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2.
Québec; INESSS; 25 mars 2021.
Não convencional em Francês | BRISA/RedTESA | ID: biblio-1151751

RESUMO

CONTEXTE: Le présent document ainsi que les constats qu'il énonce ont été rédigés en réponse à une interpellation du ministère de la Santé et des Services sociaux dans le contexte de la crise sanitaire liée à la maladie à coronavirus (COVID-19) au Québec. L'objectif est de réaliser une recension des données publiées et de mobiliser les savoirs clés afin d'informer les décideurs publics et les professionnels de la santé et des services sociaux. Bien que les constats reposent sur un repérage exhaustif des données scientifiques publiées, sur l'évaluation de la qualité méthodologique des études et sur une appréciation du niveau de preuve scientifique par paramètre clinique d'intérêt, le processus ne repose pas entièrement sur une méthode systématique ni une validation externe selon les normes habituelles à l'INESSS. Par ailleurs, les positions ne découlent pas d'un processus de consultation élaboré. Dans les circonstances d'une telle crise de santé publique, l'INESSS reste à l'affût de toutes nouvelles données, qu'elles soient de nature scientifique ou contextuelle, susceptibles de lui faire modifier cette réponse. MÉTHODOLOGIE : Questions d'évaluation Comparativement aux standards de soins, est-ce que les biothérapies ciblant l'IL-6 ou son récepteur sont efficaces et sécuritaires pour traiter les patients (adulte, enfant, femme enceinte) avec une infection au SARS-CoV-2 confirmée dont l'état, à l'amorce, exige -une hospitalisation sans recours à une oxygénothérapie; -une hospitalisation avec le recours à une oxygénothérapie non invasive (oxygène à faible débit, à haut débit, ventilation mécanique non invasive) dû à la COVID-19; -une hospitalisation avec le recours à une oxygénothérapie invasive (ventilation mécanique invasive, ECMO) dû à la COVID-19? Est-ce que chez ces populations, les avantages cliniques des biothérapies ciblant l'IL-6 ou son récepteur, comparativement aux standards de soins seuls, sont similaires? Quelle est la position des sociétés savantes, des agences règlementaires, des agences de santé publique et des agences d'évaluation des technologies en santé sur l'usage des biothérapies ciblant l'IL-6 ou son récepteur dans le traitement de la COVID-19?. RÉSULTATS: Depuis l'instauration en mars 2020 de la recherche systématique en continu de la littérature scientifique sur les médicaments à visé thérapeutique, 45 670 notices ont été recensées dont 313 études cliniques où l'intervention étudiée portait sur les biothérapies ciblant l'IL-6 ou son récepteur. De ce nombre, 9 ECRA ont été retenues. DISCUSSION: Au terme des travaux, en ce qui concerne les personnes atteintes de la COVID-19 dont l'état de santé requiert une hospitalisation, neuf études de type ECRA ont été répertoriées. Il ressort de l'état actuel des connaissances que le stade de sévérité de la maladie des personnes et la présence ou l'absence d'une inflammation systémique à l'amorce du traitement sont des facteurs importants quant à l'efficacité des biothérapies dirigées contre le récepteur de l'IL-6. En effet, sept des neuf ECRA évalués n'ont pas démontré d'effet clinique statistiquement significatif, sur le paramètre d'intérêt principal, en faveur du tocilizumab, ou du sarilumab, mais les critères de sélection des participants n'étaient pas optimaux pour évaluer l'effet d'une biothérapie immunomodulatrice étant donné que les marqueurs inflammatoires n'ont majoritairement pas été considérés comme un critère d'inclusion et que ces études incluaient des participants chez lesquels les niveaux de sévérité de la COVID-19 étaient très variables. Par ailleurs, certaines de ces études ont utilisé comme paramètre d'intérêt principal l'évolution du statut clinique sur une échelle à plusieurs échelons, alors que ce genre de paramètre présente plusieurs limites telles que de potentielles différences de sensibilité en fonction des établissements locaux ou cliniciens et l'absence d'une différence seuil pour établir un effet thérapeutique cliniquement important. De plus, ces études étaient majoritairement réalisées sur un faible nombre de participants; au global, REMAP-CAP et RECOVERY comptent pour 73 % des 6 779 participants inclus dans la présente revue rapide.


Assuntos
Pneumonia Viral/tratamento farmacológico , Interleucinas/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Avaliação em Saúde
3.
s.l; RedARETS; feb.-mar. 2021.
Não convencional em Espanhol | LILACS, BRISA/RedTESA | ID: biblio-1151438

RESUMO

CoNTEXTO: La transfusión de plasma convaleciente a una persona con una infección viral podría neutralizar el microorganismo patógeno que lo afecta y, así, darle tiempo a esa persona de poner en marcha uma respuesta inmune activa, es decir, generada por su propio sistema inmunológico. La evidencia actual muestra que el uso de plasma de convaleciente no tiene efecto en mortalidad o en requerimiento de ventilación mecánica invasiva en pacientes con enfermedad severa por COVID-19. Las recomendaciones actuales basadas en evidencia, recomiendan en contra del uso de plasma de convaleciente para el tratamiento la COVID-19. Sin embargo, evidencia reciente sugirió un beneficio potencial en el uso temprano en adultos mayores, lo cual llevó al Ministerio de Salud de la Nación a realizar una recomendación acerca de su uso en este escenario. DESCRIPCIÓN DE LA TECNOLOGÍA: La inmunización pasiva, en este caso con anticuerpos heterólogos provenientes del plasma de pacientes recuperados de un proceso infeccioso por esa misma enfermedad, aplicados en forma temprana en la evolución de la enfermedad y en concentraciones suficientes, podrían complementar la respuesta inmune y mejorar la evolución de los pacientes con enfermedad por coronavirus (COVID-19). OBJETIVO: Evaluar los efectos del tratamiento con plasma de convaleciente en pacientes con e nfermedad temprana o ultra-temprana (menos de 7 días o menos de 3 días, respectivamente) por coronavirus (COVID-19) y el impacto presupuestario derivado de su aplicación temprana o ultra-temprana en mayores de 75 años. MÉTODOS: Se realizó una evaluación de tecnología sanitaria para valorar los efectos del tratamiento con plasma de convaleciente en pacientes con enfermedad temprana o ultra-temprana (menos de 7 días o menos de 3 días, respectivamente) por coronavirus (COVID-19) y el impacto presupuestario derivado de su aplicación em mayores de 70 años y brindar herramientas para evaluar la adherencia de esta recomendación y su incorporación o no a las intervenciones terapéuticas utilizadas en el ámbito de la provincia de Rio Negro para el tratamiento de personas que padecen COVID-19. Se realizó una revisión sistemática de la evidencia disponible para responder a la pregunta de investigación y una búsqueda sistemática de recomendaciones acerca de esta terapéutica. Posteriormente se modeló um análisis de impacto presupuestario desde la perspectiva del financiador. RESULTADOS: Se identificaron 744 estudios de los cuales 21 son ECA (ensayos controlados aleatorizados) que reportaron datos y 403 no ECA que reportaron datos. Luego de exclusión de duplicados y otros tipos de estudios, fueron seleccionados 3 ECA y 2 ECNA (ensayos controlados NO aleatorizados) que respondieron a la pregunta de investigación y cumplieron con los criterios de selección con 5820 pacientes en los que se comparó la infusión temprana de plasma de convaleciente contra placebo o el uso tardío del plasma. CONCLUSIÓN: El impacto presupuestario es alto, incluso desde el punto de vista de un análisis económico conservador que no considera la logística de implementación como red de atención temprana, telefonistas, traslados, etc. A esto se suman las dificultades existentes en cuanto a factibilidad de implementación y distribución, con alto riesgo de tener un impacto negativo en la equidad. Su uso temprano, en pacientes moderados de alto riesgo y sin enfermedad severa, con un producto de muy alto título de anticuerpos, basado en su plausibilidad biológica, posee un beneficio incierto y no resulta factible de implementar, pudiendo impactar en forma negativa en la equidad del sistema de salud.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Imunoglobulinas/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Análise Custo-Benefício
6.
Nat Commun ; 12(1): 1436, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664241

RESUMO

Acute kidney injury (AKI) is a prevalent and lethal adverse event that severely affects cancer patients receiving chemotherapy. It is correlated with the collateral damage to renal cells caused by reactive oxygen species (ROS). Currently, ROS management is a practical strategy that can reduce the risk of chemotherapy-related AKI, but at the cost of chemotherapeutic efficacy. Herein, we report catalytic activity tunable ceria nanoparticles (CNPs) that can prevent chemotherapy-induced AKI without interference with chemotherapeutic agents. Specifically, in the renal cortex, CNPs exhibit catalytic activity that decomposes hydrogen peroxide, and subsequently regulate the ROS-involved genes by activating the Nrf2/Keap1 signaling pathway. These restore the redox homeostasis for the protection of kidney tubules. Under an acidic tumor microenvironment, CNPs become inert due to the excessive H+ that disrupts the re-exposure of active catalytic sites, allowing a buildup of chemotherapy-mediated ROS generation to kill cancer cells. As ROS-modulating agents, CNPs incorporated with context-dependent catalytic activity, hold a great potential for clinical prevention and treatment of AKI in cancer patients.


Assuntos
Lesão Renal Aguda/prevenção & controle , Antineoplásicos/efeitos adversos , Cério/farmacologia , Túbulos Renais/patologia , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Animais , Antineoplásicos/uso terapêutico , Domínio Catalítico , Linhagem Celular Tumoral , Cério/química , Feminino , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral
7.
Nat Commun ; 12(1): 1439, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33664251

RESUMO

Treatment of advanced melanoma with combined PD-1/CTLA-4 blockade commonly causes serious immune-mediated complications. Here, we identify a subset of patients predisposed to immune checkpoint blockade-related hepatitis who are distinguished by chronic expansion of effector memory CD4+ T cells (TEM cells). Pre-therapy CD4+ TEM cell expansion occurs primarily during autumn or winter in patients with metastatic disease and high cytomegalovirus (CMV)-specific serum antibody titres. These clinical features implicate metastasis-dependent, compartmentalised CMV reactivation as the cause of CD4+ TEM expansion. Pre-therapy CD4+ TEM expansion predicts hepatitis in CMV-seropositive patients, opening possibilities for avoidance or prevention. 3 of 4 patients with pre-treatment CD4+ TEM expansion who received αPD-1 monotherapy instead of αPD-1/αCTLA-4 therapy remained hepatitis-free. 4 of 4 patients with baseline CD4+ TEM expansion given prophylactic valganciclovir and αPD-1/αCTLA-4 therapy remained hepatitis-free. Our findings exemplify how pathogen exposure can shape clinical reactions after cancer therapy and how this insight leads to therapeutic innovations.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Infecções por Citomegalovirus/tratamento farmacológico , Hepatite A/prevenção & controle , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/imunologia , Hepatite A/imunologia , Hepatite A/virologia , Humanos , Memória Imunológica/imunologia , Melanoma/tratamento farmacológico , Valganciclovir/uso terapêutico , Carga Viral
8.
Lancet Oncol ; 22(3): e105-e118, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33662288

RESUMO

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Guias de Prática Clínica como Assunto/normas , Terapia de Salvação , Humanos , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/patologia
9.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33670304

RESUMO

Lysosomotropism is a biological characteristic of small molecules, independently present of their intrinsic pharmacological effects. Lysosomotropic compounds, in general, affect various targets, such as lipid second messengers originating from lysosomal enzymes promoting endothelial stress response in systemic inflammation; inflammatory messengers, such as IL-6; and cathepsin L-dependent viral entry into host cells. This heterogeneous group of drugs and active metabolites comprise various promising candidates with more favorable drug profiles than initially considered (hydroxy) chloroquine in prophylaxis and treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections/Coronavirus disease 2019 (COVID-19) and cytokine release syndrome (CRS) triggered by bacterial or viral infections. In this hypothesis, we discuss the possible relationships among lysosomotropism, enrichment in lysosomes of pulmonary tissue, SARS-CoV-2 infection, and transition to COVID-19. Moreover, we deduce further suitable approved drugs and active metabolites based with a more favorable drug profile on rational eligibility criteria, including readily available over-the-counter (OTC) drugs. Benefits to patients already receiving lysosomotropic drugs for other pre-existing conditions underline their vital clinical relevance in the current SARS-CoV2/COVID-19 pandemic.


Assuntos
Antivirais/farmacologia , Descoberta de Drogas , Lisossomos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Antivirais/farmacocinética , Antivirais/uso terapêutico , /metabolismo , Clorpromazina/farmacocinética , Clorpromazina/farmacologia , Clorpromazina/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Fluvoxamina/farmacocinética , Fluvoxamina/farmacologia , Fluvoxamina/uso terapêutico , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/farmacologia , Hidroxicloroquina/uso terapêutico , Interleucina-1/antagonistas & inibidores , Interleucina-1/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Lisossomos/imunologia , Lisossomos/metabolismo , Lisossomos/virologia , /fisiologia , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/uso terapêutico , Replicação Viral/efeitos dos fármacos
10.
J Vis Exp ; (168)2021 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-33645583

RESUMO

Recording of the electrical activity from one of the smallest cells of a mammalian organism- a sperm cell- has been a challenging task for electrophysiologists for many decades. The method known as "spermatozoan patch clamp" was introduced in 2006. It has enabled the direct recording of ion channel activity in whole-cell and cell-attached configurations and has been instrumental in describing sperm cell physiology and the molecular identity of various calcium, potassium, sodium, chloride, and proton ion channels. However, recording from single spermatozoa requires advanced skills and training in electrophysiology. This detailed protocol summarizes the step-by-step procedure and highlights several 'tricks-of-the-trade' in order to make it available to anyone who wishes to explore the fascinating physiology of the sperm cell. Specifically, the protocol describes recording from human and murine sperm cells but can be adapted to essentially any mammalian sperm cell of any species. The protocol covers important details of the application of this technique, such as isolation of sperm cells, selection of reagents and equipment, immobilization of the highly motile cells, formation of the tight (Gigaohm) seal between a recording electrode and the plasma membrane of the sperm cells, transition into the whole-spermatozoan mode (also known as break-in), and exemplary recordings of the sperm cell calcium ion channel, CatSper, from six mammalian species. The advantages and limitations of the sperm patch clamp method, as well as the most critical steps, are discussed.


Assuntos
Membrana Celular/fisiologia , Fenômenos Eletrofisiológicos , Espermatozoides/fisiologia , Animais , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Tamanho Celular , Dissecação , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Flagelos/efeitos dos fármacos , Flagelos/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Transporte de Íons/efeitos dos fármacos , Macaca mulatta , Masculino , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Perfusão , Progesterona/farmacologia , Soluções , Espermatozoides/citologia , Espermatozoides/efeitos dos fármacos
11.
Sci Rep ; 11(1): 5402, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686135

RESUMO

Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood-brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing-remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.


Assuntos
Sistema Nervoso Central/patologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Taurina/análogos & derivados , Animais , Apresentação do Antígeno/efeitos dos fármacos , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/imunologia , Proliferação de Células/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologia , Proteína Proteolipídica de Mielina/imunologia , Fragmentos de Peptídeos/imunologia , Recidiva , Baço/patologia , Linfócitos T/efeitos dos fármacos , Taurina/farmacologia , Ácido gama-Aminobutírico/farmacologia
12.
Sci Rep ; 11(1): 5376, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686154

RESUMO

Although the spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has resulted in a worldwide pandemic, there are currently no virus-specific drugs that are fully effective against SARS-CoV-2. Only a limited number of human-derived cells are capable of supporting SARS-CoV-2 replication and the infectivity of SARS-CoV-2 in these cells remains poor. In contrast, monkey-derived Vero cells are highly susceptibility to infection with SARS-CoV-2, although they are not suitable for the study of antiviral effects by small molecules due to their limited capacity to metabolize drugs compared to human-derived cells. In this study, our goal was to generate a virus-susceptible human cell line that would be useful for the identification and testing of candidate drugs. Towards this end, we stably transfected human lung-derived MRC5 cells with a lentiviral vector encoding angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2. Our results revealed that SARS-CoV-2 replicates efficiently in MRC5/ACE2 cells. Furthermore, viral RNA replication and progeny virus production were significantly reduced in response to administration of the replication inhibitor, remdesivir, in MRC5/ACE2 cells compared with Vero cells. We conclude that the MRC5/ACE2 cells will be important in developing specific anti-viral therapeutics and will assist in vaccine development to combat SARS-CoV-2 infections.


Assuntos
/metabolismo , Antivirais/farmacologia , Engenharia Celular , Descoberta de Drogas , Modelos Biológicos , /fisiologia , Animais , Antivirais/uso terapêutico , Linhagem Celular , Humanos , Proteínas Virais/biossíntese , Replicação Viral/efeitos dos fármacos
13.
BMC Infect Dis ; 21(1): 303, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33765944

RESUMO

BACKGROUND: Proper detection of disease-causing organisms is very critical in controlling the course of outbreaks and avoiding large-scale epidemics. Nonetheless, availability of resources to address these gaps have been difficult due to limited funding. This report sought to highlight the importance of in-country partners and non-governmental organizations in improving detection of microbiological organisms in Ghanaian Public Health Laboratories (PHLs). METHODS/CONTEXT: This study was conducted between June, 2018 to August, 2019. U. S CDC engaged the Centre for Health Systems Strengthening (CfHSS) through the Association of Public Health Laboratories to design and implement strategies for strengthening three PHLs in Ghana. An assessment of the three PHLs was done using the WHO/CDS/CSR/ISR/2001.2 assessment tool. Based on findings from the assessments, partner organizations (CfHSS/APHL/CDC) serviced and procured microbiological equipment, laboratory reagents and logistics. CfHSS provided in-house mentoring and consultants to assist with capacity building in detection of epidemic-prone infectious pathogens by performing microbiological cultures and antimicrobial susceptibility tests. RESULTS: A total of 3902 samples were tested: blood (1107), urine (1742), stool (249) and cerebrospinal fluid (CSF) (804). All-inclusive, 593 pathogenic bacteria were isolated from blood cultures (70; 11.8%); urine cultures (356; 60%); stool cultures (19; 3.2%) and from CSF samples (148; 25%). The most predominant pathogens isolated from blood, urine and stool were Staphylococcus aureus (22/70; 31%), Escherichia coli (153/356; 43%) and Vibrio parahaemolyticus (5/19; 26.3%), respectively. In CSF samples, Streptococcus pneumoniae was the most frequent pathogen detected (80/148; 54.1%). New bacterial species such as Pastuerella pneumotropica, Klebsiella oxytoca, Vibrio parahaemolyticus, and Halfnia alvei were also identified with the aid of Analytical Profile Index (API) kits that were introduced as part of this implementation. Streptococcus pneumoniae and Neisseria meningitidis detections in CSF were highest during the hot dry season. Antimicrobial susceptibility test revealed high rate of S. aureus, K. pneumoniae and E. coli resistance to gentamicin (35-55%). In urine, E. coli was highly resistant to ciprofloxacin (39.2%) and ampicillin (34%). CONCLUSION: Detection of epidemic-prone pathogens can be greatly improved if laboratory capacity is strengthened. In-country partner organizations are encouraged to support this move to ensure accurate diagnosis of diseases and correct antimicrobial testing.


Assuntos
Bactérias/isolamento & purificação , Infecções Bacterianas/diagnóstico , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/microbiologia , Sangue/microbiologia , Líquido Cefalorraquidiano/microbiologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fezes/microbiologia , Gana , Humanos , Laboratórios , Testes de Sensibilidade Microbiana , Organizações , Estudos Retrospectivos , Estações do Ano , Urina/microbiologia
14.
Lancet Neurol ; 20(4): 265-274, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33647246

RESUMO

BACKGROUND: High systolic blood pressure after successful endovascular therapy for acute ischaemic stroke is associated with increased risk of intraparenchymal haemorrhage. However, no randomised controlled trials are available to guide optimal management. We therefore aimed to assess whether an intensive systolic blood pressure target resulted in reduced rates of intraparenchymal haemorrhage compared with a standard systolic blood pressure target. METHODS: We did a multicentre, open-label, randomised controlled trial at four academic hospital centres in France. Eligible individuals were adults (aged ≥18 years) with an acute ischaemic stroke due to a large-vessel occlusion that was successfully treated with endovascular therapy. Patients were randomly assigned (1:1) to either an intensive systolic blood pressure target group (100-129 mm Hg) or a standard care systolic blood pressure target group (130-185 mm Hg), by means of a central web-based procedure, stratified by centre and intravenous thrombolysis use before endovascular therapy. In both groups, the target systolic blood pressure had to be achieved within 1 h after randomisation and maintained for 24 h with intravenous blood pressure lowering treatments. The primary outcome was the rate of radiographic intraparenchymal haemorrhage at 24-36 h and the primary safety outcome was the occurrence of hypotension. Analyses were done on an intention-to-treat basis. BP-TARGET is registered with ClinicalTrials.gov, number NCT03160677, and the trial is closed at all participating sites. FINDINGS: Between June 21, 2017, and Sept 27, 2019, 324 patients were enrolled in the four participating stroke centres: 162 patients were randomly assigned to the intensive target group and 162 to the standard target group. Four (2%) of 162 patients were excluded from the intensive target group and two (1%) of 162 from the standard target group for withdrawal of consent or legal reasons. The mean systolic blood pressure during the first 24 h after reperfusion was 128 mm Hg (SD 11) in the intensive target group and 138 mm Hg (17) in the standard target group. The primary outcome was observed in 65 (42%) of 154 patients in the intensive target group and 68 (43%) of 157 in the standard target group on brain CT within 24-36 h after reperfusion] (adjusted odds ratio 0·96, 95% CI 0·60-1·51; p=0·84). Hypotensive events were not significantly different between both groups and occurred in 12 (8%) of 158 patients in the intensive target and five (3%) of 160 in the standard target group. Mortality within the first week after randomisation occurred in 11 (7%) of 158 patients in the intensive target group and in seven (4%) of 160 in the standard target group. INTERPRETATION: An intensive systolic blood pressure target of 100-129 mm Hg after successful endovascular therapy did not reduce radiographic intraparenchymal haemorrhage rates at 24-36 h as compared with a standard care systolic blood pressure target of 130-185 mm Hg. Notably, these results are applicable to patients with successful reperfusion and systolic blood pressures of more than 130 mm Hg at the end of procedure. Further studies are needed to understand the association between blood pressure and outcomes after reperfusion. FUNDING: French Health Ministry.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hemorragia Cerebral/prevenção & controle , Procedimentos Endovasculares/métodos , /terapia , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/etiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/prevenção & controle , Masculino , Pessoa de Meia-Idade
15.
Food Chem ; 351: 129227, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33647695

RESUMO

Cold chain transportation is an important link in postharvest logistics of agricultural products. In current study, we developed a novel water-based phase change coolant (PCC), which showed longer effectiveness in maintaining low temperature condition compared with ice, and applied in preserving the postharvest mushrooms. The results showed that the novel PCC effectively inhibited water loss, as well as maintained quality attributes including firmness, color, phenolics, flavonoids, and thus prolonged the shelf-life of mushrooms. Low temperature condition created by the novel PCC treatment maintained high level of energy charge by activating the activities of SDH, CCO, H+-ATPase and Ca2+-ATPase, resulting in the delay of postharvest senescence. In addition, sufficient energy supply decreased the consumption of glutamate as carbon skeleton by inhibiting GDH activity, improved glutamate accumulation, and therefore maintained sensory properties as a result. Thus, the novel PCC might be an excellent substitute for ice in cold chain transportation of mushrooms.


Assuntos
Temperatura Baixa , Metabolismo Energético/efeitos dos fármacos , Qualidade dos Alimentos , Ácido Glutâmico/metabolismo , Transição de Fase , Cogumelos Shiitake/química , Cogumelos Shiitake/metabolismo , Cor , Cogumelos Shiitake/efeitos dos fármacos , Água/química , Água/farmacologia
16.
Food Chem ; 351: 129328, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33647697

RESUMO

A part of the fungicides used in foliar treatment penetrates into the soil. This study describes changes in the bioavailability of (essential) elements in soil, fructification, the amount of green biomass and the production of phenolic compounds related solely to the presence of triazoles (penconazole and cyproconazole) in soil, injected as a single compound or their mixture. The triazoles presence has substantially affected the bioavailability of Fe, Cu and Zn in soil. The amount of green biomass has significantly decreased, whereas the chlorophylls a and b have not been affected. As a potential mark of plant stress, the fruits of the treated variants are significantly bigger. The content of phenolics in tomato peel (e.g. quercetin, quercitrin, hesperidin, naringin, and chlorogenic, salicylic and p-coumaric acid) has been quantified. The biggest changes (increase/decrease) have been observed in the contents of p-coumaric and chlorogenic acid, quercetin and quercitrin.


Assuntos
Biomassa , Frutas/efeitos dos fármacos , Frutas/crescimento & desenvolvimento , Lycopersicon esculentum/efeitos dos fármacos , Fenóis/metabolismo , Solo/química , Triazóis/farmacologia , Disponibilidade Biológica , Fungicidas Industriais/análise , Fungicidas Industriais/farmacologia , Lycopersicon esculentum/crescimento & desenvolvimento , Lycopersicon esculentum/metabolismo , Triazóis/análise
17.
Ann Agric Environ Med ; 28(1): 122-126, 2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33775077

RESUMO

INTRODUCTION AND OBJECTIVE: The COVID-19 pandemic causes vital concerns due to the lack of proved, effective, and safe therapy. Chloroquine and hydroxychloroquine seem to be useful, but recently serious concerns regarding their adverse events have risen. The aim of the study was to broaden the general perspective of chloroquine and hydroxychloroquine use in COVID-19 treatment, based on an analysis of their current safety profile among patients with rheumatic diseases. MATERIAL AND METHODS: The study was based on a group of 152 patients with rheumatic diseases, aged 20-78 years, treated either with chloroquine or hydroxychloroquine. Analyzed data included age, gender, comorbidities, type of drug, dosage, treatment duration, and reported adverse events. Cases of drug withdrawal related to adverse events were also recorded. RESULTS: The dosage was consistent in both groups: 250 mg of chloroquine or 200 mg of hydroxychloroquine daily. 77.6% of patients did not experience any adverse reactions to the treatment. Hydroxychloroquine showed better safety profile, with 10.9% of patients reporting side-ffects, compared to 28.9% in patients treated with chloroquine. The overall incidence of ophthalmic complications was 6.6%. For both drugs, no statistically significant correlation between adverse events and age, chronic heart or liver disease, or hypertension was found. CONCLUSIONS: Chloroquine and hydroxychloroquine at lower doses, as used in rheumatic diseases, prove to be relatively safe. Data from the literature show that high dosage as recommended in COVID-19 treatment may pose a risk of toxicity and require precise management, but prophylactic, long-term use of lower, safe doses might be a promising solution.


Assuntos
Antirreumáticos/efeitos adversos , Cloroquina/efeitos adversos , Hidroxicloroquina/efeitos adversos , Doenças Reumáticas/tratamento farmacológico , Adulto , Idoso , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Cloroquina/administração & dosagem , Cloroquina/uso terapêutico , Olho/efeitos dos fármacos , Feminino , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/uso terapêutico , Masculino , Pessoa de Meia-Idade
18.
Int J Nanomedicine ; 16: 1869-1888, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33716502

RESUMO

Background and Purpose: Around 40-50% of diffuse large-B cell lymphoma (DLBCL) patients suffer from refractory disease or relapse after R-CHOP first-line treatment. Many ongoing clinical trials for DLBCL patients involve microtubule targeting agents (MTAs), however, their anticancer activity is limited by severe side effects. Therefore, we chose to improve the therapeutic window of the MTA monomethyl auristatin E developing a nanoconjugate, T22-AUR, that selectively targets the CXCR4 receptor, which is overexpressed in many DLBCL cells (CXCR4+) and associated with poor prognosis. Methods: The T22-AUR specificity towards CXCR4 receptor was performed by flow cytometry in different DLBCL cell lines and running biodistribution assays in a subcutaneous mouse model bearing CXCR4+ DLBCL cells. Moreover, we determined T22-AUR cytotoxicity using cell viability assays, cell cycle analysis, DAPI staining and immunohistochemistry. Finally, the T22-AUR antineoplastic effect was evaluated in vivo in an extranodal CXCR4+ DLBCL mouse model whereas the toxicity analysis was assessed by histopathology in non-infiltrated mouse organs and by in vitro cytotoxic assays in human PBMCs. Results: We demonstrate that the T22-AUR nanoconjugate displays CXCR4-dependent targeting and internalization in CXCR4+ DLBCL cells in vitro as well as in a subcutaneous DLBCL mouse model. Moreover, it shows high cytotoxic effect in CXCR4+ DLBCL cells, including induction of G2/M mitotic arrest, DNA damage, mitotic catastrophe and apoptosis. Furthermore, the nanoconjugate shows a potent reduction in lymphoma mouse dissemination without histopathological alterations in non-DLBCL infiltrated organs. Importantly, T22-AUR also exhibits lack of toxicity in human PBMCs. Conclusion: T22-AUR exerts in vitro and in vivo anticancer effect on CXCR4+ DLBCL cells without off-target toxicity. Thus, T22-AUR promises to become an effective therapy for CXCR4+ DLBCL patients.


Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Nanoconjugados/uso terapêutico , Oligopeptídeos/uso terapêutico , Receptores CXCR4/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/patologia , Linfoma Difuso de Grandes Células B/genética , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Oligopeptídeos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/patologia , Distribuição Tecidual/efeitos dos fármacos
19.
Circ Heart Fail ; 14(3): e007767, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33724883

RESUMO

BACKGROUND: The expense of clinical trials mandates new strategies to efficiently generate evidence and test novel therapies. In this context, we designed a decentralized, patient-centered randomized clinical trial leveraging mobile technologies, rather than in-person site visits, to test the efficacy of 12 weeks of canagliflozin for the treatment of heart failure, regardless of ejection fraction or diabetes status, on the reduction of heart failure symptoms. METHODS: One thousand nine hundred patients will be enrolled with a medical record-confirmed diagnosis of heart failure, stratified by reduced (≤40%) or preserved (>40%) ejection fraction and randomized 1:1 to 100 mg daily of canagliflozin or matching placebo. The primary outcome will be the 12-week change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes will be daily step count and other scales of the Kansas City Cardiomyopathy Questionnaire. RESULTS: The trial is currently enrolling, even in the era of the coronavirus disease 2019 (COVID-19) pandemic. CONCLUSIONS: CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) is deploying a novel model of conducting a decentralized, patient-centered, randomized clinical trial for a new indication for canagliflozin to improve the symptoms of patients with heart failure. It can model a new method for more cost-effectively testing the efficacy of treatments using mobile technologies with patient-reported outcomes as the primary clinical end point of the trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04252287.


Assuntos
Canagliflozina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Telemedicina , Actigrafia/instrumentação , Canagliflozina/efeitos adversos , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Monitores de Aptidão Física , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Aplicativos Móveis , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Telemedicina/instrumentação , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Função Ventricular Esquerda/efeitos dos fármacos
20.
Trials ; 22(1): 209, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726804

RESUMO

OBJECTIVES: The main goal of the COVIDENZA trial is to evaluate if inhibition of testosterone signalling by enzalutamide can improve the outcome of patients hospitalised for COVID-19. The hypothesis is based on the observation that the majority of patients in need of intensive care are male, and the connection between androgen receptor signalling and expression of TMPRSS2, an enzyme important for SARS-CoV-2 host cell internalization. TRIAL DESIGN: Hospitalised COVID-19 patients will be randomised (2:1) to enzalutamide plus standard of care vs. standard of care designed to identify superiority. PARTICIPANTS: Included participants, men or women above 50 years of age, must be hospitalised for PCR confirmed COVID-19 symptoms and not in need of immediate mechanical ventilation. Major exclusion criteria are breast-feeding or pregnant women, hormonal treatment for prostate or breast cancer, treatment with immunosuppressive drugs, current symptomatic unstable cardiovascular disease (see Additional file 1 for further details). The trial is registered at Umeå University Hospital, Region Västerbotten, Sweden and 8 hospitals are approved for inclusion in Sweden. INTERVENTION AND COMPARATOR: Patients randomised to the treatment arm will be treated orally with 160 mg (4x40 mg) enzalutamide (Xtandi®) daily, for five consecutive days. The study is not placebo controlled. The comparator is standard of care treatment for patients hospitalised with COVID-19. MAIN OUTCOMES: The primary endpoints of the study are (time to) need of mechanical ventilation or discharge from hospital as assessed by a clinical 7-point ordinal scale (up to 30 days after inclusion). RANDOMISATION: Randomisation was stratified by center and sex. Each strata was randomized separately with block size six with a 2:1 allocation ratio (enzalutamide + "standard of care": "standard of care"). The randomisation list, with consecutive subject numbers, was generated by an independent statistician using the PROC PLAN procedure of SAS version 9.4 software (SAS Institute, Inc, Cary, North Carolina) BLINDING (MASKING): This is an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The trial is designed to have three phases. The first, an exploration phase of 45 participants (30 treatment and 15 control) will focus on safety and includes a more extensive laboratory assessment as well as more frequent safety evaluation. The second prolongation phase, includes the first 100 participants followed by an interim analysis to define the power of the study. The third phase is the continuation of the study up to maximum 600 participants included in total. TRIAL STATUS: The current protocol version is COVIDENZA v2.0 as of September 10, 2020. Recruitment started July 29, 2020 and is presently in safety pause after the first exploration phase. Recruitment is anticipated to be complete by 31 December 2021. TRIAL REGISTRATION: Eudract number 2020-002027-10 ClinicalTrials.gov Identifier: NCT04475601 , registered June 8, 2020 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
Antivirais/uso terapêutico , Feniltioidantoína/análogos & derivados , /efeitos dos fármacos , Antivirais/efeitos adversos , /virologia , Ensaios Clínicos Fase II como Assunto , Feminino , Interações Hospedeiro-Patógeno , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Feniltioidantoína/efeitos adversos , Feniltioidantoína/uso terapêutico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Suécia , Fatores de Tempo , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos
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