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1.
Sci Rep ; 10(1): 13866, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807895

RESUMO

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.


Assuntos
Betacoronavirus/efeitos dos fármacos , Biologia Computacional/métodos , Infecções por Coronavirus/metabolismo , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/metabolismo , Aminopiridinas/farmacologia , Benzodioxóis/farmacologia , Betacoronavirus/química , Sítios de Ligação , Infecções por Coronavirus/virologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Conformação Proteica , Domínios Proteicos/efeitos dos fármacos , Mapas de Interação de Proteínas/efeitos dos fármacos , Simeprevir/farmacologia , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo
2.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1167-1170, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798393

RESUMO

OBJECTIVE: To investigate the effect of chidamide on the killing activity of NK (Natural killer cell, NK) cells targeting K562 cells and its related mechanism. METHODS: K562 cells were pretreated with chidamide at different concentrations and cocultured with NK cells at different effect-target ratios. The killing effect of chidamide on K562 cells by NK cells, the expression of natural killer group 2 member D (NKG2D) ligands and apoptosis rate of K562 cells were detected by flow cytometry. RESULTS: The killing sensitivity of NK cells to K562 cells could be enhanced by chidamide. The expression of ULBP2 on K562 cell surface could be up-regulate, however, the expression of ULBP1 and MICA/MICB showed no statistically difference as compared with control group. Chidamide showed no obvious cytotoxicity to K562 cells. CONCLUSION: Chidamide can significantly improve killing efficiency of NK cells on K562 cells, which may be related to the up-regulation of ULBP2 expression.


Assuntos
Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais/imunologia , Aminopiridinas , Benzamidas , Proteínas Ligadas por GPI , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Células K562 , Subfamília K de Receptores Semelhantes a Lectina de Células NK
3.
N Engl J Med ; 383(3): 229-239, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32668113

RESUMO

BACKGROUND: Systemic oral phosphodiesterase type 4 (PDE-4) inhibitors have been effective in the treatment of psoriasis. Roflumilast cream contains a PDE-4 inhibitor that is being investigated for the topical treatment of psoriasis. METHODS: In this phase 2b, double-blind trial, we randomly assigned adults with plaque psoriasis in a 1:1:1 ratio to use roflumilast 0.3% cream, roflumilast 0.15% cream, or vehicle (placebo) cream once daily for 12 weeks. The primary efficacy outcome was the investigator's global assessment (IGA) of a status of clear or almost clear at week 6 (assessed on a 5-point scale of plaque thickening, scaling, and erythema; a score of 0 indicates clear, 1 almost clear, and 4 severe). Secondary outcomes included an IGA score indicating clear or almost clear plus a 2-grade improvement in the IGA score for the intertriginous area and the change in the Psoriasis Area and Severity Index (PASI) score (range, 0 to 72, with higher scores indicating worse disease). Safety was also assessed. RESULTS: Among 331 patients who underwent randomization, 109 were assigned to roflumilast 0.3% cream, 113 to roflumilast 0.15% cream, and 109 to vehicle cream. An IGA score indicating clear or almost clear at week 6 was observed in 28% of the patients in the roflumilast 0.3% group, in 23% in the roflumilast 0.15% group, and in 8% in the vehicle group (P<0.001 and P = 0.004 vs. vehicle for roflumilast 0.3% and 0.15%, respectively). Among the approximately 15% of patients overall who had baseline intertriginous psoriasis of at least mild severity, an IGA score at week 6 indicating clear or almost clear plus a 2-grade improvement in the intertriginous-area IGA score occurred in 73% of the patients in the roflumilast 0.3% group, 44% of those in the roflumilast 0.15% group, and 29% of those in the vehicle group. The mean baseline PASI scores were 7.7 in the roflumilast 0.3% group, 8.0 in the roflumilast 0.15% group, and 7.6 in the vehicle group; the mean change from baseline at week 6 was -50.0%, -49.0%, and -17.8%, respectively. Application-site reactions occurred with similar frequency in the roflumilast groups and the vehicle group. CONCLUSIONS: Roflumilast cream administered once daily to affected areas of psoriasis was superior to vehicle cream in leading to a state of clear or almost clear at 6 weeks. Longer and larger trials are needed to determine the durability and safety of roflumilast in psoriasis. (Funded by Arcutis Biotherapeutics; ARQ-151 201 ClinicalTrials.gov number, NCT03638258.).


Assuntos
Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , Psoríase/tratamento farmacológico , Creme para a Pele/administração & dosagem , Administração Tópica , Adulto , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 4/efeitos adversos , Índice de Gravidade de Doença
4.
J Chromatogr A ; 1625: 461194, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709309

RESUMO

Quantitative analysis of glycans released from glycoproteins using high-performance liquid chromatography (HPLC) requires fluorescent tag labeling to enhance sensitivity and selectivity. However, the methods required to remove large amounts of excess labeling reagents from the reaction mixture are time-consuming. Furthermore, these methods, including solvent extraction and solid phase extraction (SPE), often impair quantitative analysis. Here, we developed an online sample cleanup procedure for HPLC analysis of 2-aminopyridine (AP)-labeled glycans using a six-port/two-way valve and two small columns: one packed with a strong cation exchange resin (SCX) and the other comprising ODS silica gel. AP-labeled glycans delivered from an injection port were separated from excess AP by passing through an SCX column (4.6 mm i.d., 1 cm long) regulated to 40°C. The AP-labeled glycans were trapped on an ODS column (4.6 mm i.d., 1 cm long) to further separate them from inorganic contaminants. By changing the valve position after 2 min to connect the ODS column to an analysis column, AP-labeled glycans trapped in the ODS column were eluted with an acetonitrile-containing eluent followed by hydrophilic interaction liquid chromatography (HILIC) separation on an amide column or reversed-phase mode separation on a C30 column. This method was successfully used to analyze N-linked glycans released from several glycoprotein samples.


Assuntos
Aminopiridinas/química , Cromatografia Líquida de Alta Pressão/métodos , Polissacarídeos/química , Cromatografia por Troca Iônica , Cromatografia de Fase Reversa , Glicoproteínas/metabolismo , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Polissacarídeos/isolamento & purificação , Extração em Fase Sólida
6.
Cancer Sci ; 111(9): 3313-3326, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32619077

RESUMO

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2-phase study consisting of a dose-escalation phase to determine the maximum-tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose-expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose-escalation phase, the maximum-tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non-Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non-Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non-Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Idoso , Idoso de 80 Anos ou mais , Aminopiridinas/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Biomarcadores , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Japão , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/administração & dosagem , Resultado do Tratamento
7.
N Engl J Med ; 382(23): e85, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32492318
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(3): 737-741, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-32552929

RESUMO

OBJECTIVE: To investigate the efficacy and safety of combination chidamide and hematopoietic stem cell transplantation (HSCT) in the treatment of childhood acute T lymphoblastic leukemia (T-ALL). METHODS: Seven children with acute T lymphoblastic leukemia received hematopoietic stem cell transplantation in SUN Yat-Sen Memorial Hospital of SUN Yat-Sen University were selected. 7 cases of T-ALL were divided into 2 groups: HSCT plus chidamide-treated group (4 cases) and traditional HSCT-treated group (3 cases) as control. The incidence of GVHD and other related complications, as well as implantation, recurrence and survival were compared between the two groups, and the side effects of chidamide were observed. All the patients were follow-up until January 2019. RESULTS: All the 7 patients were alive and, there was no difference in the incidence of acute GVHD between the HSCT plus chidamides treated group and the traditional HSCT-treated group. The implantation rate of HSCT was 100%, and there were no recurrence occurred. During the application of chidamide, 3 cases showed adverse reactions, of which 2 cases had adverse reactions of grade 3 or higher, and 2 cases were hematological adverse reactions (neutropenia, thrombocytopenia), other adverse reactions were non-hematologic adverse reactions (transaminase elevation, fatigue, nausea, vomiting), there were no serious adverse reactions occurred. In the HSCT plus chidamide-treated group, 2 cases were found that mature lymphocytes were not expressed by tumors, during examing for minimal redidaul disease (MRD). Compared with the immunophenotype and TCR rearrangement at first diagnosis, the results did not support the source of residual T-ALL tumor cells. During the review of MRD, it was found that the abnormal T cells showed an increasing trend, indicating that chidamide might induce leukemia cell differentiation through some pathways. CONCLUSION: Hematopoietic stem cell transplantation is still an effective method to cure children's T-ALL. In some cases, abnormal T-cell nonclonal amplification occurs during the application of chidamide, and the children with T-ALL can tolerable adverse reactions of chidamide.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Aminopiridinas , Benzamidas , Criança , Humanos , Recidiva , Transplante Homólogo
11.
Plant Dis ; 104(9): 2449-2454, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32579058

RESUMO

Cucumber target spot, caused by Corynespora cassiicola, is a devastating fungal disease in greenhouses in China. Lack of resistant cultivars and unscientific use of fungicides aggravated the difficulty to manage this disease. In recent years, resistance of C. cassiicola to benzimidazoles, quinone outside inhibitors, and succinate dehydrogenase inhibitors has occurred in China. Here, we tested the fluazinam sensitivity distribution of 79 C. cassiicola isolates from different provinces in China based on mycelial growth inhibition. The EC50 values of fluazinam ranged from 0.1002 to 0.3129 µg/ml with a mean of 0.2136 ± 0.0495 µg/ml, and the sensitivity frequency was normally distributed (P = 0.2083, Shapiro-Wilk test). Meanwhile, the EC50 values for spore germination inhibition ranged from 0.0992 to 0.2278 µg/ml with a mean of 0.1499 ± 0.0504 µg/ml. This indicated that fluazinam exhibited an excellent in vitro fungicidal activity on both mycelial growth and spore germination. In addition, fluazinam also exhibited a good in planta control efficacy on detached cucumber leaves in the protective and curative assays. Moreover, the biological and physiological characteristics of C. cassiicola as affected by fluazinam were determined. Fluazinam not only significantly inhibited respiration and adenosine triphosphate production but also caused the increase of cell membrane permeability and the dysfunctions of cellular homeostasis. Interestingly, we found that fluazinam especially damaged vacuole structures, causing the redistribution of vacuole substances. Taken together, our findings provide not only essential references for resistance management of C. cassiicola but also interesting insights for further revealing the action mode of fluazinam against plant pathogens.


Assuntos
Ascomicetos , Cucumis sativus , Aminopiridinas , China , Doenças das Plantas
12.
Environ Sci Pollut Res Int ; 27(28): 35000-35007, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32583109

RESUMO

Fluazinam (FZN) is a dinitroaniline fungicide. To evaluate the environmental risk of FZN in aquatic environments and ascertain the potential danger to typical aquatic organisms in China, the acute toxicity of FZN to representative aquatic organisms, including Brachydanio rerio, Chlorella vulgaris Beij., Daphnia magna Straus, and Xenopus laevis, was measured, and its bioaccumulation properties in Brachydanio rerio were further investigated. The results showed that the acute toxicity of FZN to Brachydanio rerio and Xenopus laevis is extremely high, and the bioaccumulation factor BCF8d of FZN in Brachydanio rerio ranges between 2287 and 3570, implying that it has high bioaccumulation properties. FZN poses a strong environmental risk for aquatic organisms and possesses great bioaccumulation properties, which may cause pollution to aquatic environments.


Assuntos
Chlorella vulgaris , Poluentes Químicos da Água , Aminopiridinas , Animais , Organismos Aquáticos , Bioacumulação , China , Daphnia , Peixe-Zebra
15.
Lancet Oncol ; 21(6): 763-775, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32353342

RESUMO

BACKGROUND: Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. METHODS: This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1-21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT02675231) and is ongoing for long-term survival follow-up. FINDINGS: Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7-25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9-12·6) and group C (5·7 months, 5·4-7·0; HR 0·67 [95% CI 0·45-1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2-7·2) and group C (HR 0·94 [0·64-1·38]; p=0·77). The most common grade 3-4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. INTERPRETATION: The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. FUNDING: Eli Lilly and Company.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Antagonistas do Receptor de Estrogênio/administração & dosagem , Fulvestranto/administração & dosagem , Receptor ErbB-2/antagonistas & inibidores , Receptores Estrogênicos/efeitos dos fármacos , Trastuzumab/administração & dosagem , Idoso , Aminopiridinas/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Argentina , Austrália , Benzimidazóis/efeitos adversos , Brasil , Neoplasias da Mama/enzimologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Progressão da Doença , Antagonistas do Receptor de Estrogênio/efeitos adversos , Europa (Continente) , Feminino , Fulvestranto/efeitos adversos , Humanos , Pessoa de Meia-Idade , América do Norte , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , República da Coreia , Transdução de Sinais , Fatores de Tempo , Trastuzumab/efeitos adversos
17.
Cochrane Database Syst Rev ; 5: CD002309, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32356609

RESUMO

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea, and a reduction in lung function, quality of life, and life expectancy. Apart from smoking cessation, no other treatments that slow lung function decline are available. Roflumilast and cilomilast are oral phosphodiesterase-4 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD. This Cochrane Review was first published in 2011, and was updated in 2017 and 2020. OBJECTIVES: To evaluate the efficacy and safety of oral PDE4 inhibitors for management of stable COPD. SEARCH METHODS: We identified randomised controlled trials (RCTs) from the Cochrane Airways Trials Register (date of last search 9 March 2020). We found other trials at web-based clinical trials registers. SELECTION CRITERIA: We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two independent review authors selected trials for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. We assessed our confidence in the evidence by using GRADE recommendations. Primary outcomes were change in lung function (minimally important difference (MID) = 100 mL) and quality of life (scale 0 to 100; higher score indicates more limitations). MAIN RESULTS: We found 42 RCTs that met the inclusion criteria and were included in the analyses for roflumilast (28 trials with 18,046 participants) or cilomilast (14 trials with 6457 participants) or tetomilast (1 trial with 84 participants), with a duration between six weeks and one year or longer. These trials included people across international study centres with moderate to very severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades II to IV), with mean age of 64 years. We judged risks of selection bias, performance bias, and attrition bias as low overall amongst the 39 published and unpublished trials. Lung function Treatment with a PDE4 inhibitor was associated with a small, clinically insignificant improvement in forced expiratory volume in one second (FEV1) over a mean of 40 weeks compared with placebo (mean difference (MD) 49.33 mL, 95% confidence interval (CI) 44.17 to 54.49; participants = 20,815; studies = 29; moderate-certainty evidence). Forced vital capacity (FVC) and peak expiratory flow (PEF) were also improved over 40 weeks (FVC: MD 86.98 mL, 95% CI 74.65 to 99.31; participants = 22,108; studies = 17; high-certainty evidence; PEF: MD 6.54 L/min, 95% CI 3.95 to 9.13; participants = 4245; studies = 6; low-certainty evidence). Quality of life Trials reported improvements in quality of life over a mean of 33 weeks (St George's Respiratory Questionnaire (SGRQ) MD -1.06 units, 95% CI -1.68 to -0.43; participants = 7645 ; moderate-certainty evidence). Incidence of exacerbations Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation over a mean of 40 weeks (odds ratio (OR) 0.78, 95% CI 0.73 to 0.84; participants = 20,382; studies = 27; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, five more remained exacerbation-free during the study period compared with those given placebo (number needed to treat for an additional beneficial outcome (NNTB) 20, 95% CI 16 to 27). No change in COPD-related symptoms nor in exercise tolerance was found. Adverse events More participants in the treatment groups experienced an adverse effect compared with control participants over a mean of 39 weeks (OR 1.30, 95% CI 1.22 to 1.38; participants = 21,310; studies = 30; low-certainty evidence). Participants experienced a range of gastrointestinal symptoms such as diarrhoea, nausea, vomiting, or dyspepsia. Diarrhoea was more commonly reported with PDE4 inhibitor treatment (OR 3.20, 95% CI 2.74 to 3.50; participants = 20,623; studies = 29; high-certainty evidence), that is, for every 100 people treated with PDE4 inhibitors, seven more suffered from diarrhoea during the study period compared with those given placebo (number needed to treat for an additional harmful outcome (NNTH) 15, 95% CI 13 to 17). The likelihood of psychiatric adverse events was higher with roflumilast 500 µg than with placebo (OR 2.13, 95% CI 1.79 to 2.54; participants = 11,168; studies = 15 (COPD pool data); moderate-certainty evidence). Roflumilast in particular was associated with weight loss during the trial period and with an increase in insomnia and depressive mood symptoms. Participants treated with PDE4 inhibitors were more likely to withdraw from trial participation; on average, 14% in the treatment groups withdrew compared with 8% in the control groups. Mortality No effect on mortality was found (OR 0.98, 95% CI 0.77 to 1.24; participants = 19,786; studies = 27; moderate-certainty evidence), although mortality was a rare event during these trials. AUTHORS' CONCLUSIONS: For this current update, five new studies from the 2020 search contributed to existing findings but made little impact on outcomes described in earlier versions of this review. PDE4 inhibitors offered a small benefit over placebo in improving lung function and reducing the likelihood of exacerbations in people with COPD; however, they had little impact on quality of life or on symptoms. Gastrointestinal adverse effects and weight loss were common, and the likelihood of psychiatric symptoms was higher, with roflumilast 500 µg. The findings of this review provide cautious support for the use of PDE4 inhibitors in COPD. In accordance with GOLD 2020 guidelines, they may have a place as add-on therapy for a subgroup of people with persistent symptoms or exacerbations despite optimal COPD management (e.g. people whose condition is not controlled by fixed-dose long-acting beta2-agonist (LABA) and inhaled corticosteroid (ICS) combinations). More longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation, or mortality in COPD.


Assuntos
Aminopiridinas/administração & dosagem , Benzamidas/administração & dosagem , Ácidos Cicloexanocarboxílicos/administração & dosagem , Nitrilos/administração & dosagem , Inibidores da Fosfodiesterase 4/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Tiazóis/administração & dosagem , Administração Oral , Aminopiridinas/efeitos adversos , Benzamidas/efeitos adversos , Ácidos Cicloexanocarboxílicos/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Diarreia/induzido quimicamente , Progressão da Doença , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Nitrilos/efeitos adversos , Pico do Fluxo Expiratório/efeitos dos fármacos , Inibidores da Fosfodiesterase 4/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/mortalidade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazóis/efeitos adversos , Capacidade Vital/efeitos dos fármacos
20.
Zhonghua Xue Ye Xue Za Zhi ; 41(4): 292-296, 2020 Apr 14.
Artigo em Chinês | MEDLINE | ID: mdl-32447932

RESUMO

Objective: To explore the effect and mechanism of low-dose chidamide on the treatment of primary immune thrombocytopenia (ITP) . Methods: Passive ITP animal model and active ITP animal model were established by C57BL/6J mice. Different doses of chidamide (0, 0.01, 0.1, 0.5, and 5 mg/kg) were orally administrated twice a week for 120 hours in passive ITP mice. Secondly, low-dose chidamine (0.1 mg/kg) was given intragastrically administrated twice a week in active ITP mice. The platelet counts in the peripheral blood before and after treatment were detected. Four weeks later, mice were executed to prepare splenocyte suspension; natural regulatory T cells (CD4(+)CD25(+)Foxp3(+) nTreg cells) in splenocyte suspension were detected by flow cytometry. Serum IL-6 was measured by ELISA. Peripheral blood mononuclear cells from ITP patients were co-cultured with low-dose chidamide in vitro. After incubation for 72 hours, CD4(+)CD25(+)Foxp3(+) Treg cells of mononuclear cells was detected. CD4(+)CD25(+) Treg cells and CD4(+)CD25(-) effector T cells were separated by immunomagnetic beads. The Treg cells and effector T cells were co cultured in a ratio of 1∶4, and treated with low-dose chidamide. The proliferation of effector T cells was detected. Results: Chidamide with low dose (0.1 mg/kg) significantly improved platelet counts in passive ITP mouse model, as well as in the ITP active mouse model and reduced the mortality related to bleeding. Low-dose chidamide significantly increased the number and proportion of nTreg cells in mouse splenocytes, and decreased serum IL-6 level in active ITP mice. In ITP patients, low-dose chidamide also significantly expanded Treg cells in the PBMC culture system. Besides, the proliferation of effector T cells was suppressed. Conclusion: Low-dose chidamide enhances the proliferation of CD4(+)CD25(+)Foxp3(+) regulatory T cells to mediate immunosuppressive function. Serum IL-6 is inhibited for further immune tolerance. In vivo animal study suggestes that low-dose chidamide has a novel therapeutic effect on ITP.


Assuntos
Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Púrpura Trombocitopênica Idiopática , Animais , Fatores de Transcrição Forkhead , Humanos , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Linfócitos T Reguladores
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