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2.
Protein Cell ; 11(10): 723-739, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32754890

RESUMO

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.


Assuntos
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Oxirredutases/antagonistas & inibidores , Pandemias , Pneumonia Viral/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular , Infecções por Coronavirus/virologia , Crotonatos/farmacologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Humanos , Vírus da Influenza A/efeitos dos fármacos , Leflunomida/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/uso terapêutico , Oxirredutases/metabolismo , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Pirimidinas/biossíntese , Vírus de RNA/fisiologia , Relação Estrutura-Atividade , Tiazóis/uso terapêutico , Toluidinas/farmacologia , Ubiquinona/metabolismo , Replicação Viral/efeitos dos fármacos
3.
Brasília; s.n; 25 jul. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117709

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 13 artigos e 8 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Antivirais/uso terapêutico , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Estudos Transversais , Estudos de Coortes , Interleucinas/antagonistas & inibidores , Corticosteroides/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Leflunomida/uso terapêutico , Hidroxicloroquina/uso terapêutico , Imunossupressores/uso terapêutico , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Bloqueadores Neuromusculares/uso terapêutico
4.
Brasília; s.n; 7 jul. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1117630

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 17 artigos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Esteroides/uso terapêutico , Avaliação da Tecnologia Biomédica , Vitamina D/uso terapêutico , Varfarina/uso terapêutico , Ivermectina/uso terapêutico , Ceftriaxona/uso terapêutico , Cloroquina/uso terapêutico , Metotrexato/uso terapêutico , Corticosteroides/uso terapêutico , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Oseltamivir/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Lopinavir/uso terapêutico , Infliximab/uso terapêutico , Leflunomida/uso terapêutico , Amoxicilina/uso terapêutico , Hidroxicloroquina/uso terapêutico , Ácido Micofenólico/uso terapêutico
5.
Breast Cancer Res ; 22(1): 60, 2020 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503622

RESUMO

BACKGROUND: Mitochondrial dynamics underlies malignant transformation, cancer progression, and response to treatment. Current research presents conflicting evidence for functions of mitochondrial fission and fusion in tumor progression. Here, we investigated how mitochondrial fission and fusion states regulate underlying processes of cancer progression and metastasis in triple-negative breast cancer (TNBC). METHODS: We enforced mitochondrial fission and fusion states through chemical or genetic approaches and measured migration and invasion of TNBC cells in 2D and 3D in vitro models. We also utilized kinase translocation reporters (KTRs) to identify single cell effects of mitochondrial state on signaling cascades, PI3K/Akt/mTOR and Ras/Raf/MEK/ERK, commonly activated in TNBC. Furthermore, we determined effects of fission and fusion states on metastasis, bone destruction, and signaling in mouse models of breast cancer. RESULTS: Enforcing mitochondrial fission through chemical or genetic approaches inhibited migration, invasion, and metastasis in TNBC. Breast cancer cells with predominantly fissioned mitochondria exhibited reduced activation of Akt and ERK both in vitro and in mouse models of breast cancer. Treatment with leflunomide, a potent activator of mitochondrial fusion proteins, overcame inhibitory effects of fission on migration, signaling, and metastasis. Mining existing datasets for breast cancer revealed that increased expression of genes associated with mitochondrial fission correlated with improved survival in human breast cancer. CONCLUSIONS: In TNBC, mitochondrial fission inhibits cellular processes and signaling pathways associated with cancer progression and metastasis. These data suggest that therapies driving mitochondrial fission may benefit patients with breast cancer.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Dinâmica Mitocondrial/fisiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Carboxiliases/genética , Carboxiliases/metabolismo , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Humanos , Imunossupressores/farmacologia , Leflunomida/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
s.l; s.n; 3 jun. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1099470

RESUMO

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referente ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 16 artigos.


Assuntos
Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Ribavirina/uso terapêutico , Avaliação da Tecnologia Biomédica , Imunoglobulinas/uso terapêutico , Cloroquina/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Interferons/uso terapêutico , Ciclosporina/uso terapêutico , Corticosteroides/uso terapêutico , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Dexmedetomidina/uso terapêutico , Lopinavir/uso terapêutico , Rituximab/uso terapêutico , Leflunomida/uso terapêutico , Hidroxicloroquina/uso terapêutico
7.
Z Rheumatol ; 79(6): 574-577, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32514854

RESUMO

A case with rheumatoid arthritis and insufficient compensation under disease-modifying combined long-term therapy with methotrexate and leflunomide is reported. After recovery from a COVID-19 infection, a tumor necrosis factor (TNF) inhibitor therapy was initiated. Until now no reactivation of the COVID-19 infection with positive SARS-CoV­2 antibody status has occurred.


Assuntos
Anticorpos Antivirais/sangue , Artrite Reumatoide/tratamento farmacológico , Terapia Biológica , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Artrite Reumatoide/virologia , Betacoronavirus , Humanos , Leflunomida/uso terapêutico , Metotrexato/uso terapêutico , Pandemias , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Ativação Viral
8.
Clin Rheumatol ; 39(9): 2797-2802, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32562070

RESUMO

Recurrences of COVID-19 were observed in a patient with long-term usage of hydroxychloroquine, leflunomide, and glucocorticoids due to her 30-year history of rheumatoid arthritis (RA). Tocilizumab was applied and intended to target both COVID-19 and RA. However, disease of this patient aggravated after usage of tocilizumab. After the discussion of a multiple disciplinary team (MDT) including rheumatologists, antimicrobial treatments were applied to target the potential opportunistic infections (Pneumocystis jirovecii and Aspergillus fumigatus), which were authenticated several days later via high throughput sequencing. As an important cytokine in immune responses, IL-6 can be a double-edged sword: interference in the IL-6-IL-6 receptor signaling may save patients from cytokine release storm (CRS), but can also weaken the anti-infectious immunity, particularly in rheumatic patients, who may have received a long-term treatment with immunosuppressive/modulatory agents. Thus, we suggest careful considerations before and close monitoring in the administration of tocilizumab in rheumatic patients with COVID-19. Besides tocilizumab, several disease-modifying antirheumatic drugs (DMARDs) can also be applied in the treatment of COVID-19. Therefore, we also reviewed and discussed the application of these DMARDs in COVID-19 condition.


Assuntos
Antivirais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Infecções por Coronavirus/terapia , Glucocorticoides/uso terapêutico , Pneumonia por Pneumocystis/diagnóstico , Pneumonia Viral/terapia , Aspergilose Pulmonar/diagnóstico , Idoso , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Aspergilose , Aspergillus fumigatus , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Infecções por Coronavirus/fisiopatologia , Tosse/etiologia , Síndrome da Liberação de Citocina/etiologia , Desprescrições , Progressão da Doença , Dispneia/etiologia , Feminino , Glucocorticoides/efeitos adversos , Humanos , Hidroxicloroquina/uso terapêutico , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Interleucina-6/sangue , Leflunomida/efeitos adversos , Leflunomida/uso terapêutico , Pulmão/diagnóstico por imagem , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/imunologia , Metilprednisolona/uso terapêutico , Oxigenoterapia , Pandemias , Pneumocystis carinii , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/etiologia , Pneumonia por Pneumocystis/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Pneumonia Viral/fisiopatologia , Aspergilose Pulmonar/tratamento farmacológico , Aspergilose Pulmonar/etiologia , Aspergilose Pulmonar/imunologia , Recidiva , Tomografia Computadorizada por Raios X
9.
Vascular ; 28(5): 609-611, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32356683

RESUMO

INTRODUCTION: Noninfectious aortitis has been increasingly reported worldwide with a growing prevalence in western medicine. Attributed to our increasingly diverse population, western surgeons must be vigilant to promptly differentiate these cases from its more common infectious counterpart in order to ensure subsequent appropriate management of these patients. METHODS: We present a case report of a 71-year-old Indo-Caribbean male who presented with nonspecific abdominal and back pain, found to have aortitis of a noninfectious etiology.Results and conclusion: While our patient's process was ultimately managed without surgical intervention, the varied clinical presentation along with the lack of specific laboratory markers pose a challenge for surgeons to appropriately diagnose and manage aortitis. Appropriate diagnostic imaging, the utilization of a multidisciplinary team, and close patient monitoring are key components for effective management of this increasingly prevalent disease process.


Assuntos
Aortite/etiologia , Dor Abdominal/etiologia , Idoso , Aortite/diagnóstico por imagem , Aortite/tratamento farmacológico , Dor nas Costas/etiologia , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Leflunomida/uso terapêutico , Masculino , Metilprednisolona/uso terapêutico , Resultado do Tratamento
10.
Brasília; s.n; 29 abr. 2020.
Não convencional em Português | LILACS, BRISA/RedTESA, PIE | ID: biblio-1097408

RESUMO

Essa é uma produção do Departamento de Ciência e Tecnologia (Decit) da Secretaria de Ciência, Tecnologia, Inovação e Insumos Estratégicos em Saúde (SCTIE) do Ministério da Saúde (Decit/SCTIE/MS), que tem como missão promover a ciência e tecnologia e o uso de evidências científicas para a tomada de decisão do SUS, tendo como principal atribuição o incentivo ao desenvolvimento de pesquisas em saúde no Brasil, de modo a direcionar os investimentos realizados em pesquisa pelo Governo Federal às necessidades de saúde pública. Informar sobre as principais evidências científicas descritas na literatura internacional sobre tratamento farmacológico para a COVID-19. Além de resumir cada estudo identificado, o informe apresenta também uma avaliação da qualidade metodológica e a quantidade de artigos publicados, de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, entre outros). Foram encontrados 13 artigos e 7 protocolos.


Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Avaliação da Tecnologia Biomédica , Metilprednisolona/uso terapêutico , Famotidina/uso terapêutico , Cloroquina/uso terapêutico , Azitromicina/uso terapêutico , Ritonavir/uso terapêutico , Combinação de Medicamentos , Lopinavir/uso terapêutico , Meloxicam/uso terapêutico , Leflunomida/uso terapêutico , Hidroxicloroquina/uso terapêutico
11.
Ann Rheum Dis ; 79(5): 556-565, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32241795

RESUMO

OBJECTIVES: To evaluate the cost-effectiveness of treat-to-target strategies among recently diagnosed patients with rheumatoid arthritis (RA) using methotrexate (MTX) and a step-down glucocorticoid (GC) scheme (COBRA Slim) compared with (1) this combination with either sulphasalazine (COBRA Classic) or leflunomide (COBRA Avant-Garde) in high-risk patients and (2) MTX without GCs (Tight-Step-Up, TSU) in low-risk patients. METHODS: The incremental cost-utility was calculated from a healthcare perspective in the intention-to-treat population (n=379) of the 2-year open-label pragmatic randomised controlled Care in early RA trial. Healthcare costs were collected prospectively through electronic trial records. Quality-adjusted life years (QALYs) were estimated using mapping algorithms for EuroQoL-5 Dimension. Multiple imputation was used to handle missing data and bootstrapping to calculate CIs. Robustness was tested with biological disease-modifying antirheumatic drugs at biosimilar prices. RESULTS: In the high-risk group, Classic (∆k€1.464, 95% CI -0.198 to 3.127) and Avant-Garde (∆k€0.636, 95% CI -0.987 to 2.258) were more expensive compared with Slim and QALYs were slightly worse for Classic (∆-0.002, 95% CI -0.086 to 0.082) and Avant-Garde (∆-0.009, 95% CI -0.102 to 0.084). This resulted in the domination of Classic and Avant-Garde by Slim. In the low-risk group, Slim was cheaper (∆k€-0.617, 95% CI -2.799 to 1.566) and QALYs were higher (∆0.141, 95% CI 0.008 to 0.274) compared with TSU, indicating Slim dominated. Results were robust against the price of biosimilars. CONCLUSIONS: The combination of MTX with a GC bridging scheme is less expensive with comparable health utility than more intensive step-down combination strategies or a conventional step-up approach 2 years after initial treatment. TRIAL REGISTRATION NUMBER: NCT01172639.


Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/economia , Leflunomida/administração & dosagem , Medição da Dor , Sulfassalazina/administração & dosagem , Idoso , Artrite Reumatoide/diagnóstico , Análise Custo-Benefício , Quimioterapia Combinada , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Amplitude de Movimento Articular/fisiologia , Indução de Remissão , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento
12.
Zhongguo Zhong Yao Za Zhi ; 45(4): 764-774, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32237476

RESUMO

To systematically evaluate the effects of Tripterygium Glycosides Tablets alone or in combination with methotrexate(MTX) and leflunomide(LEF) on the levels of pro-inflammatory cytokines in patients or animal models with rheumatoid arthritis(RA), and to provide reference for clinical application and related basic research, this study systematically searched databases of CNKI, VIP, WanFang, PubMed, Embase and Cochrane Library, collected relevant clinical or animal experimental studies, used risk assessment tools to evaluate the quality of research, and used Revman 5.3 software to conduct Meta-analysis or descriptive analysis of the outcome indicators included in the literatures. Of the 1 709 papers retrieved, 3 clinical studies and 12 animal experiments were included. The results showed that compared with MTX alone, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of peripheral blood TNF-α(SMD=-8.88,95%CI[-10.77,-6.99],P<0.000 01),IL-1ß(P<0.000 01) and IL-6(SMD=-8.63, 95%CI[-10.57,-6.69], P<0.000 01) in RA patients. Compared with LEF alone, the combination of Tripterygium Glycosides Tablets and LEF could not further reduce the expression levels of TNF-α(P=0.20), IL-1ß(P=0.17), IL-6(P=0.31). In RA animal model, compared with model group, Tripterygium Glycosides Tablets could reduce the expression levels of peripheral blood IL-1ß(SMD=-6.29,95%CI[-9.64,-2.93],P<0.000 2)in peripheral blood(SMD=-1.39,95%CI[-1.77,-1.02],P<0.000 01), joint fluid(P<0.000 01) and paw plasma(P=0.02), and also reduce the expression levels of TNF-α in RA animal model group. Compared with MTX alone, Tripterygium Glycosides Tablets alone reduced the same levels of TNF-α(P=0.42) and IL-6(P=0.08) in joint fluid, while Tripterygium Glycosides Tablets combined with MTX could further reduce the levels of IL-6(P=0.000 1) in joint fluid; compared with LEF alone, Tripterygium Glycosides Tablets have the similar effects on reducing the expression levels of peripheral blood TNF-α(P=0.16), IL-1ß(P=0.32), IL-6(P=0.12), while Tripterygium Glycosides Tablets combined with LEF could further reduce the expression levels of TNF-α(P=0.008), IL-1ß(P=0.02), IL-6(P<0.000 1) in peripheral blood. Therefore, Tripterygium Glycosides Tablets combined with MTX could further reduce the expression levels of pro-inflammatory cytokines in peripheral blood of RA patients. Tripterygium Glycosides Tablets alone could reduce the expression levels of pro-inflammatory cytokines in peripheral blood and local joint of RA animal models. Tripterygium Glycosides Tablets combined with MTX or LEF could further reduce the express levels of pro-inflammatory cytokines in peripheral blood of RA animal models. Due to the limitation of literature, this conclusion needs to be further validated.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Glicosídeos/uso terapêutico , Tripterygium/química , Animais , Citocinas , Humanos , Leflunomida/uso terapêutico , Metotrexato/uso terapêutico , Comprimidos
13.
Nat Cell Biol ; 22(4): 372-379, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32231306

RESUMO

The availability of nucleotides has a direct impact on transcription. The inhibition of dihydroorotate dehydrogenase (DHODH) with leflunomide impacts nucleotide pools by reducing pyrimidine levels. Leflunomide abrogates the effective transcription elongation of genes required for neural crest development and melanoma growth in vivo1. To define the mechanism of action, we undertook an in vivo chemical suppressor screen for restoration of neural crest after leflunomide treatment. Surprisingly, we found that alterations in progesterone and progesterone receptor (Pgr) signalling strongly suppressed leflunomide-mediated neural crest effects in zebrafish. In addition, progesterone bypasses the transcriptional elongation block resulting from Paf complex deficiency, rescuing neural crest defects in ctr9 morphant and paf1(alnz24) mutant embryos. Using proteomics, we found that Pgr binds the RNA helicase protein Ddx21. ddx21-deficient zebrafish show resistance to leflunomide-induced stress. At a molecular level, nucleotide depletion reduced the chromatin occupancy of DDX21 in human A375 melanoma cells. Nucleotide supplementation reversed the gene expression signature and DDX21 occupancy changes prompted by leflunomide. Together, our results show that DDX21 acts as a sensor and mediator of transcription during nucleotide stress.


Assuntos
RNA Helicases DEAD-box/genética , Melanócitos/metabolismo , Crista Neural/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Receptores de Progesterona/genética , Proteínas de Peixe-Zebra/genética , Animais , Linhagem Celular Tumoral , RNA Helicases DEAD-box/metabolismo , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Leflunomida/farmacologia , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Crista Neural/efeitos dos fármacos , Crista Neural/crescimento & desenvolvimento , Nucleotídeos , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Progesterona/metabolismo , Ligação Proteica , Receptores de Progesterona/metabolismo , Transdução de Sinais , Estresse Fisiológico/genética , Elongação da Transcrição Genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
14.
Cochrane Database Syst Rev ; 3: CD003965, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32162319

RESUMO

BACKGROUND: IgA nephropathy is the most common glomerulonephritis world-wide. IgA nephropathy causes end-stage kidney disease (ESKD) in 15% to 20% of affected patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a Cochrane review first published in 2003 and updated in 2015. OBJECTIVES: To determine the benefits and harms of immunosuppression strategies for the treatment of IgA nephropathy. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 9 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgA nephropathy in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data. Estimates of treatment effect were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Risks of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE methodology. MAIN RESULTS: Fifty-eight studies involving 3933 randomised participants were included. Six studies involving children were eligible. Disease characteristics (kidney function and level of proteinuria) were heterogeneous across studies. Studies evaluating steroid therapy generally included patients with protein excretion of 1 g/day or more. Risk of bias within the included studies was generally high or unclear for many of the assessed methodological domains. In patients with IgA nephropathy and proteinuria > 1 g/day, steroid therapy given for generally two to four months with a tapering course probably prevents the progression to ESKD compared to placebo or standard care (8 studies; 741 participants: RR 0.39, 95% CI 0.23 to 0.65; moderate certainty evidence). Steroid therapy may induce complete remission (4 studies, 305 participants: RR 1.76, 95% CI 1.03 to 3.01; low certainty evidence), prevent doubling of serum creatinine (SCr) (7 studies, 404 participants: RR 0.43, 95% CI 0.29 to 0.65; low certainty evidence), and may lower urinary protein excretion (10 studies, 705 participants: MD -0.58 g/24 h, 95% CI -0.84 to -0.33;low certainty evidence). Steroid therapy had uncertain effects on glomerular filtration rate (GFR), death, infection and malignancy. The risk of adverse events with steroid therapy was uncertain due to heterogeneity in the type of steroid treatment used and the rarity of events. Cytotoxic agents (azathioprine (AZA) or cyclophosphamide (CPA) alone or with concomitant steroid therapy had uncertain effects on ESKD (7 studies, 463 participants: RR 0.63, 95% CI 0.33 to 1.20; low certainty evidence), complete remission (5 studies; 381 participants: RR 1.47, 95% CI 0.94 to 2.30; very low certainty evidence), GFR (any measure), and protein excretion. Doubling of serum creatinine was not reported. Mycophenolate mofetil (MMF) had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, infection, and malignancy. Death was not reported. Calcineurin inhibitors compared with placebo or standard care had uncertain effects on complete remission, SCr, GFR, protein excretion, infection, and malignancy. ESKD and death were not reported. Mizoribine administered with renin-angiotensin system inhibitor treatment had uncertain effects on progression to ESKD, complete remission, GFR, protein excretion, infection, and malignancy. Death and SCr were not reported. Leflunomide followed by a tapering course with oral prednisone compared to prednisone had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, and infection. Death and malignancy were not reported. Effects of other immunosuppressive regimens (including steroid plus non-immunosuppressive agents or mTOR inhibitors) were inconclusive primarily due to insufficient data from the individual studies in low or very low certainty evidence. The effects of treatments on death, malignancy, reduction in GFR at least of 25% and adverse events were very uncertain. Subgroup analyses to determine the impact of specific patient characteristics such as ethnicity or disease severity on treatment effectiveness were not possible. AUTHORS' CONCLUSIONS: In moderate certainty evidence, corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults and children with IgA nephropathy and proteinuria. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low-quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents including CPA, AZA, or MMF improve clinical outcomes in IgA nephropathy.


Assuntos
Glomerulonefrite por IGA/tratamento farmacológico , Imunossupressores/uso terapêutico , Esteroides/uso terapêutico , Adulto , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/uso terapêutico , Causas de Morte , Criança , Intervalos de Confiança , Creatinina/sangue , Esquema de Medicação , Quimioterapia Combinada , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Falência Renal Crônica/mortalidade , Falência Renal Crônica/prevenção & controle , Falência Renal Crônica/terapia , Leflunomida/efeitos adversos , Leflunomida/uso terapêutico , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/uso terapêutico , Proteinúria/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Ribonucleosídeos/efeitos adversos , Ribonucleosídeos/uso terapêutico , Risco , Esteroides/administração & dosagem , Esteroides/efeitos adversos
15.
Phytomedicine ; 68: 153136, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32062477

RESUMO

BACKGROUND: The high discontinuation rate in RA patients who use LEF might be attributed to their intolerance rather than irresponsibility. The concomitant administration of Leflunomide (LEF) with Chinese herbal medicine (CHM) provides a potential solution to preventing the adverse drug reactions (ADRs) induced by LEF during the treatment of rheumatoid arthritis (RA). PURPOSE: To investigate whether co-administration of LEF with CHM could bring in both increased therapeutic outcomes and reduced ADRs due to the framework of treatment at the level of entire body. STUDY DESIGN: The mechanism of LEF in RA treatment and the ADRs it induced was introduced based on recent papers. Reported clinical examples of CHM concurrent use with LEF was revealed to provide more evidence. The management of the ADRs caused by LEF was suggested by current researches on the concomitant therapy of CHM with LEF. RESULTS: The active ingredients, compounds and medicinal herbs all demonstrated properties in relieving toxicities and reducing ADRs when used with LEF and reported in several clinical cases. The wide application of concurrent use of CHM with LEF is however hindered by the complex pathogenesis of RA which requires further scientific grounds for diagnosis and treatment. CONCLUSION: This review introduced that the adoption of CHM is emerging as a novel strategy for the management of ADRs caused by LEF.


Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Leflunomida/efeitos adversos , Antirreumáticos/uso terapêutico , Humanos , Leflunomida/uso terapêutico
16.
J Med Case Rep ; 14(1): 26, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32019572

RESUMO

BACKGROUND: Treatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy. CASE PRESENTATION: A 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 µg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found. For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered. CONCLUSIONS: Under a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas , Imunossupressores/efeitos adversos , Leflunomida/efeitos adversos , Metotrexato/efeitos adversos , Microangiopatias Trombóticas/induzido quimicamente , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade
18.
Ren Fail ; 42(1): 122-130, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31957527

RESUMO

Objective: To evaluate the clinical efficacy and safety of leflunomide (LEF) combined with prednisone for the treatment of PLA2R-associated primary membranous nephropathy (PMN) and changes in anti-PLA2R antibody titers after treatment.Methods: Sixty patients with nephrotic syndrome, biopsy-proven MN and anti-PLA2R antibody positivity were included in this study conducted from December 2017 to February 2019. The patients were randomly divided into an experimental group (n = 30) and a control group (n = 30). The patients in the experimental group were treated with LEF combined with prednisone, whereas the patients in the control group were treated with cyclophosphamide (CTX) combined with prednisone. We assessed 24-h urinary protein and serum albumin levels, kidney function markers, blood lipid levels and anti-PLA2R antibody titers before and after treatment. Adverse reactions during treatment were recorded.Results: After 16 weeks of treatment, there were 2 cases of complete remission and 6 cases of partial remission in the experimental group, with a total effective rate of 26.67%. In the control group, there were 4 cases of complete remission and 8 cases of partial remission, with a total effective rate of 40% (p > .05). After 24 weeks of treatment, the total effective rates of the experimental and control groups were 66.67% and 76.67%, respectively (p > .05). There were no significant differences in 24-h urinary protein, serum albumin, kidney function marker or blood lipid levels between the two groups after treatment (p > .05). However, there were fewer adverse reactions in the experimental group than in the control group (p < .05). After treatment, serum anti-PLA2R antibody titers were clearly decreased in patients with complete remission and partial remission (p < .05), but these levels remained relatively high in patients without remission (p > .05).Conclusion: LEF combined with prednisone has a certain efficacy for the treatment of PLA2R-associated PMN and provokes few adverse reactions. A large-sample randomized double-blind controlled study with a long follow-up period is needed to verify the efficacy of LEF combined with prednisone.


Assuntos
Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/tratamento farmacológico , Leflunomida/uso terapêutico , Síndrome Nefrótica/complicações , Prednisona/uso terapêutico , Adulto , Autoanticorpos/sangue , Biomarcadores/sangue , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/uso terapêutico , Leflunomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Proteinúria/tratamento farmacológico , Receptores da Fosfolipase A2/imunologia , Indução de Remissão , Albumina Sérica
19.
Clin Exp Rheumatol ; 38 Suppl 124(2): 69-78, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31969231

RESUMO

OBJECTIVES: Inflammatory fibrosis of aortic lesions promoted by type II macrophages (M2) is one of the most serious incidents in Takayasu's arteritis (TAK), and the currently available therapies can not effectively block the inflammatory fibrosis. Here we explored whether leflunomide (LEF) could improve the fibrosis by down-regulating M2 in TAK. METHODS: Peripheral blood mono-nuclear cells (PBMCs) from 16 TAK patients were treated by leflunomide, and the ratio of M1/M2 macrophages and apoptosis of M2 were detected by flow cytometry. Supernatant levels of cytokines and chemokines secreted by M2 were measured by ELISAs. mRNA expression of profibrotic factors in M2 were analysed by real time PCR. Western blotting was used to analyse the activation of signal transducer activator of transcription (STAT)-6. RESULTS: LEF could inhibit M2 polarisation by curtailing STAT6 phosphorylation. LEF could also promote apoptosis of M2 and reduce the release of M2-derived CCL22 as well as the expression of profibrotic cytokines including CCL22 and TGF-ß in M2. CONCLUSIONS: LEF could potentially reduce vascular fibrosis by down-regulating the number and function of M2, which, eventually, could alleviate inflammatory fibrosis of aortic lesions in TAK patients.


Assuntos
Leflunomida/uso terapêutico , Macrófagos/efeitos dos fármacos , Arterite de Takayasu/tratamento farmacológico , Doenças Vasculares/tratamento farmacológico , Quimiocina CCL22 , Citocinas , Fibrose/tratamento farmacológico , Humanos , Fator de Transcrição STAT6 , Fator de Crescimento Transformador beta1
20.
Gastroenterology ; 158(4): 1000-1015, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31743734

RESUMO

BACKGROUND & AIMS: Mutations in the tetratricopeptide repeat domain 7A gene (TTC7A) cause intestinal epithelial and immune defects. Patients can become immune deficient and develop apoptotic enterocolitis, multiple intestinal atresia, and recurrent intestinal stenosis. The intestinal disease in patients with TTC7A deficiency is severe and untreatable, and it recurs despite resection or allogeneic hematopoietic stem cell transplant. We screened drugs for those that prevent apoptosis of in cells with TTC7A deficiency and tested their effects in an animal model of the disease. METHODS: We developed a high-throughput screen to identify compounds approved by the US Food and Drug Administration that reduce activity of caspases 3 and 7 in TTC7A-knockout (TTC7A-KO) HAP1 (human haploid) cells and reduce the susceptibility to apoptosis. We validated the effects of identified agents in HeLa cells that stably express TTC7A with point mutations found in patients. Signaling pathways in cells were analyzed by immunoblots. We tested the effects of identified agents in zebrafish with disruption of ttc7a, which develop intestinal defects, and colonoids derived from biopsy samples of patients with and without mutations in TTC7A. We performed real-time imaging of intestinal peristalsis in zebrafish and histologic analyses of intestinal tissues from patients and zebrafish. Colonoids were analyzed by immunofluorescence and for ion transport. RESULTS: TTC7A-KO HAP1 cells have abnormal morphology and undergo apoptosis, due to increased levels of active caspases 3 and 7. We identified drugs that increased cell viability; leflunomide (used to treat patients with inflammatory conditions) reduced caspase 3 and 7 activity in cells by 96%. TTC7A-KO cells contained cleaved caspase 3 and had reduced levels of phosphorylated AKT and X-linked inhibitor of apoptosis (XIAP); incubation of these cells with leflunomide increased levels of phosphorylated AKT and XIAP and reduced levels of cleaved caspase 3. Administration of leflunomide to ttc7a-/- zebrafish increased gut motility, reduced intestinal tract narrowing, increased intestinal cell survival, increased sizes of intestinal luminal spaces, and restored villi and goblet cell morphology. Exposure of patient-derived colonoids to leflunomide increased cell survival, polarity, and transport function. CONCLUSIONS: In a drug screen, we identified leflunomide as an agent that reduces apoptosis and activates AKT signaling in TTC7A-KO cells. In zebrafish with disruption of ttc7a, leflunomide restores gut motility, reduces intestinal tract narrowing, and increases intestinal cell survival. This drug might be repurposed for treatment of TTC7A deficiency.


Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Leflunomida/farmacologia , Proteínas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Colo/citologia , Técnicas de Inativação de Genes , Haploidia , Humanos , Doenças Inflamatórias Intestinais/genética , Fosforilação/efeitos dos fármacos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo
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