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1.
Anticancer Res ; 40(9): 4869-4874, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878774

RESUMO

BACKGROUND/AIM: In the present study, we evaluated the efficacy of adjuvant administration of oral recombinant methioninase (o-rMETase) against recurrence and metastasis in a 4T1 murine breast-cancer syngeneic model. MATERIALS AND METHODS: 4T1 cells were orthotopically implanted into the 2nd mammary fat pad of BALB/c mice. The 4T1 orthotopic syngeneic models were randomized into 2 groups after primary tumor resection: untreated control and o-rMETase (100 units, oral, daily, 2 weeks). RESULTS: The frequency and extent of local recurrence were reduced by o-rMETase. The number of individual cancer cells and metastatic nodules on the lung surface was significantly lower in the o-rMETase-treated mice than the untreated control mice. CONCLUSION: Adjuvant o-rMETase inhibited local recurrence and lung metastasis after primary tumor resection.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Liases de Carbono-Enxofre/administração & dosagem , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/tratamento farmacológico , Administração Oral , Animais , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Esquema de Medicação , Feminino , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/cirurgia , Camundongos , Camundongos Endogâmicos BALB C , Recidiva Local de Neoplasia/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Emerg Med Clin North Am ; 38(4): 871-889, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32981623

RESUMO

Massive gastrointestinal hemorrhage is a life-threatening condition that can result from numerous causes and requires skilled resuscitation to decrease patient morbidity and mortality. Successful resuscitation begins with placement of large-bore intravenous or intraosseous access; early blood product administration; and early consultation with a gastroenterologist, interventional radiologist, and/or surgeon. Activate a massive transfusion protocol when initial red blood cell transfusion does not restore effective perfusion or the patient's shock index is greater than 1.0. Promptly reverse coagulopathies secondary to oral anticoagulant or antiplatelet use. Use thromboelastography or rotational thromboelastometry to guide further transfusions. Secure a definitive airway and minimize aspiration.


Assuntos
Hemorragia Gastrointestinal/terapia , Manuseio das Vias Aéreas , Antibacterianos/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticoagulantes/efeitos adversos , Antifibrinolíticos/uso terapêutico , Oclusão com Balão , Fatores de Coagulação Sanguínea/administração & dosagem , Transfusão de Sangue/métodos , Cateteres , Serviço Hospitalar de Emergência , Fator Xa/administração & dosagem , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiologia , Humanos , Infusões Intraósseas , Infusões Intravenosas , Anamnese , Exame Físico , Inibidores da Bomba de Prótons/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Ressuscitação , Tromboelastografia , Vasoconstritores/uso terapêutico
3.
Nat Commun ; 11(1): 4458, 2020 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-32895383

RESUMO

In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.


Assuntos
Diabetes Mellitus Experimental/dietoterapia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fator 1 de Crescimento de Fibroblastos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Hipotálamo/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteína Relacionada com Agouti/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Glicemia/análise , Comunicação Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Dieta Hiperlipídica/efeitos adversos , Sacarose na Dieta/administração & dosagem , Sacarose na Dieta/efeitos adversos , Humanos , Hipotálamo/citologia , Hipotálamo/patologia , Injeções Intraventriculares , Leptina/genética , Masculino , Melanocortinas/metabolismo , Hormônios Estimuladores de Melanócitos/administração & dosagem , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , RNA-Seq , Receptor Tipo 4 de Melanocortina/genética , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Indução de Remissão/métodos , Transdução de Sinais/efeitos dos fármacos , Análise de Célula Única , Técnicas Estereotáxicas , Transcriptoma/efeitos dos fármacos
4.
Ann Hematol ; 99(11): 2689-2698, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32974838

RESUMO

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0-tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 ( ClinicalTrials.gov identifier). Date of registration: July 9, 2019.


Assuntos
Fator VIII , Hemofilia A , Adolescente , Adulto , Idoso , Estudos Cross-Over , Fator VIII/administração & dosagem , Fator VIII/farmacocinética , Meia-Vida , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética
5.
Lancet Diabetes Endocrinol ; 8(8): 683-692, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32707116

RESUMO

BACKGROUND: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. METHODS: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). FINDINGS: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. INTERPRETATION: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. FUNDING: European Union.


Assuntos
Nanismo Hipofisário/tratamento farmacológico , Nanismo Hipofisário/mortalidade , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/efeitos adversos , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Mortalidade/tendências , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Fatores de Tempo , Adulto Jovem
6.
Arch Virol ; 165(9): 2065-2071, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32613291

RESUMO

Mink enteritis virus (MEV) is a parvovirus that causes acute enteritis in mink. The capsid protein VP2 of MEV is a major immunogenicity that is important for disease prevention. In this study, this protein was expressed in Spodoptera frugiperda 9 cells using a recombinant baculovirus system and was observed to self-assemble into virus-like particles (VLPs) with a high hemagglutination (HA) titer (1:216). A single-dose injection of VLPs (HA titer, 1:256) resulted in complete protection of mink against virulent MEV challenge for at least 180 days. These data suggest that these MEV VLPs could be used as a vaccine for the prevention of viral enteritis in mink.


Assuntos
Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Enterite Viral do Vison/prevenção & controle , Vírus da Enterite do Vison/imunologia , Animais , Baculoviridae/genética , Baculoviridae/metabolismo , Proteínas do Capsídeo/administração & dosagem , Expressão Gênica , Vison/imunologia , Vison/virologia , Enterite Viral do Vison/imunologia , Enterite Viral do Vison/virologia , Vírus da Enterite do Vison/genética , Vírus da Enterite do Vison/patogenicidade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Células Sf9 , Spodoptera , Vacinas Virais/administração & dosagem , Vacinas Virais/genética , Vacinas Virais/imunologia , Virulência
7.
Nat Commun ; 11(1): 3546, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669559

RESUMO

Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin's effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression.


Assuntos
Carcinoma Epitelial do Ovário/secundário , Citocinas/metabolismo , Lectinas/metabolismo , Omento/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/secundário , Animais , Carcinoma Epitelial do Ovário/sangue , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/terapia , Linhagem Celular Tumoral/transplante , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Citocinas/administração & dosagem , Citocinas/sangue , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Proteínas Ligadas por GPI/administração & dosagem , Proteínas Ligadas por GPI/sangue , Proteínas Ligadas por GPI/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Lactoferrina/metabolismo , Lectinas/administração & dosagem , Lectinas/sangue , Metaloproteinase 1 da Matriz/metabolismo , Camundongos , Invasividade Neoplásica/patologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Ovário , Proteínas Recombinantes/administração & dosagem , Taxa de Sobrevida , Microambiente Tumoral
8.
Nat Commun ; 11(1): 3545, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32669564

RESUMO

Group A Streptococcus (GAS) infection causes a range of diseases, but vaccine development is hampered by the high number of serotypes. Here, using reverse vaccinology the authors identify SPy_2191 as a cross-protective vaccine candidate. From 18 initially identified surface proteins, only SPy_2191 is conserved, surface-exposed and inhibits both GAS adhesion and invasion. SPy_2191 immunization in mice generates bactericidal antibodies resulting in opsonophagocytic killing of prevalent and invasive GAS serotypes of different geographical regions, including M1 and M49 (India), M3.1 (Israel), M1 (UK) and M1 (USA). Resident splenocytes show higher interferon-γ and tumor necrosis factor-α secretion upon antigen re-stimulation, suggesting activation of cell-mediated immunity. SPy_2191 immunization significantly reduces streptococcal load in the organs and confers ~76-92% protection upon challenge with invasive GAS serotypes. Further, it significantly suppresses GAS pharyngeal colonization in mice mucosal infection model. Our findings suggest that SPy_2191 can act as a universal vaccine candidate against GAS infections.


Assuntos
Proteínas de Bactérias/imunologia , Proteção Cruzada/imunologia , Infecções Estreptocócicas/prevenção & controle , Vacinas Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Animais , Aderência Bacteriana/imunologia , Linhagem Celular , Clonagem Molecular , Modelos Animais de Doenças , Feminino , Humanos , Imunogenicidade da Vacina , Camundongos , Testes de Neutralização , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Sorogrupo , Infecções Estreptocócicas/microbiologia , Vacinas Estreptocócicas/administração & dosagem , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologia
9.
Neurol Sci ; 41(9): 2325-2329, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32656711

RESUMO

The sudden worldwide outbreak of Coronavirus Disease 2019 (COVID-19) has certainly provided new challenges in the management of acute ischaemic stroke, and the risk-benefit ratio of intravenous thrombolysis in COVID-19 positive patients is not well known. We describe four COVID-19 patients treated with intravenous thrombolysis for acute ischaemic stroke. Although rt-PA administration is the main therapeutic strategy, our patients experienced unpredictable complications and showed atypical features: the overall mortality was very high. In conclusion, in this article, we provide information about these cases and discuss the possible explanation behind this trend.


Assuntos
Betacoronavirus , Isquemia Encefálica/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Administração Intravenosa , Idoso , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico por imagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Proteínas Recombinantes/administração & dosagem , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem
10.
Am Heart J ; 227: 19-30, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32663660

RESUMO

BACKGROUND: Current guidelines recommend anticoagulation therapy during primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI). However, whether anticoagulation should be continued after pPCI has not been well investigated. METHODS/DESIGN: The RIGHT trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in STEMI patients treated with pPCI evaluating the prolongation of anticoagulation after the procedure. Patients are randomized in a 1:1 fashion to receive either prolonged anticoagulant or matching placebo (no anticoagulation) for at least 48 hours after the procedure. When randomized to anticoagulation prolongation, the patient is assigned to intravenous unfractionated heparin (UFH) or subcutaneous enoxaparin or intravenous bivalirudin (same drug and same regimen at each center). The primary efficacy endpoint is the composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, stent thrombosis (definite) or urgent revascularization (any vessel) at 30 days. The primary safety endpoint is major bleeding (BARC 3-5) at 30 days. Based on a superiority design and assuming a 35% relative risk reduction (from 7% to 4.5%), 2856 patients will be enrolled, accounting for a 5% drop-out rate (α = 0.05 and power = 80%). CONCLUSION: The RIGHT trial tests the hypothesis that post-procedural anticoagulation is superior to no anticoagulation in reducing ischemic events in STEMI patients undergoing pPCI.


Assuntos
Anticoagulantes/administração & dosagem , Enoxaparina/administração & dosagem , Heparina/administração & dosagem , Hirudinas/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Intervenção Coronária Percutânea , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Método Duplo-Cego , Humanos , Estudos Multicêntricos como Assunto/métodos , Período Pós-Operatório , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Fatores de Tempo
11.
In Vivo ; 34(3 Suppl): 1593-1596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-536995

RESUMO

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Liases de Carbono-Enxofre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Metionina/metabolismo , Pneumonia Viral/tratamento farmacológico , Capuzes de RNA/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Administração Oral , Antivirais/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/uso terapêutico , Betacoronavirus/fisiologia , Liases de Carbono-Enxofre/administração & dosagem , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Metanálise como Assunto , Metilação/efeitos dos fármacos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pseudomonas putida/enzimologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , S-Adenosilmetionina/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacos
12.
Trials ; 21(1): 548, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32560746

RESUMO

OBJECTIVES: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may trigger severe pneumonia in coronavirus disease of 2019 (COVID-19) patients through release of damage-associated molecular patterns (DAMPs) and recruitment of neutrophils in the lungs. Activated neutrophils induce inflammation and severe alveolar injury by releasing neutrophil extracellular traps (NETs). The backbones of many DAMPs and NETs are made of extracellular, cell-free DNA decorated with highly toxic compounds such as elastase, myeloperoxidase and citrullinated histones. Dornase alfa is a FDA-approved recombinant human DNAse 1 for the treatment of cystic fibrosis, which cleaves extracellular DNA and may break up cell-free DNA, loosening sticky mucus in the distal airways and reducing NETs-induced toxicity on alveolar pneumocytes. The COVIDornase trial intends to define the impact of aerosolized intra-tracheal dornase alfa administration on the severity and progression of acute respiratory distress syndrome (ARDS) in COVID-19 patients. This drug might make lung mucus thinner and looser, promoting improved clearance of secretions and reduce extracellular double-stranded DNA-induced hyperinflammation in alveoli, preventing further damage to the lungs. TRIAL DESIGN: COVIDornase is a prospective, randomized, controlled, 2-arm (1:1 ratio), multicentric, open-label clinical trial. PARTICIPANTS: The study will recruit mechanically ventilated patients hospitalized in the intensive care unit (ICU) in the recruiting centres (at the time of writing: The Rothschild foundation hospital in Paris, the Strasbourg university hospitals, and Metz-Thionville hospital) who have been diagnosed with COVID-19 and meet ARDS criteria. INCLUSION CRITERIA: - Adult patient (age ≥ 18 years old); - Hospitalized in ICU; - With severe COVID-19 pneumonia and ARDS according to Berlin criteria (PaO2/FiO2 < 300 and PEEP > 5 cmH2O); - Intubated for less than 8 days; - With an anticipated duration of mechanical ventilation > 48 hours; - Carrier of an arterial catheter; - For whom 4 PaO2/FiO2 values over the preceding 24 hours are available; NON-INCLUSION CRITERIA: - Known hypersensitivity to dornase alfa or any of its excipients; - Pregnant or breastfeeding status; - Patient under legal protection. INTERVENTION AND COMPARATOR: Intervention 1, Study group Dornase alfa (Pulmozyme®, Roche, Switzerland) will be administered by aerosol, at a dose of 2500 IU twice daily, 12 hours apart, for 7 consecutive days, using a vibrating mesh nebulizer (Aerogen Solo®, Aerogen, Ireland). The remainder of the management will be performed in accordance with good clinical practice, including mechanical ventilation (protective ventilation, PEEP > 5 cmH2O, tracheal balloon pressure check every 4 hours or automatic device, 30° head of the bed elevation, tidal volume 6-8mL/kg, plateau pressure < 30 cmH2O), neuromuscular blockers if necessary, prone position if PaO2/FiO2 < 150, early enteral nutrition, glycemic control and a sedation protocol based on the RASS score. Intervention 2, Comparator Patients will receive usual care in accordance with good practice (as detailed above), without aerosols. MAIN OUTCOMES: The primary outcome is the occurrence of at least one grade improvement between D0 (inclusion) and D7 in the ARDS scale severity (Berlin criteria). For instance from "severe" to "moderate" or from "moderate" to "mild". RANDOMISATION: All consecutive patients meeting the inclusion criteria will be randomised 1:1 using an eCRF-based, computer-generated randomisation table, either to the dornase alfa arm or to the control arm. An interim analysis will be performed after inclusion of 20 patients. Inclusions may be stopped at the interim analysis per data safety and monitoring board (DSMB) advice, if statistical analyses conclude on the futility or efficacy of the intervention or by other DSMB decision. BLINDING (MASKING): The participants and caregivers will not be blinded to study group assignment. Those assessing the outcomes will be blinded to study group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Fifty patients will be randomized to each group, 100 patients in total. TRIAL STATUS: Protocol version number 2, April 29th, 2020. Recruitment is ongoing. The trial started recruitment on the 21st April 2020. We estimate recruitment will finish August 21st 2020. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov on 21 April 2020, updated on 8 May 2020. Trial registration number is NCT04355364. 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/complicações , Desoxirribonuclease I/administração & dosagem , Pneumonia Viral/complicações , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Adulto , Aerossóis , Desoxirribonuclease I/efeitos adversos , Humanos , Pandemias , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Traqueia
13.
In Vivo ; 34(3 Suppl): 1593-1596, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32503816

RESUMO

The Covid-19 pandemic is a world-wide crisis without an effective therapy. While most approaches to therapy are using repurposed drugs that were developed for other diseases, it is thought that targeting the biology of the SARS-CoV-2 virus, which causes Covid-19, can result in an effective therapeutic treatment. The coronavirus RNA cap structure is methylated by two viral methyltransferases that transfer methyl groups from S-adenosylmethionine (SAM). The proper methylation of the virus depends on the level of methionine in the host to form SAM. Herein, we propose to restrict methionine availability by treating the patient with oral recombinant methioninase, aiming to treat Covid-19. By restricting methionine we not only interdict viral replication, which depends on the viral RNA cap methyaltion, but also inhibit the proliferation of the infected cells, which have an increased requirement for methionine. Most importantly, the virally-induced T-cell- and macrophage-mediated cytokine storm, which seems to be a significant cause for Covid-19 deaths, can also be inhibited by restricting methionine, since T-cell and macrophrage activation greatly increases the methionine requirement for these cells. The evidence reviewed here suggests that oral recombinant methioninase could be a promising treatment for coronavirus patients.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Liases de Carbono-Enxofre/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Metionina/metabolismo , Pneumonia Viral/tratamento farmacológico , Capuzes de RNA/efeitos dos fármacos , Processamento Pós-Transcricional do RNA/efeitos dos fármacos , RNA Viral/efeitos dos fármacos , Administração Oral , Antivirais/administração & dosagem , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/uso terapêutico , Betacoronavirus/fisiologia , Liases de Carbono-Enxofre/administração & dosagem , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/prevenção & controle , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/efeitos dos fármacos , Metanálise como Assunto , Metilação/efeitos dos fármacos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pseudomonas putida/enzimologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico , S-Adenosilmetionina/metabolismo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacos
14.
Mol Genet Metab ; 130(4): 227-229, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561366

RESUMO

Fabry disease is an X-linked disease due to a deficiency of the lysosomal enzyme alpha-galactosidase A. Clinical symptoms in classically affected males include acroparesthesia, anhydrosis and angiokeratoma, which may present during childhood followed by cardiac, cerebral and renal complications. Even though pulmonary involvement is not widely appreciated by clinicians, an obstructive lung disease is another recognized component of Fabry disease. Coronavirus Disease-19 (COVID-19), caused by the SARS-CoV-2 virus was labeled as a global pandemic and patients with Fabry disease can be considered at high risk of developing severe complications. The impact of COVID-19 on patients with Fabry disease receiving enzyme replacement therapy is still unknown. Many patients who receive treatment in the hospital experienced infusion disruptions due to fear of infection. Effects of temporary treatment interruption was described in more detail in other lysosomal storage diseases, but the recommencement of therapy does not fully reverse clinical decline due to the temporary discontinuation. When possible, home-therapy seems to be the most efficient way to maintain enzyme replacement therapy access during pandemic. Sentence take-home message: Home-therapy, when possible, seems to be the most efficient way to maintain enzyme replacement therapy access during pandemic in patients with Fabry disease.


Assuntos
Betacoronavirus/patogenicidade , Continuidade da Assistência ao Paciente/normas , Infecções por Coronavirus/prevenção & controle , Terapia de Reposição de Enzimas/normas , Doença de Fabry/terapia , Terapia por Infusões no Domicílio/normas , Pneumopatias Obstrutivas/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Adulto , Continuidade da Assistência ao Paciente/organização & administração , Continuidade da Assistência ao Paciente/estatística & dados numéricos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Terapia de Reposição de Enzimas/estatística & dados numéricos , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Feminino , Terapia por Infusões no Domicílio/estatística & dados numéricos , Humanos , Controle de Infecções/normas , Infusões Intravenosas , Isoenzimas/administração & dosagem , Pneumopatias Obstrutivas/diagnóstico , Pneumopatias Obstrutivas/etiologia , Masculino , Pessoa de Meia-Idade , Pneumonia Viral/complicações , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Proteínas Recombinantes/administração & dosagem , Índice de Gravidade de Doença , Fatores de Tempo , alfa-Galactosidase/administração & dosagem
15.
J Sports Sci ; 38(16): 1924-1932, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32543279

RESUMO

Athlete Biological Passport (ABP) is an indirect approach, implemented by WADA, aimed at detecting blood manipulation based on abnormal changes in haematological markers. Cases report the use of hyperhydration as masking method during anti-doping urine sample collection which could potentially mask suspicious fluctuations on ABP profiles. This study investigated the hyperhydration effect on haemoglobin concentration, reticulocyte percentage and OFF-hr score (an algorithm based on haemoglobin concentration and reticulocyte percentage), with and without recombinant human erythropoietin (rHuEPO) administration. A five-week clinical study performed; Baseline and rHuEPO Phase. Water and a sports drink were used as hyperhydration agents. To examine the hyperhydration effect on the normal ABP profile per volunteer, hyperhydration was implemented at 0, 24 and 48 hours during the baseline. During the rHuEPO phase, volunteers received Epoetin beta (3000 IU) with hyperhydration to be implemented at 0, 24 and 48 hours after drug administration. Blood and urine samples were collected and analysed according to WADA guidelines. No significant effect on ABP markers was observed due to hyperhydration at any time during the study. Pre- and post-hyperhydration data were not statistically different compared to individual baseline data. In conclusion, hyperhydration does not affect the ABP haematological markers under the examined conditions.


Assuntos
Biomarcadores/sangue , Doping nos Esportes , Comportamento de Ingestão de Líquido , Hemoglobinas/análise , Contagem de Reticulócitos , Adulto , Biomarcadores/urina , Bebidas Energéticas , Eritropoetina/administração & dosagem , Humanos , Masculino , Proteínas Recombinantes/administração & dosagem , Detecção do Abuso de Substâncias/métodos , Fatores de Tempo , Água
16.
Int J Infect Dis ; 96: 562-566, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32474201

RESUMO

OBJECTIVES: The purpose of this study was to analyze the clinical characteristics of chronic hepatitis B (CHB) cured by antiviral therapy. METHODS: Forty-two patients with CHB were enrolled. All patients had been treated with peginterferon (Peg-IFN) in combination with nucleoside analogue (NA) therapy for variable amounts of time, and all had been successfully cured of the disease. RESULTS: The combined treatment time for all participants was 124.7 ± 58.8 weeks, and the average Peg-IFN treatment time was 102.6 ± 56.1 weeks. At 24 weeks, Hepatitis B surface antigen (HBsAg) and Hepatitis B e antigen (HBeAg) had decreased more than 50% from baseline. Multivariate logistic regression analysis of the week 96 HBsAg-clearing group and the non-HBsAg-clearing group showed a statistically significant difference in baseline HBV DNA levels and week 48 HBsAg levels. Those which baseline HBV DNA was < 2.75 log10 IU/mL, and week 48 HBsAg levels were < 0.88 log10 IU/mL were more likely to achieve rapid HBsAg clearance at 96 weeks. This suggests that low levels of baseline HBV DNA and week 48 HBsAg are a predictor of rapid HBsAg clearance at 96 weeks. CONCLUSIONS: Individualized extension of combination therapy to more than 96 weeks depending on the patient's response and adverse reaction conditions can help achieve a clinical cure. Patients with low baseline HBV DNA and low HBsAg levels at 48 weeks achieve HBsAg clearance more quickly than other populations.


Assuntos
Antivirais/administração & dosagem , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Interferon-alfa/administração & dosagem , Nucleosídeos/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Quimioterapia Combinada , Feminino , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/metabolismo , Antígenos E da Hepatite B/genética , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Hepatite B Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
17.
Expert Opin Pharmacother ; 21(11): 1359-1366, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32511020

RESUMO

INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a heterogeneous group of rare diseases characterized by the abnormal production and impaired degradation of pulmonary surfactant as a result of malfunctioning of alveolar macrophages. This is due to the downstream dysregulation of the GM-CSF pathway, which can be caused by specific autoantibodies (autoimmune, aPAP formerly known as idiopathic iPAP), direct injury to alveolar macrophages (e.g. by toxic inhaled agents.), or by genetic defects (hereditary or congenital PAP). Few pharmacotherapy options are currently available to treat this disease. AREA COVERED: The authors discuss the exogenous administration of GM-CSF, rituximab, and the potential role of cholesterol lowering medications in this review. The authors, furthermore, provide their opinion on the available pharmacotherapeutic options and give their future perspectives. EXPERT OPINION: Inhaled GM-CSF remains the most commonly used therapy in patients with iPAP but other inhaled therapies such as PPARγ activators should be considered, especially in patients who are partially responsive or unresponsive to traditional treatments.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Rituximab/uso terapêutico , Administração por Inalação , Animais , Autoanticorpos/imunologia , Ensaios Clínicos como Assunto , Terapia Genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/efeitos adversos , Humanos , Injeções Subcutâneas , Metabolismo dos Lipídeos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Proteinose Alveolar Pulmonar/genética , Proteinose Alveolar Pulmonar/imunologia , Proteinose Alveolar Pulmonar/metabolismo , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos
19.
Transl Stroke Res ; 11(3): 322-325, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-186593

RESUMO

The COVID-19 pandemic is associated with neurological symptoms and complications including stroke. There is hypercoagulability associated with COVID-19 that is likely a "sepsis-induced coagulopathy" and may predispose to stroke. The SARS-CoV-2 virus binds to angiotensin-converting enzyme 2 (ACE2) present on brain endothelial and smooth muscle cells. ACE2 is a key part of the renin angiotensin system (RAS) and a counterbalance to angiotensin-converting enzyme 1 (ACE1) and angiotensin II. Angiotensin II is proinflammatory, is vasoconstrictive, and promotes organ damage. Depletion of ACE2 by SARS-CoV-2 may tip the balance in favor of the "harmful" ACE1/angiotensin II axis and promote tissue injury including stroke. There is a rationale to continue to treat with tissue plasminogen activator for COVID-19-related stroke and low molecular weight heparinoids may reduce thrombosis and mortality in sepsis-induced coagulopathy.


Assuntos
Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Acidente Vascular Cerebral/virologia , Betacoronavirus/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Feminino , Humanos , Masculino , Pandemias , Peptidil Dipeptidase A/administração & dosagem , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/epidemiologia , Proteínas Recombinantes/administração & dosagem , Acidente Vascular Cerebral/tratamento farmacológico , Ativador de Plasminogênio Tecidual/sangue , Ativador de Plasminogênio Tecidual/uso terapêutico
20.
Eur Heart J Acute Cardiovasc Care ; 9(3): 209-214, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: covidwho-165340

RESUMO

Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus/efeitos dos fármacos , Cloroquina/toxicidade , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Administração Intravenosa , Alanina/administração & dosagem , Alanina/farmacologia , Alanina/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/administração & dosagem , Antivirais/farmacologia , Antivirais/uso terapêutico , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/epidemiologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Lopinavir/farmacologia , Lopinavir/uso terapêutico , Pandemias , Pneumonia Viral/epidemiologia , Pirazinas/farmacologia , Pirazinas/uso terapêutico , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico
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