storm mediated by JAK-STAT pathway in severe COVID-19, the possible mechanisms of baricitinib on reducing the viral entry into the target cells and cytokine storm, the key points of pharmaceutical care based on the latest research reports, clinical trials progress and drug instruction from the US FDA, so as to provide reference for the treatment of severe COVID-19.


Assuntos
Azetidinas/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Azetidinas/farmacologia , Betacoronavirus/metabolismo , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 1/metabolismo , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Sulfonamidas/farmacologia , Resultado do Tratamento , Montagem de Vírus/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
15.
Trials ; 21(1): 626, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641154

RESUMO

OBJECTIVES: To determine if a specific immunomodulatory intervention reduces progression of COVID-19-related disease to organ failure or death, compared to standard of care (SoC). TRIAL DESIGN: Randomised, parallel 3-arm (1:1:1 ratio), open-label, Phase IV platform trial of immunomodulatory therapies in patients with late stage 1 or stage 2 COVID-19-related disease, with a diagnosis based either on a positive assay or high suspicion of COVID-19 infection by clinical and/or radiological assessment. PARTICIPANTS: Patients aged 18 and over, with a clinical picture strongly suggestive of COVID-19-related disease (with/without a positive COVID-19 test) AND a Risk count (as defined below) >3 OR ≥3 if risk count includes "Radiographic severity score >3". A risk count is calculated by the following features on admission (1 point for each): radiographic severity score >3, male gender, non-white ethnicity, diabetes, hypertension, neutrophils >8.0 x109/L, age >40 years and CRP >40 mg/L. Patients should be considered an appropriate subject for intervention with immunomodulatory therapies in the opinion of the investigator and be able to be maintained on venous thromboembolism prophylaxis during the inpatient dosing period, according to local guidelines. The complete inclusion and exclusion criteria as detailed in the additional file 1 should be fulfilled. Patients will be enrolled prior to the need for invasive mechanical ventilation, cardiac or renal support. Participants will be recruited across multiple centres including initially at Cambridge University Hospitals NHS Foundation Trust, King's College Hospital NHS Foundation Trust, Guy's and St Thomas' NHS Foundation Trust, University Hospital of Wales, Gloucestershire Royal Hospitals NHS Foundation Trust and The Royal Wolverhampton NHS Trust. INTERVENTION AND COMPARATOR: Each active comparator arm will be compared against standard of care (SoC). The immunomodulatory drugs were selected from a panel of licenced candidates by a drug evaluation committee, which considered potential efficacy, potential toxicity, scalability and novelty of each strategy. The initial active arms comprise baricitinib and ravulizumab. Baricitinib will be given 4 mg orally (once daily (OD)) on days 1-14 or until day of discharge. The dose will be reduced to 2 mg OD for patients aged > 75 years and those with an estimated Cockcroft Gault creatinine clearance of 30-60 ml/min. Ravulizumab will be administered intravenously once according to the licensed weight-based dosing regimen (see Additional file 1). Each active arm will be compared with standard of care alone. No comparisons will be made between active arms in this platform trial. MAIN OUTCOMES: The primary outcome is the incidence (from baseline up to Day 14) of any one of the events (whichever comes first): death, invasive mechanical ventilation, extra corporeal membrane oxygenation, cardiovascular organ support (inotropes or balloon pump), or renal failure (estimated Cockcroft Gault creatinine clearance <15ml/min). RANDOMISATION: Eligible patients will be randomised using a central web-based randomisation service (Sealed Envelope) in a 1:1:1 ratio, stratified by site to one of the treatment arms or SoC. BLINDING (MASKING): This is an open-label trial. Data analysis will not be blinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): There is no fixed sample size for this study. Serial interim analyses will be triggered by an Independent Data Monitoring Committee (IDMC), including analysis after 125 patients are recruited to each arm, 375 in total assuming 3 arms. Additional interim analyses are projected after 229 patients per arm, and potentially then after 469 per arm, but additional analyses may be triggered by the IDMC. TRIAL STATUS: TACTIC-R Protocol version number 2.0 date May 20, 2020, recruitment began May 7, 2020 and the end trial will be the date 18 months after the last patient's last visit. The recruitment end date cannot yet be accurately predicted. TRIAL REGISTRATION: Registered on EU Clinical Trials Register EudraCT Number: 2020-001354-22 Registered: 6 May 2020 It was registered on ClinicalTrials.gov ( NCT04390464 ) and on ISRCTN (ISRCTN11188345) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Azetidinas/efeitos adversos , Azetidinas/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Pandemias , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico
16.
Infection ; 48(5): 767-771, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32642806
17.
Virus Res ; 286: 198070, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32569708

RESUMO

SARS-CoV-2 is the agent responsible for COVID-19. The infection can be dived into three phases: mild infection, the pulmonary phase and the inflammatory phase. Treatment options for the pulmonary phase include: Hydroxychloroquine, Remdesivir, Lopinavir/Ritonavir. The inflammatory phase includes therapeutic options like Tocilizumab, Anakinra, Baricitinib, Eculizumab, Emapalumab and Heparin. Human clinical trials are starting to show some results, in some cases like that of Remdesivir and corticosteroids these are controversial. Coagulopathy is a common complication in severe cases, inflammation and coagulation are intertwined and cross-talking between these two responses is known to happen. A possible amplification of this cross-talking is suggested to be implicated in the severe cases that show both a cytokine storm and coagulopathy.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Coagulação Intravascular Disseminada/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Azetidinas/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/virologia , Combinação de Medicamentos , Heparina/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Lopinavir/uso terapêutico , Pandemias , Pneumonia Viral/virologia , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico
18.
Nat Rev Rheumatol ; 16(8): 465-470, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561873

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1ß or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.


Assuntos
Artrite Reumatoide/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artralgia , Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Assistência à Saúde , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Inibidores de Janus Quinases/uso terapêutico , Mialgia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Reumatologia , Sulfonamidas/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia
19.
Pharmacotherapy ; 40(8): 843-856, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32542785

RESUMO

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib's immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients' immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.


Assuntos
Azetidinas/farmacologia , Azetidinas/uso terapêutico , Infecções por Coronavirus/complicações , Inflamação/tratamento farmacológico , Inflamação/etiologia , Janus Quinases/antagonistas & inibidores , Pneumonia Viral/complicações , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Área Sob a Curva , Azetidinas/administração & dosagem , Azetidinas/efeitos adversos , Betacoronavirus , Ensaios Clínicos como Assunto , Citocinas/metabolismo , Interações Medicamentosas , Humanos , Interferon Tipo I/biossíntese , Taxa de Depuração Metabólica , Pandemias , Peptidil Dipeptidase A/biossíntese , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos
20.
Lancet ; 395(10240): 1835-1844, 2020 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-32534646

RESUMO

BACKGROUND: IMspire150 aimed to evaluate first-line combination treatment with BRAF plus MEK inhibitors and immune checkpoint therapy in BRAFV600 mutation-positive advanced or metastatic melanoma. METHODS: IMspire150 was a randomised, double-blind, placebo-controlled phase 3 study done at 112 institutes in 20 countries. Patients with unresectable stage IIIc-IV, BRAFV600 mutation-positive melanoma were randomly assigned 1:1 to 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (atezolizumab group) or atezolizumab placebo, vemurafenib, and cobimetinib (control group). In cycle 1, all patients received vemurafenib and cobimetinib only; atezolizumab placebo was added from cycle 2 onward. Randomisation was stratified by lactate dehydrogenase concentration and geographical region. Blinding for atezolizumab was achieved by means of an identical intravenous placebo, and blinding for vemurafenib was achieved by means of a placebo tablet. The primary outcome was investigator-assessed progression-free survival. This trial (ClinicalTrials.gov, NCT02908672) is ongoing but no longer recruiting patients. FINDINGS: Between Jan 13, 2017, and April 26, 2018, 777 patients were screened and 514 were enrolled and randomly assigned to the atezolizumab group (n=256) or control group (n=258). At a median follow-up of 18·9 months (IQR 10·4-23·8), progression-free survival as assessed by the study investigator was significantly prolonged with atezolizumab versus control (15·1 vs 10·6 months; hazard ratio [HR] 0·78; 95% CI 0·63-0·97; p=0·025). Common treatment-related adverse events (>30%) in the atezolizumab and control groups were blood creatinine phosphokinase increased (51·3% vs 44·8%), diarrhoea (42·2% vs 46·6%), rash (40·9%, both groups), arthralgia (39·1% vs 28·1%), pyrexia (38·7% vs 26·0%), alanine aminotransferase increased (33·9% vs 22·8%), and lipase increased (32·2% vs 27·4%); 13% of patients in the atezolizumab group and 16% in the control group stopped all treatment because of adverse events. INTERPRETATION: The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAFV600 mutation-positive advanced melanoma. FUNDING: F Hoffmann-La Roche and Genentech.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azetidinas/uso terapêutico , Melanoma/tratamento farmacológico , Piperidinas/uso terapêutico , Vemurafenib/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azetidinas/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Piperidinas/efeitos adversos , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Vemurafenib/efeitos adversos
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