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BACKGROUND: In some patients, coronavirus disease 2019 (COVID-19) is accompanied by loss of smell and taste, and this has been reportedly associated with exposure to air pollutants. This study investigated the relationship between the occurrence of chemosensory dysfunction in COVID-19 patients and air pollutant concentrations in Korea. METHODS: Information on the clinical symptom of chemosensory dysfunction, the date of diagnosis, residential area, age, and sex of 60,194 confirmed COVID-19 cases reported to the Korea Disease Control and Prevention Agency from January 20 to December 31, 2020 was collected. In addition, the daily average concentration of air pollutants for a week in the patients' residential area was collected from the Ministry of Environment based on the date of diagnosis of COVID-19. A binomial logistic regression model, using age and gender, standardized smoking rate, number of outpatient visits, 24-hour mean temperature and relative humidity at the regional level as covariates, was used to determine the effect of air pollution on chemosensory dysfunction. RESULTS: Symptoms of chemosensory dysfunction were most frequent among patients in their 20s and 30s, and occurred more frequently in large cities. The logistic analysis showed that the concentration of particulate matter 10 (PM10) and 2.5 (PM2.5) up to 2 days before the diagnosis of COVID-19 and the concentration of sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) at least 7 days before the diagnosis of COVID-19 affected the development of chemosensory dysfunction. In the logistic regression model adjusted for age, sex, standardized smoking rate, number of outpatient visits, and daily average temperature and relative humidity, it was found that an increase in the interquartile range of PM10, PM2.5, SO2, NO2, and CO on the day of diagnosis increased the incidence of chemosensory dysfunction 1.10, 1.10, 1.17, 1.31, and 1.19-fold, respectively. In contrast, the O3 concentration had a negative association with chemosensory dysfunction. CONCLUSION: High concentrations of air pollutants such as PM10, PM2.5, SO2, NO2, and CO on the day of diagnosis increased the risk of developing chemosensory dysfunction from COVID-19 infection. This result underscores the need to actively prevent exposure to air pollution and prevent COVID-19 infection. In addition, policies that regulate activities and products that create high amounts of harmful environmental wastes may help in promoting better health for all during COVID-19 pandemic.
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Poluentes Atmosféricos , Poluição do Ar , COVID-19 , Ozônio , Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/análise , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , COVID-19/complicações , COVID-19/epidemiologia , Monóxido de Carbono/análise , China/epidemiologia , Humanos , Dióxido de Nitrogênio/efeitos adversos , Dióxido de Nitrogênio/análise , Ozônio/efeitos adversos , Ozônio/análise , Pandemias , Material Particulado/efeitos adversos , Material Particulado/análise , Dióxido de Enxofre/efeitos adversos , Dióxido de Enxofre/análiseRESUMO
For drugs with enhanced serious safety risks, Risk Evaluation and Mitigation Strategy (REMS) may be required. Pexidartinib is approved for treatment of adult symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Its approval was conditional on its prescription via a mandatory REMS due to serious and potentially fatal liver injury seen in clinical trials. Turalio® REMS aims to mitigate this risk by ensuring provider education on pexidartinib use and required REMS components, prescriber adherence to baseline and periodic monitoring, and enrolling patients in a registry to further assess safe use and acute, chronic and irreversible hepatotoxicity. Through Turalio REMS, benefits of treating patients with pexidartinib may be preserved.
For drugs with serious side effects, specific safety measures may be put in place to manage these serious side effects in the form of Risk Evaluation and Mitigation Strategy (REMS) programs. Pexidartinib (Turalio®) is approved for treatment of adults who have symptoms of severe tenosynovial giant cell tumor or have limitations in function that do not improve with surgery. Turalio® has an REMS program because liver injuries that can be serious or fatal were seen in Pexidartinib clinical trials. This program aims to decrease the seriousness of the liver injuries by assuring doctors and pharmacists are educated on how to use the drug, patients are advised of this potential risk and that baseline and periodic monitoring of patients are conducted.
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Tumor de Células Gigantes de Bainha Tendinosa , Avaliação de Risco e Mitigação , Adulto , Aminopiridinas/uso terapêutico , Tumor de Células Gigantes de Bainha Tendinosa/tratamento farmacológico , Humanos , Pirróis/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
Aim: Pexidartinib was approved for the treatment of tenosynovial giant cell tumors with a required Risk Evaluation and Mitigation Strategy (REMS) to ensure its safe use. As required by the REMS, a survey was conducted to document the knowledge, attitudes and behavior (KAB) of patients/caregivers and healthcare providers (HCPs) regarding the risk of serious and potentially fatal liver injury due to pexidartinib, the need for liver testing prior to and during treatment and the need for patient counseling about this risk. Patients & methods: The KAB survey was conducted among 40 patients and 18 HCPs enrolled in the pexidartinib REMS. Results: Among patients, 87.5% demonstrated understanding of key risk message (KRM) 1 (risk of serious liver injury), 87.5% demonstrated understanding of KRM2 (liver testing requirement) and 77.5% demonstrated understanding of both KRMs. Among HCPs, 83.3% demonstrated understanding of KRM1, 88.9% demonstrated understanding of KRM2, 100% demonstrated understanding of KRM3 (patient counseling) and 83.3% demonstrated understanding of all three KRMs. Conclusion: The KAB surveys demonstrated that the educational goals of the pexidartinib REMS were being achieved.
Lay abstract Pexidartinib is a prescription medicine used to treat adults who have a tenosynovial giant cell tumor that is not likely to improve with surgery. Because of the risk of serious liver problems, pexidartinib is available only through a restricted program called a Risk Evaluation and Mitigation Strategy (REMS) that enrolls both patients and healthcare providers (HCPs). As part of the REMS, information is collected about their knowledge, attitudes and behavior (KAB) regarding the potential for pexidartinib to cause liver problems that may be severe and can lead to death. This KAB survey was conducted among 40 patients and 18 HCPs enrolled in the pexidartinib REMS. The results indicated that among patients, over three-quarters demonstrated understanding of the risk of serious liver injury and the need for regular liver testing. Among HCPs, 83.3100% demonstrated understanding of the risk of serious liver injury, the need for regular liver testing and the requirement to counsel their patients about this risk. In conclusion, the KAB surveys demonstrated that the educational goals of the pexidartinib REMS were being achieved.
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Cuidadores , Conhecimentos, Atitudes e Prática em Saúde , Aminopiridinas , Pessoal de Saúde , Humanos , PirróisRESUMO
BACKGROUND: IK is a splicing factor that promotes spliceosome activation and contributes to pre-mRNA splicing. Although the molecular mechanism of IK has been previously reported in vitro, the physiological role of IK has not been fully understood in any animal model. Here, we generate an ik knock-out (KO) zebrafish using the CRISPR/Cas9 system to investigate the physiological roles of IK in vivo. RESULTS: The ik KO embryos display severe pleiotropic phenotypes, implying an essential role of IK in embryonic development in vertebrates. RNA-seq analysis reveals downregulation of genes involved in skeletal muscle differentiation in ik KO embryos, and there exist genes having improper pre-mRNA splicing among downregulated genes. The ik KO embryos display impaired neuromuscular junction (NMJ) and fast-twitch muscle development. Depletion of ik reduces myod1 expression and upregulates pax7a, preventing normal fast muscle development in a non-cell-autonomous manner. Moreover, when differentiation is induced in IK-depleted C2C12 myoblasts, myoblasts show a reduced ability to form myotubes. However, inhibition of IK does not influence either muscle cell proliferation or apoptosis in zebrafish and C2C12 cells. CONCLUSION: This study provides that the splicing factor IK contributes to normal skeletal muscle development in vivo and myogenic differentiation in vitro.
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Citocinas/genética , Músculo Esquelético/embriologia , Fatores de Processamento de RNA/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Citocinas/metabolismo , Embrião não Mamífero/embriologia , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário , Fatores de Processamento de RNA/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismoRESUMO
Excessive alcohol consumption causes the cellular and tissue damage. The toxic metabolites of ethanol are harmful to multiple organ systems, such as the central nervous system, skeletal muscles, and liver, and cause alcohol-induced diseases like cancer, as well as induce hepatotoxicity, and alcoholic myopathy. Alcohol exposure leads to a surge in hepatic alcohol metabolism and oxygen consumption, a decrease in hepatic ATP, and the rapid accumulation of lipid within hepatocytes. Several pathologies are closely linked to defective mitochondrial dynamics triggered by abnormal mitochondrial function and cellular homeostasis, raising the possibility that novel drugs targeting mitochondrial dynamics may have therapeutic potential in restoring cellular homeostasis in ethanol-induced hepatotoxicity. Rutin is a phytochemical polyphenol known to protect cells from cytotoxic chemicals. We investigated the effects of rutin on mitochondrial dynamics induced by ethanol. We found that rutin enhances mitochondrial dynamics by suppressing mitochondrial fission and restoring the balance of the mitochondrial dynamics. Mitochondrial elongation following rutin treatment of ethanol exposed cells was accompanied by reduced DRP1 expression. These data suggest that rutin plays an important role in remodeling of mitochondrial dynamics to alleviate hepatic steatosis and enhance mitochondrial function and cell viability.
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PURPOSE: This analysis evaluated the relationship between concentrations of quizartinib and its active metabolite AC886 and QT interval corrected using Fridericia's formula (QTcF) in patients with relapsed/refractory acute myeloid leukemia (AML) treated in the phase 3 QuANTUM-R study (NCT02039726). METHODS: The analysis dataset included 226 patients with AML. Quizartinib dihydrochloride was administered as daily doses of 20, 30, and 60 mg. Nonlinear mixed-effects modeling was performed using observed quizartinib and AC886 concentrations and time-matched mean electrocardiogram measurements. RESULTS: Observed QTcF increased with quizartinib and AC886 concentrations; the relationship was best described by a nonlinear maximum effect (Emax) model. The predicted mean increase in QTcF at the maximum concentration of quizartinib and AC886 associated with 60 mg/day was 21.1 ms (90% CI, 18.3-23.6 ms). Age, body weight, sex, race, baseline QTcF, QT-prolonging drug use, hypomagnesemia, and hypocalcemia were not significant predictors of QTcF. Hypokalemia (serum potassium < 3.5 mmol/L) was a statistically significant covariate affecting baseline QTcF, but no differences in ∆QTcF (change in QTcF from baseline) were predicted between patients with versus without hypokalemia at the same quizartinib concentration. The use of concomitant QT-prolonging drugs did not increase QTcF further. CONCLUSION: QTcF increase was dependent on quizartinib and AC886 concentrations, but patient factors, including sex and age, did not affect the concentration-QTcF relationship. Because concomitant strong cytochrome P450 3A (CYP3A) inhibitor use significantly increases quizartinib concentration, these results support the clinical recommendation of quizartinib dose reduction in patients concurrently receiving a strong CYP3A inhibitor. CLINICAL TRIAL REGISTRATION: NCT02039726 (registered January 20, 2014).
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Benzotiazóis/farmacologia , Eletrocardiografia/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzotiazóis/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/uso terapêuticoRESUMO
BACKGROUND: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib. MATERIALS, AND METHODS: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. RESULTS: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. CONCLUSION: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. IMPLICATIONS FOR PRACTICE: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.
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Doença Hepática Induzida por Substâncias e Drogas , Tumor de Células Gigantes de Bainha Tendinosa , Aminopiridinas , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Humanos , Fígado , PirróisRESUMO
Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (Cmax ) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure.
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Benzotiazóis/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Benzotiazóis/administração & dosagem , Benzotiazóis/metabolismo , Superfície Corporal , Ensaios Clínicos como Assunto , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/metabolismo , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidoresRESUMO
BACKGROUND: Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents. OBJECTIVES: This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. RESULTS: Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI: 0.73 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups. CONCLUSIONS: Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.
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Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Embolia/etiologia , Embolia/prevenção & controle , Inibidores do Fator Xa/uso terapêutico , Hepatopatias/complicações , Piridinas/uso terapêutico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Varfarina/uso terapêutico , Idoso , Anticoagulantes/farmacologia , Método Duplo-Cego , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/farmacologia , Tiazóis/farmacologia , Resultado do Tratamento , Varfarina/farmacologiaRESUMO
We isolated isobavachalcone (IBC) from Angelica keiskei (AK) as an anti-obesity component. IBC dose-dependently inhibited 3T3-L1 adipocyte differentiation by down-regulating adipogenic factors. At the mitotic clonal expansion stage (MCE), IBC caused cell cycle arrest in G0/G1 with decreased expression of cell cycle-regulating proteins. IBC also inhibited autophagic flux by inducing intracellular accumulation of LC3B and SQSTM1/p62 proteins while decreasing expression levels of regulating factors for autophagy initiation. In parallel with the inhibition of adipocyte differentiation, IBC decreased intrahepatic fat deposits and rescued the liver steatosis in high fat cholesterol diet-fed zebrafish. In this study, we found that IBC isolated from AK suppresses mitotic clonal expansion and autophagy flux of adipocytes and also shows anti-obesity activity in a high cholesterol-diet zebrafish model by decreasing intrahepatic fat deposits. These results suggest that IBC could be a leading pharmacological compound for the development of anti-obesity drugs.
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Adipogenia/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Chalconas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Angelica/química , Animais , Fármacos Antiobesidade/química , Ciclo Celular/efeitos dos fármacos , Chalconas/química , Camundongos , Peixe-ZebraRESUMO
BACKGROUND: The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction) compared higher-dose edoxaban regimen (HD-ER) and lower-dose edoxaban regimen with well-managed warfarin in 21 105 patients with atrial fibrillation. The risk factors and clinical impact of gastrointestinal bleeding (GIB) in this trial have not been described in detail. METHODS AND RESULTS: This analysis was undertaken to identify risk factors for major GIB (MGIB) and compare the severity and outcomes of GIB with edoxaban and warfarin. During 2.8 years mean follow-up, there were 579 MGIB (1.22% per year), of which 63 were life-threatening or fatal (0.13% per year). Male sex, increased age, prior GIB, concomitant aspirin, lower baseline hemoglobin, renal dysfunction, and higher HAS-BLED and CHADS2 scores were independently associated with the risk of MGIB. Whereas the annual rate of MGIB was higher with HD-ER than with warfarin (1.53% and 1.25%, respectively; hazard ratio, 1.23; 95% confidence interval, 1.02-1.48; P=0.033), the annual rates of life-threatening or fatal GIB were similar (0.15% and 0.18%, respectively). Several indicators of more severe GIB, including hemodynamic instability, hospitalization, ≥ 4 U transfusion, and hemoglobin loss ≥5 g/dL, were similar with HD-ER and warfarin, whereas surgery required to manage bleeding was less frequent with HD-ER. Lower-dose edoxaban regimen, which achieved 50% lower trough edoxaban levels, was associated with significantly less MGIB than warfarin. CONCLUSIONS: MGIB occurred more frequently with HD-ER than warfarin. The rates of life-threatening or fatal GIB were low and similar with both HD-ER and warfarin. Clinical outcomes were generally favorable. The correlation between dose, trough edoxaban level, and the risk of GIB risk suggests GIB is exposure-related. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.
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Anticoagulantes/efeitos adversos , Fibrilação Atrial/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/efeitos adversos , Hemorragia Gastrointestinal/induzido quimicamente , Piridinas/efeitos adversos , Tiazóis/efeitos adversos , Varfarina/efeitos adversos , Idoso , Anticoagulantes/administração & dosagem , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/mortalidade , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Feminino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/mortalidade , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Tiazóis/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Varfarina/administração & dosagemRESUMO
BACKGROUND: Anticoagulation is often avoided in patients with atrial fibrillation who are at an increased risk of falling. OBJECTIVES: This study assessed the relative efficacy and safety of edoxaban versus warfarin in the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial in patients with atrial fibrillation judged to be at increased risk of falling. METHODS: We performed a pre-specified analysis of the ENGAGE AF-TIMI 48, comparing patients with versus without increased risk of falling. RESULTS: Nine hundred patients (4.3%) were judged to be at increased risk of falling. These patients were older (median, 77 vs. 72 years; p < 0.001), and had a higher prevalence of comorbidities including prior stroke/transient ischemic attack, diabetes, and coronary artery disease. After multivariable adjustment, patients at increased risk of falling experienced more bone fractures caused by falling (adjusted hazard ratio [HRadj]: 1.88; 95% confidence interval [CI]: 1.49 to 2.38; p < 0.001), major bleeding (HRadj: 1.30; 95% CI: 1.04 to 1.64; p = 0.023), life-threatening bleeding (HRadj: 1.67; 95% CI: 1.11 to 2.50; p = 0.013), and all-cause death (HRadj: 1.45; 95% CI: 1.23 to 1.70; p < 0.001), but not ischemic events including stroke/systemic embolic event (HRadj: 1.16; 95% CI: 0.89 to 1.51; p = 0.27). No treatment interaction was observed between either dosing regimens of edoxaban and warfarin for the efficacy and safety outcomes. Treatment with edoxaban resulted in a greater absolute risk reduction in severe bleeding events and all-cause mortality compared with warfarin. CONCLUSIONS: Edoxaban is an attractive alternative to warfarin in patients at increased risk of falling, because it is associated with an even greater absolute reduction in severe bleeding events and mortality. (Effective aNticaoGulation with factor xA next Generation in Atrial Fibrillation [ENGAGE AF-TIMI 48]; NCT00781391).
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Acidentes por Quedas/estatística & dados numéricos , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Inibidores do Fator Xa/uso terapêutico , Piridinas/uso terapêutico , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Varfarina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Método Simples-CegoRESUMO
This study was performed to evaluate the protective effects of fucoidan against the decreased function of primary cultured bovine brain microvessel endothelial cells (BBMECs) after exposure to diesel exhaust particles (DEPs). BBMECs were extracted from bovine brains and cultured until confluent. To evaluate the function of BBMECs, we performed a permeability test using cell-by-cell equipment and by Western blot analysis for zonular occludens-1 (ZO-1), which is a tight junction protein of BMECs, and evaluated oxidative stress in BBMECs using the DCFH-DA assay and the CUPRAC-BCS assay. The increased oxidative stress in BBMECs following DEP exposure was suppressed by fucoidan. In addition, permeability of BBMECs induced by DEP exposure was decreased by fucoidan treatment. Our results showed that fucoidan protects against BBMEC disruption induced by DEP exposure. This study provides evidence that fucoidan might protect the central nervous system (CNS) against DEP exposure.
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Encéfalo/irrigação sanguínea , Células Endoteliais/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Phaeophyceae/química , Extratos Vegetais/farmacologia , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Alga Marinha/química , Emissões de Veículos/toxicidade , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Microvasos/citologia , Microvasos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Polissacarídeos/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
Edoxaban is a once-daily direct oral anticoagulant (DOAC). The Hokusai-VTE study revealed that, after initial treatment with heparin, edoxaban was non-inferior to and safer than vitamin K antagonists (VKA) in the prevention of recurrent deep-vein thrombosis and pulmonary embolism. This is the first report on the clinical relevance and management of bleeding events with edoxaban. All major bleeding events were classified blindly by three study-independent adjudicators. Pre-defined criteria were used to classify severity of clinical presentation and, separately, the clinical course and outcome into four categories. Major bleeding occurred in 56 patients treated with edoxaban and 65 patients treated with VKA. The severest categories (3 or 4) of the clinical presentation were assigned to 46 % of the major bleeding episodes in edoxaban recipients versus 58 % of the major bleeds in VKA recipients (odds ratio [OR] 0.62, 95 % confidence interval [CI] 0.30-1.27, p = 0.19). Clinical course was classified as severe (category 3 or 4) in 23 % of the edoxaban and 29 % of the VKA associated bleeds (OR 0.73, 95 % CI 0.32-1.66, p = 0.46). In conclusion, edoxaban associated major bleeding events have a comparable clinical presentation and course to major bleeds with VKA in patients treated for venous thromboembolism in the Hokusai-VTE study. These results may assure physicians that it is safe to prescribe this medication. If a major bleeding during edoxaban treatment occurs, its clinical presentation and clinical course are not worse than in VKA-treated patients.
Assuntos
Anticoagulantes/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Hemorragia/etiologia , Piridinas/administração & dosagem , Tiazóis/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Vitamina K/antagonistas & inibidores , Varfarina/administração & dosagem , Administração Oral , Anticoagulantes/efeitos adversos , Método Duplo-Cego , Inibidores do Fator Xa/efeitos adversos , Hemorragia/classificação , Hemorragia/terapia , Humanos , Piridinas/efeitos adversos , Fatores de Risco , Tiazóis/efeitos adversos , Varfarina/efeitos adversosRESUMO
A major constituent of urban air pollution is diesel exhaust, a complex mixture of gases, chemicals, and particles. Recent evidence suggests that exposure to air pollution can increase the risk of a fatal stroke, cause cerebrovascular damage, and induce neuroinflammation and oxidative stress that may trigger neurodegenerative diseases, such as Parkinson's disease. The specific aim of this study was to determine whether ultrafine diesel exhaust particles (DEPs), the particle component of exhaust from diesel engines, can induce oxidative stress and effect dopamine metabolism in PC-12 cells. After 24 h exposure to DEPs of 200 nm or smaller, cell viability, ROS and nitric oxide (NO(2)) generation, and levels of dopamine (DA) and its metabolites, (dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)), were evaluated. Results indicated cell viability was not significantly changed by DEP exposure. However, ROS showed dramatic dose-dependent changes after DEP exposure (2.4 fold increase compared to control at 200 µg/mL). NO(2) levels were also dose-dependently increased after DEP exposure. Although not in a dose-dependent manner, upon DEP exposure, intracellular DA levels were increased while DOPAC and HVA levels decreased when compared to control. Results suggest that ultrafine DEPs lead to dopamine accumulation in the cytoplasm of PC-12 cells, possibly contributing to ROS formation. Further studies are warranted to elucidate this mechanism.
Assuntos
Poluentes Atmosféricos/toxicidade , Dopamina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Emissões de Veículos/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , L-Lactato Desidrogenase/metabolismo , Nitratos/metabolismo , Células PC12 , Tamanho da Partícula , Ratos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Two cell-binding domains from FGF-2 (fibroblast growth factor-2) were shown to increase cell attachment and osteoblastic differentiation. Two synthetic peptides derived from FGF-2, namely residues 36-41 (F36; PDGRVD) and 77-83 (F77; KEDGRLL), were prepared and their N-termini further modified for ease of surface immobilization. Chitosan membranes were used in the present study as mechanical supportive biomaterials for peptide immobilization. Peptides could be stably immobilized on to the surface of chitosan membranes. The adhesion of mesenchymal stem cells to the peptide (F36 and F77)-immobilized chitosan membrane was increased in a dose-dependent manner and completely inhibited by soluble RGD (Arg-Gly-Asp) and anti-integrin antibody, indicating the existence of an interaction between F36/F77 and integrin. Peptide-immobilized chitosan supported human bone-marrow-derived mesenchymal-stem-cell differentiation into osteoblastic cells, as demonstrated by alkaline phosphate expression and mineralization. Taken together, the identified peptide-immobilized chitosan membranes were able to support cell adhesion and osteoblastic differentiation; thus these peptides might be useful as bioactive agents for osteoblastic differentiation and surface-modification tools in bone regenerative therapy.
Assuntos
Diferenciação Celular , Quitosana/metabolismo , Proteínas Imobilizadas/farmacologia , Células-Tronco Mesenquimais/citologia , Oligopeptídeos/metabolismo , Osteoblastos/citologia , Osteogênese , Sequência de Aminoácidos , Análise de Variância , Adesão Celular/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Humanos , Proteínas Imobilizadas/genética , Proteínas Imobilizadas/metabolismo , Integrinas/antagonistas & inibidores , Integrinas/metabolismo , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/ultraestrutura , Microscopia Confocal , Dados de Sequência Molecular , Oligopeptídeos/farmacologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Alinhamento de SequênciaRESUMO
BACKGROUND: Some differences exist among various Hepatitis B virus (HBV) DNA quantification assays due to lack of standardization and besides clinical usefulness has not been firmly elucidated in Korean HBV patients. METHODS: We compared Bayer VERSANT HBV DNA 3.0 Assay (VERSANT 3.0) with Digene Hybrid Capture II HBV DNA Test (HC-II) according to HBeAg status and ALT levels in 232 HBV-infected Korean patients. One hundred and seventeen sera with undetectable DNA levels by HC-II were further analyzed by Real-Q HBV quantification assay (BioSewoom). RESULTS: Although VERSANT 3.0 and HC-II showed an excellent correlation (r=0.9739), the results (copies/mL) by VERSANT 3.0 were 0.45 log(10) higher than those by HC-II. HBV DNA levels were higher in HBeAg-positive group than in HBeAg-negative group (P=0.002), and in abnormal ALT group than in normal ALT group (P<0.0001). The detection rate of HBV DNA by VERSANT 3.0 was lower in HBeAg-negative and normal ALT group (n=68) than in HBeAg-positive or abnormal ALT group (n=164) (35.3% vs 89.6%, P<0.0001). Fifty two sera out of 61 sera with undetectable DNA by VERSANT 3.0 were measurable by Real-Q with mean value of 3.26 log(10) copies/mL. CONCLUSIONS: VERSANT 3.0 and HC-II showed an excellent correlation, but a little difference (0.45 log10) existed. VERSANT 3.0 effectively measured clinically relevant HBV DNA levels in most HBV-infected patients in Korea. However, more sensitive assays are needed for patients with negative HBeAg and normal ALT to see the low copies of HBV DNA levels.
Assuntos
DNA Viral/análise , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/diagnóstico , Hibridização de Ácido Nucleico/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , DNA Viral/genética , Interpretação Estatística de Dados , Feminino , Antígenos E da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Análise de Regressão , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Fibroblast growth factor (FGF)-2 regulates a variety of cellular functions, such as proliferation and differentiation, by binding to cell surface FGF receptors (FGFRs) in the presence of heparin proteoglycans. FGF-2 is known as a heparin-binding growth factor, but the localization of the heparin binding site has not been fully investigated until now. We used two potential heparin binding domains of FGF-2, the residues 105-111 (F105, YKRSRYT) and 119-135 (F119, KRTGQYKLGSKTGPGQK). Peptides could be stably immobilized onto the surface of tissue culture plates. Using solid phase binding assays, we demonstrated that both peptides had higher binding affinity toward heparin compared with nonbinding control sequence. The biological significance of these sites was tested by cell attachment and osteoblast differentiation studies. Cell attachment to the peptides F105 and F119 increased in a dose-dependent manner. Heparin and heparinase treatments decreased cell adhesion to both F105 and F119. This demonstrates that both F105 and F119 interact with cell-surface heparan sulfate proteoglycans, suggesting that FGF-2 has two heparin binding sites. In addition, osteoblast differentiation, confirmed by ALPase activity and mineralization, was increased by surface immobilized peptide F105 and F119. Taken together, these heparin binding peptides could be applied as biological agents enhancing osteoblast differentiation as well as surface modification tools in the tissue regeneration area, especially for bone regeneration.