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1.
Medicine (Baltimore) ; 98(50): e18331, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31852127

RESUMO

This study assessed sex differences in cardiac and motor functions, quality of life (QoL), and mental status in Chinese chronic heart failure (CHF) patients after metoprolol treatment.This single-center prospective study, conducted from February 2013 to April 2016, included CHF patients (men and women) with resting heart rate (HR) >80 beats/min using metoprolol continuous release tablets. Metoprolol-induced changes in cardiac and motor functions, QoL, and mental status at 1, 3, 6, 9, and 12 months from baseline, within and between the sexes, were analyzed. Descriptive data were represented as counts, percentages, and mean ± standard deviation. Differences at various follow-up periods were compared using repeated measures one-way analysis of variance, followed by post hoc Dunnett's multiple comparison test. Statistical significance was considered at P < .05.Compared with men, women reported significantly higher systolic blood pressure (SBP) (122.28 ±â€Š6.76 vs 125.47 ±â€Š6.67 mm Hg, P < .05) and Veterans Specific Activity Questionnaire score (8.16 ±â€Š0.98 vs 8.47 ±â€Š0.89, P = .05) at 12 months. Men reported higher Hospital Anxiety and Depression Scale scores for depression than women at 1 month (10.27 vs 8.83, P < .05) and for anxiety at 12 months (8.4 vs 7.72, P < .05). Metoprolol significantly decreased HR and Minnesota Living with Heart Failure Questionnaire score in men (64.5 ±â€Š3.13 and 53.7 ±â€Š8.00) and women (65.38 ±â€Š3.32 and 53.85 ±â€Š8.42, respectively). Ejection fraction (%, men: 50.00 ±â€Š4.45, women: 50.72 ±â€Š4.09), cardiac index (L/min/m, men: 2.70 ±â€Š0.25, women: 2.78 ±â€Š0.23), 6-minute walk test distance (m, men: 414.41 ±â€Š20.84, women: 420.34 ±â€Š20.35), and short form-8 questionnaire scores (men: 52.05 ±â€Š1.94, women: 52.19 ±â€Š2.58) increased significantly in both the sexes (P < .001 for all) at 12 months. Copenhagen Burnout Inventory score significantly increased in men (mean score 62.43, P < .05).Metoprolol treatment improves cardiac and motor functions, QoL, and anxiety scores but causes greater depression and burnout in men and women. Sex was seen to affect mental status of CHF patients the most.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/psicologia , Metoprolol/uso terapêutico , Qualidade de Vida , Fatores Sexuais , Adulto , Idoso , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Grupo com Ancestrais do Continente Asiático/psicologia , China , Doença Crônica , Depressão/tratamento farmacológico , Depressão/etiologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento
2.
N Engl J Med ; 381(24): 2304-2314, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31633896

RESUMO

BACKGROUND: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials. METHODS: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol. RESULTS: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group. CONCLUSIONS: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Metoprolol/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Volume Expiratório Forçado , Hospitalização/estatística & dados numéricos , Humanos , Estimativa de Kaplan-Meier , Masculino , Metoprolol/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Falha de Tratamento
3.
Anticancer Res ; 39(10): 5703-5707, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570470

RESUMO

BACKGROUND/AIM: Anthracyclines, such as doxorubicin, though widely used in anticancer therapy, they are associated with cardiotoxic side-effects. The aim of this trial was to investigate long-term follow-up cardiotoxicity findings in patients treated with doxorubicin and concomitant metoprolol or enalapril 10 years earlier. PATIENTS AND METHODS: Overall, 147 patients were randomized into the treatment arms. A total of 125 patients treated with doxorubicin without evidence of heart disease at the start of chemotherapy were analyzed. They were followed-up for up to 10 years after treatment start. RESULTS AND CONCLUSION: A total of 47 patients completed the follow-up and 21 patients died, none due to cardiotoxicity events. Clinical signs of heart failure were not seen in any patients and no statistically significant differences between baseline and 10-year findings were seen for echocardiographic variables. No evidence of long-term cardiotoxicity was seen and nor metoprolol or enalapril offered an additional benefit.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Enalapril/uso terapêutico , Linfoma/tratamento farmacológico , Metoprolol/uso terapêutico , Adolescente , Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Cardiotoxicidade/etiologia , Doxorrubicina/uso terapêutico , Ecocardiografia/métodos , Feminino , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos
4.
Med Arch ; 73(2): 72-75, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31391690

RESUMO

Introduction: The most appropriate choice of pharmacological treatment of heart rhythm disorders occurring in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidity is often a topic of debate between pulmonologists and cardiologists in clinical practice, although numerous studies and clinical trials have demonstrated evidence to support the use of selective beta-blockers (BBs) in these patients. Aim: To examine the difference in the number of exacerbations in patients treated with a combination of verapamil and digoxin or BB alone in patients with different COPD stages. Patients and methods: The study included 68 patients (n = 68) diagnosed with COPD who were followed-up during a 12-month period, and the number of exacerbations were analyzed. The patients were divided into two groups according to the stage of COPD: GOLD II (moderate), and GOLD III (severe), and in each group a subdivision was established in relation to the use of either a combination of verapamil and digoxin or the use of BBs alone in pharmacological treatment. The inclusion criteria for patients were defined as following: a) established diagnosis of COPD according to present or deteriorated relevant clinical symptoms and signs, b) the ejection fraction (EF) of a left ventricle (LV) >35%, and c) spirometric cut-points classified as GOLD II (FEV1 / FVC <0.7, FEV1 predicted 50-80%), or GOLD III (FEV1/FVC <0.7, FEV1 predicted 30-50%) stage of the COPD. The exclusion criteria were EF of LV <35% and a lethal outcome during a follow-up period (2 patients were encountered). Exacerbation was defined as functional deterioration of the COPD symptoms verified by spirometric functional testing, frequency of hospitalizations according to GOLD stage assignment or verified clinical symptoms deterioration. Results: Regardless the pharmacological treatment, there is a statistically significant increase in the number of COPD exacerbations, in a 12-month period follow-up, in the GOLD III group (severe) compared to the GOLD II group (moderate). In the group of patients taking verapamil and digoxin, a two-tailed t-test was used to analyze the results between the GOLD II and GOLD III stage groups, p = 0.01, and 2. In the group of patients taking BBs, a two-tailed t-test was also used to analyze the results between the GOLD II and GOLD III stage groups, p = 0.003). Within the COPD GOLD II stage group, there appears to be no statistically significant difference in the number of exacerbations between the patients taking verapamil and digoxin (n = 24) and the patients taking BBs alone (n = 15), although, in patients taking BBs alone, there appears to be a trend towards a decrease in the exacerbations compared to the number of exacerbations in patients taking verapamil and digoxin (p = 0.007). Within the COPD GOLD III stage group, there is no difference in the number of exacerbations between the patients taking verapamil and digoxin (n = 20), and the patients taking BBs alone (n = 9), as analyzed by a two-tailed t-test, p = 0.577. Conclusion: Use of selective BBs in the treatment of cardiovascular comorbidity in patients with COPD represents a far better choice of pharmacological approach in the treatment of patients diagnosed with COPD GOLD II (moderate) stage.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Arritmias Cardíacas/epidemiologia , Bisoprolol/uso terapêutico , Estudos de Casos e Controles , Digoxina/uso terapêutico , Progressão da Doença , Volume Expiratório Forçado , Humanos , Metoprolol/uso terapêutico , Nebivolol/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Índice de Gravidade de Doença , Verapamil/uso terapêutico , Capacidade Vital
5.
Int Immunopharmacol ; 74: 105733, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288151

RESUMO

INTRODUCTION: Takotsubo syndrome (TS) is an acute cardiac syndrome that mimics acute coronary syndrome (ACS) but lacks coronary obstruction and is associated with sudden physical or psychiatric episodes. Several hypotheses have been proposed for the TS mechanism, but the precise cause of this syndrome remains poorly known. Recent studies noted TS patients with acute endogenous catecholamine discharge, which could trigger an oxidative stress response and inflammatory action. METHODS: A single dose of the selective ß-adrenergic agonist isoprenaline (ISO) was used to induce a takotsubo-like (TS-like) model. Different icariin or metoprolol doses were supplied as cardioprotective agents by intragastric administration (IG), and lipopolysaccharides (LPS) were assessed to investigate the possible mechanism of action of icariin. Transthoracic echocardiography was used to study cardiac function and morphology. The amounts of intracellular lipids and myocardial fibrosis, which represent the degree of cardiac impairment, were assessed by histological analysis. Real-time polymerase chain reaction (RT-PCR) was performed to analyze a variety of anti-oxidant elements and inflammatory factors, and Western blotting was conducted to analyze the expression of signaling pathway proteins involved in the development of TS. RESULTS: The TS-like incidence in rats was lowest with icariin precondition at 2-h post-ISO administration, and both the left ventricular ejection fraction (LVEF) and ejection volume per minute were higher than those of the other groups. However, LPS administration increased the incidence of TS and aggravated cardiac impairment. Moreover, ISO significantly increased the levels of both reactive oxygen species (ROS) and TLR4/NF-κB signaling pathway proteins compared to those of the Sha-group, whereas icariin remarkably decreased the ROS levels and increased anti-oxidant element expression while reducing pro-inflammatory factor secretion and suppressing TLR4/NF-κB signaling pathway protein expression. However, the cardioprotective effect of icariin was significantly weakened by combining treatment with LPS. CONCLUSION: Icariin prevented ISO-induced TS-like cardiac dysfunction in rats. The effects were induced mainly through maintenance of the dynamic balance of the ROS system, promotion of anti-oxidant element activity, and suppression of TLR4/NF-κB signaling pathway protein expression. Furthermore, the ability of icariin to increase anti-inflammatory and reduce pro-inflammatory factor secretion may be involved in the protective process.


Assuntos
Cardiotônicos/uso terapêutico , Flavonoides/uso terapêutico , Miocárdio/patologia , Cardiomiopatia de Takotsubo/tratamento farmacológico , Animais , Modelos Animais de Doenças , Ecocardiografia , Fibrose , Humanos , Isoproterenol , Masculino , Metoprolol/uso terapêutico , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/metabolismo
7.
Medicine (Baltimore) ; 98(27): e16183, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277123

RESUMO

RATIONALE: Apical hypertrophic cardiomyopathy (AHCM) is a rare form of hypertrophic cardiomyopathy which affects predominantly the apex of the left ventricle. Generally, left ventricular enlargement is not present in AHCM; additionally, endomyocardial fibrosis, and calcification are also rare. PATIENT CONCERNS: A 61-year-old female (Case 1) and a 60-year-old female (Case 2) both presented with the symptoms of atypical chest pain, dyspnoea, exercise intolerance, palpitations. DIAGNOSIS: Magnetic resonance and single-photon emission computed tomography (SPECT) revealed apical hypertrophic cardiomyopathy. Furthermore, 2D-transthoracic echocardiogram showed left atrium and ventricular enlargement, as well as endomyocardial fibrosis and calcification. Based on these findings, the patients were diagnosed with AHCM. INTERVENTIONS: Both the patients were treated with ACEI, metoprolol, and aspirin. Additionally, both these patient underwent genetic test. OUTCOMES: The results of the genetic test of the 2 cases for hypertrophic cardiomyopathy (HCM) were negative. However, the gene mutation for dilated cardiomyopathy (TMPO) was detected in one of the cases. No change in condition during follow-up. LESSONS: In past reports, Apical hypertrophic cardiomyopathy has been shown to have a benign prognosis. But in this case report, the imaging studies of the 2 patients suggest a poor prognosis. Furthermore, diagnosing cardiomyopathy should require multimodality imaging examinations to rule out differential diagnoses.


Assuntos
Calcinose/complicações , Cardiomiopatia Hipertrófica/complicações , Fibrose Endomiocárdica/complicações , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aspirina/uso terapêutico , Calcinose/diagnóstico por imagem , Calcinose/tratamento farmacológico , Calcinose/patologia , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/patologia , Ecocardiografia , Eletrocardiografia , Fibrose Endomiocárdica/diagnóstico por imagem , Fibrose Endomiocárdica/tratamento farmacológico , Feminino , Humanos , Imagem por Ressonância Magnética , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Tomografia Computadorizada de Emissão de Fóton Único
8.
Clin Lab ; 65(5)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31115220

RESUMO

BACKGROUND: CYP2D6*10 is mainly responsible for the large pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Asian patients. Utilizing an efficient method for identifying the CYP2D6*10 genotypes is clinically important for evaluating the pharmacokinetic effect of administration of metoprolol. This study attempted to evaluate the effectiveness of the two methods used to detect the rs1065852 and rs1135840 SNPs of the CYP2D6*10 gene. METHODS: Blood samples were processed for the collection of genomic DNA from 198 subjects across Chinese population, and detection of CYP2D6*10 (rs1065852 and rs1135840) was performed using the PyroMark Q24 pyrose-quencing and matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-TOF MS). The discordant results were further validated with Sanger sequencing. We eventually attempted to assess some features of these two methods including reliability, rapidness, being appropriate, and cost-effectiveness. RESULTS: Genotyping of rs1065852 and rs1135840 detected by MALDI-TOF MS were concordant with those identified by PyroMark Q24 pyrosequencing in all 198 (100%) individuals. The hands-on-time and the turnaround time were shorter in the PyroMark Q24 pyrosequencing method than in the MALDI-TOF MS method for SNP of CYP2D6*10. In terms of being cost-effective and high-throughput, the MALDI-TOF MS method outperformed the PyroMark Q24 pyrosequencing method. CONCLUSIONS: CYP2D6*10 genotypes detected by PyroMark Q24 pyrosequencing and MALDI-TOF-MS showed that both methods were reliable, rapid, appropriate, and cost-effective methods. These methods are valuable for clinical applications.


Assuntos
Citocromo P-450 CYP2D6/genética , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Polimorfismo de Nucleotídeo Único , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Idoso , Anti-Hipertensivos/sangue , Anti-Hipertensivos/metabolismo , Anti-Hipertensivos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , China , Análise Custo-Benefício , Citocromo P-450 CYP2D6/metabolismo , Feminino , Genótipo , Técnicas de Genotipagem/economia , Humanos , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Metoprolol/sangue , Metoprolol/metabolismo , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
9.
Biomed Pharmacother ; 115: 108900, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054510

RESUMO

BACKGROUND: Recently, the development of cardiovascular disease (CVD) has been proved to be closely associated with depression in which 5-HT plays a crucial role. Ginseng Fruit Saponin (GFS) and Metoprolol are two drugs which have beneficial effects on the cardiovascular system in Myocardial Infarction (MI) mice. However, their effects on depression-like behaviors after MI and its underlying mechanisms remain unknown. We aimed to investigate their antidepressive-like effects as well as their impacts on the 5-HT system. METHODS: The MI model was established by ligating left anterior descending coronary artery. Mice were administered with GFS, Metoprolol or saline for 4 weeks. Cardiac function was evaluated and depressive-like behaviors were quantified at the end of the experiments. Masson's staining was used to assess myocardial fibrosis while immunohistochemistry, western blot, ELISA and qPCR were performed to analyze the levels of 5-HT and its related genes. RESULTS: Compared with MI groups, Both GFS and Metoprolol treatments significantly improved cardiac function and reduced myocardial fibrosis. Moreover, GFS but not Metoprolol increased the levels of 5-HT in the cortex and rescued depression-like behaviors in MI mice. CONCLUSIONS: GFS has potential antidepressive effects and the mechanisms involve the regulation of 5-HT concentrations in the cortex.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Panax notoginseng/química , Saponinas/uso terapêutico , Serotonina/metabolismo , Animais , Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Frutas/química , Masculino , Metoprolol/administração & dosagem , Metoprolol/uso terapêutico , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/psicologia , Saponinas/administração & dosagem , Serotonina/sangue
10.
Neurology ; 93(2): e135-e142, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31127070

RESUMO

OBJECTIVE: To verify the previously reported association between long-term use of ß2-adrenoreceptor (ß2AR) agonist and antagonist with reduced and increased risk of Parkinson disease (PD), respectively. METHODS: We obtained odds ratios (ORs) associating time of ß2AR agonist and antagonist use with PD risk in nationwide Danish health registries. RESULTS: We included 2,790 patients with PD and 11,160 controls. Long-term ß2AR agonist use was associated with reduced PD risk (OR 0.57, 95% confidence interval [CI] 0.40-0.82) in this cohort. Unexpectedly, short-term ß2AR agonist use was equally associated (OR 0.64, 95% CI 0.42-0.98). Because ß2AR agonists are prescribed mostly for chronic obstructive pulmonary disease (COPD), often caused by long-term nicotine abuse, we analyzed other markers of smoking. Diagnosis of COPD (OR 0.51, 95% CI 0.37-0.69) and use of inhaled corticosteroids (OR 0.78, 95% CI 0.59-1.02) or inhaled anticholinergics (OR 0.41, 95% CI 0.25-0.67) were also inversely associated with PD. Increased PD risk was not found for all ß2AR antagonists but only for propranolol and metoprolol. Associations were markedly stronger for short-term than long-term use. CONCLUSION: We confirmed ß2AR agonist use to be associated with reduced PD risk and ß2AR antagonist use with increased PD risk. However, our data indicate the association of ß2AR agonists to be indirectly mediated by smoking, which is repeatedly associated with reduced risk of PD. The association of ß2AR antagonists indicates reverse causation, with PD symptoms triggering their prescription rather than ß2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between ß2AR agonists and antagonists and PD risk.


Assuntos
Agonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Doença de Parkinson/epidemiologia , Administração por Inalação , Corticosteroides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antagonistas Colinérgicos/uso terapêutico , Dinamarca/epidemiologia , Feminino , Humanos , Masculino , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Propranolol/uso terapêutico , Fatores de Proteção , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Sistema de Registros , Fatores de Risco , Fumar/epidemiologia
11.
Orphanet J Rare Dis ; 14(1): 105, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077250

RESUMO

BACKGROUND: X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the ß-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function. METHODS TRIAL DESIGN: Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting. INCLUSION CRITERIA: DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events. RESULTS: From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed. CONCLUSIONS: Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size. CLINICAL TRIAL REGISTRATION: DRKS-number 00000115, EudraCT-number 2009-009871-36.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Enalapril/uso terapêutico , Metoprolol/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Disfunção Ventricular Esquerda/prevenção & controle , Adolescente , Cardiomiopatias/prevenção & controle , Criança , Método Duplo-Cego , Enalapril/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Metoprolol/efeitos adversos , Resultado do Tratamento
12.
PLoS One ; 14(4): e0214740, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964911

RESUMO

Pulmonary hypertension (PH) increases the work of the right ventricle (RV) and causes right-sided heart failure. This study examined RV mitochondrial function and ADP transfer in PH animals advancing to right heart failure, and investigated a potential therapy with the specific ß1-adrenergic-blocker metoprolol. Adult Wistar rats (317 ± 4 g) were injected either with monocrotaline (MCT, 60 mg kg-1) to induce PH, or with an equivalent volume of saline for controls (CON). At three weeks post-injection the MCT rats began oral metoprolol (10 mg kg-1 day-1-) or placebo treatment until heart failure was observed in the MCT group. Mitochondrial function was then measured using high-resolution respirometry from permeabilised RV fibres. Relative to controls, MCT animals had impaired mitochondrial function but maintained coupling between myofibrillar ATPases and mitochondria, despite an increase in ADP diffusion distances. Cardiomyocytes from the RV of MCT rats were enlarged, primarily due to an increase in myofibrillar protein. The ratio of mitochondria per myofilament area was decreased in both MCT groups (p ≤ 0.05) in comparison to control (CON: 1.03 ± 0.04; MCT: 0.74 ± 0.04; MCT + BB: 0.74 ± 0.03). This not only implicates impaired energy production in PH, but also increases the diffusion distance for metabolites within the MCT cardiomyocytes, adding an additional hindrance to energy supply. Together, these changes may limit energy supply in MCT rat hearts, particularly at high cardiac workloads. Metoprolol treatment did not delay the onset of heart failure symptoms, improve mitochondrial function, or regress RV hypertrophy.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Metoprolol/farmacologia , Mitocôndrias/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Administração Oral , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Animais , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/prevenção & controle , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/tratamento farmacológico , Masculino , Metoprolol/uso terapêutico , Mitocôndrias/metabolismo , Monocrotalina/toxicidade , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miofibrilas/metabolismo , Miofibrilas/patologia , Fosforilação Oxidativa/efeitos dos fármacos , Efeito Placebo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
13.
Gene ; 703: 112-119, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-30965129

RESUMO

This study aims to investigate the different clinically relevant allele variants (allele frequencies) of CYP2D6 gene and to determine whether a specific genotype of CYP2D6 gene (based on genetic polymorphism "allelic types" and combination) have impact on metoprolol effectiveness (clinical outcome) in patients who have acute coronary syndrome (ACS). The study included 250 patients with ACS who were classified into 2 study groups, 125 patients received metoprolol and served as a study group (Group1) and 125 who received no metoprolol therapy (due to contraindication to the medication) and served as a control group (Group 2). Venous blood samples were taken from all participants for DNA extraction. Urine samples were also collected to assess the metabolic ratio using High-performance liquid chromatography (HPLC) technique. There was significant variation in the distribution of Iraqi patients with respect to CYP2D6 allelic polymorphism as compared to similar patients in other countries. Besides, this significant difference existed in patients' outcome in terms of morbidity and mortality in respect to variable genotypes and phenotypes. We recommend a dose individualization of metoprolol in patients with ACS is essential to improve patients' outcome.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Antiarrítmicos/uso terapêutico , Citocromo P-450 CYP2D6/genética , Metoprolol/uso terapêutico , Variantes Farmacogenômicos , Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/urina , Adulto , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Feminino , Frequência do Gene , Humanos , Iraque , Masculino , Metoprolol/farmacocinética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento
14.
Medicine (Baltimore) ; 98(12): e14676, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30896616

RESUMO

RATIONALE: Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in genes encoding sarcomeric proteins. One of the most commonly mutated HCM genes is the MYBPC3 gene. Mutations in this gene lead mainly to truncation of the protein, which gives rise to a relatively severe phenotype. Analyses of gene mutations associated with HCM are valuable for molecular diagnosis, genetic counseling, and management of familial HCM. PATIENT CONCERNS: A 12-year-old boy presented with palpitations and dyspnea after exercise for 1 year. Echocardiography showed myocardial asymmetric hypertrophy of the ventricular septum, the anterior wall, and the lateral wall of the left ventricle. The thickness of the interventricular septum was estimated to be 33 mm. ECG showed left ventricular high voltage and ST-T changes. He had been diagnosed with HCM 3 months previously. DIAGNOSES: Due to his clinical presentation, he was determined to have HCM via a molecular analysis, revealing compound heterozygotes (p.R597W and p.Q1012Sfs*8) in the MYBPC3 gene. INTERVENTIONS: The patient was prescribed metoprolol to slow the heart rate and increase diastolic filling time. OUTCOMES: The boy was treated with metoprolol 6.75 mg b.i.d. Approximately 3 months later, review of the echocardiography showed that the peak velocity across the LVOT dropped to 2.3 m/seconds and that the pressure gradient dropped to 21 mm Hg. LESSONS: A custom next-generation sequencing (NGS) technology for the HCM panel allowed us to identify compound heterozygous mutations in the MYBPC3 gene, confirming NGS as a molecular diagnostic tool.


Assuntos
Cardiomiopatia Hipertrófica Familiar/diagnóstico , Cardiomiopatia Hipertrófica Familiar/genética , Proteínas de Transporte/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Criança , China , Eletrocardiografia , Humanos , Masculino , Metoprolol/uso terapêutico
15.
BMJ Case Rep ; 12(2)2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30755424

RESUMO

Acute generalised exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction characterised by the appearance of erythematous plaques and papules with overlying non-follicular pinpoint pustules. Drugs are the cause of AGEP in approximately 90% of cases. The most common causes include anti-infective agents (aminopenicillins, quinolones, antibacterial sulfonamides and terbinafine), antimalarials and diltiazem. To the best of our knowledge, to date there has only been one report of hydrochlorothiazide-induced AGEP. There has never been a case report of losartan-induced AGEP. Here, we present a case of AGEP that is the second case purportedly caused by hydrochlorothiazide.


Assuntos
Pustulose Exantematosa Aguda Generalizada/patologia , Anti-Infecciosos/efeitos adversos , Oftalmopatias/tratamento farmacológico , Hidroclorotiazida/efeitos adversos , Impetigo/tratamento farmacológico , Pustulose Exantematosa Aguda Generalizada/tratamento farmacológico , Administração Tópica , Idoso de 80 Anos ou mais , Anti-Infecciosos/uso terapêutico , Betametasona/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Oftalmopatias/patologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Hidroclorotiazida/uso terapêutico , Impetigo/patologia , Metoprolol/uso terapêutico , Resultado do Tratamento
16.
Medicine (Baltimore) ; 98(4): e14252, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30681618

RESUMO

Psychological disorders, such as depression and anxiety, are known to be associated with chronic heart failure (CHF). The present study was conducted to evaluate the effect of mental status on quality of life (QoL) in metoprolol treated CHF patients with depression, anxiety, and burn-out.This single-center prospective study was conducted between February 2013 and April 2016, enrolled CHF patients (resting heart rate >80 bpm) with depression, anxiety, and burn out at baseline. Hospital anxiety and depression scale (HADS) and Copenhagen burnout inventory (CBI) were used to assess the depression-anxiety status and burn-out status, respectively. Change in QoL was evaluated as the endpoint at 1st, 3rd, 6th, and 12th month from baseline using Minnesota Living with Heart Failure Questionnaire (MLHFQ) and short form-8 (SF-8) scales. A student t test was used to determine the change and P value < .05 was considered statistically significant. One hundred fifty-four patients were enrolled (median age 66 years; 65.58% males) and divided into 8 groups based on the HADS and CBI scores at baseline. Overall, the mean SF8 score and MLHFQ scores in different mental status groups showed a significant improvement (P < .05) in QoL from baseline to 12th month, with no significant difference reported between the groups. With regard to the follow-up periods, there was a deterioration in QoL until 3rd month, after which there was a significant improvement (P < .05).There was a significant improvement in QoL in metoprolol treated CHF patients with depression, anxiety, and burn-out.


Assuntos
Antiarrítmicos/uso terapêutico , Ansiedade/etiologia , Depressão/etiologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/psicologia , Metoprolol/uso terapêutico , Qualidade de Vida/psicologia , Idoso , China , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento
17.
J Hypertens ; 37(1): 116-124, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29995697

RESUMO

AIM: Progression of chronic kidney disease (CKD) may be accelerated by tissue hypoxia due to impaired blood supply. This could be induced by small artery narrowing resulting in abnormally high intrarenal vascular resistance (RVR). We investigated whether a reduction in RVR achieved by adding vasodilating medical therapy (AVT) is superior to adding nonvasodilating medical therapy (AnonVT) regarding tissue oxygenation and preservation of kidney function. METHODS: Eighty-three grade 3 and 4 CKD patients [estimated glomerular filtration rate (GFR) 34.6 ml/min per 1.73 m] were randomized to either AVT with amlodipine and/or renin angiotensin blockade or AnonVT with the nonvasodilating beta-blocker metoprolol. Investigations were performed at baseline and after 18 months of therapy. Systemic vasodilation was documented in the forearm vasculature using resting venous occlusion plethysmography. GFR was measured as Chrome-EDTA plasma clearance. Using MRI, renal artery blood flow was measured for calculation of RVR and for estimating renal oxygenation (R2*). RESULTS: AVT and AnonVT achieved as planned similar blood pressure levels throughout the study. At follow-up, resistance had decreased by 7% (P < 0.05) and RVR by 12% (P < 0.05) in the AVT group, whereas in the AnonVT group, resistance increased by 39% (P < 0.01), whereas RVR remained unchanged. At follow-up, no significant differences in cortical or medullary R2* values between AVT and AnonVT were observed, and the GFR decline was similar in the two groups (3.0 vs. 3.3 ml/min per 1.73 m). CONCLUSION: Long-term intensified vasodilation treatment reduced peripheral and RVR, but this was not associated with improvement of R2* or protection against loss of kidney function in CKD patients.


Assuntos
Anti-Hipertensivos/uso terapêutico , Insuficiência Renal Crônica , Vasodilatadores/uso terapêutico , Anlodipino/uso terapêutico , Angiotensinas/uso terapêutico , Progressão da Doença , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Metoprolol/uso terapêutico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/fisiopatologia , Resistência Vascular
18.
Sleep Breath ; 23(1): 227-233, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29951886

RESUMO

PURPOSE: ß-Blocker use has been controversial for a long time in the management of hypertensive patients with obstructive sleep apnea (OSA). The aim of present study was to compare the effects of metoprolol on BP lowering with amlodipine in hypertensive OSA patients. METHODS: Hypertensive subjects with OSA were randomly assigned to metoprolol and amlodipine groups, receiving 12 weeks of oral either metoprolol (47.5 mg once daily) or amlodipine (5 mg once daily) treatment. At baseline and after the 12-week treatment period, 24-h ambulatory blood pressure monitoring was performed in both groups. RESULTS: Both of metoprolol and amlodipine treatments significantly lowered 24-h blood pressure (BP) (from 143/88 to 132.3/81.6 mmHg; from 141.3/84.5 to 133.7/80.8 mmHg), daytime BP (from 146/90.2 to 136.4/84.6 mmHg; from 145.1/87.6 to 138.2/84.1 mmHg), and nighttime BP (from 139.1/83.9 to 125.7/76.2 mmHg; from 134.5/78.5 to 125.8/74.1 mmHg) (all P < 0.05). But there were no significant differences between the groups in BP variability (P > 0.05). Besides, metoprolol significantly reduced daytime heart rate (HR) (P < 0.05), while 24-h and nighttime HR values had no remarkable changes compared with baseline (P > 0.05). CONCLUSIONS: Metoprolol had similar therapeutic effects on BP lowering as amlodipine and could not decrease HR during the nighttime in hypertensive patients with OSA.


Assuntos
Anlodipino/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Metoprolol/uso terapêutico , Apneia Obstrutiva do Sono/tratamento farmacológico , Administração Oral , Adulto , Idoso , Anlodipino/efeitos adversos , Monitorização Ambulatorial da Pressão Arterial , Estudos de Coortes , Comorbidade , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/complicações , Masculino , Metoprolol/efeitos adversos , Pessoa de Meia-Idade , Polissonografia , Estudos Prospectivos , Apneia Obstrutiva do Sono/complicações
20.
J Pharm Biomed Anal ; 164: 373-381, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30439665

RESUMO

BACKGROUND: Therapy-refractory arterial hypertension is defined as a blood pressure (BP) in a subset of patients who fail to achieve BP control despite a three-drug regimen (including a diuretic). Various factors have impact on loss of therapy response. Drug-drug-interactions (DDIs) may cause altered pharmacokinetics (PK) of antihypertensive drugs. Upregulation of activity and expression of cytochrome P450 (CYP) enzymes can result in decreased plasma drug levels. Besides these PK considerations a significant problem could be nonadherence to drug therapy. In this regard Therapeutic Drug Monitoring (TDM) is a useful tool for detecting nonadherence. Therefore a LC-MS/MS-method for determination of Metoprolol (MET), Amlodipine (AML), Canrenone (CAN) and Hydrochlorothiazide (HCT) was developed. METHODS: An UHPLC-MS/MS method was developed and validated for simultaneous determination of MET, AML, CAN and HCT in plasma matrix. Extraction of serum samples consisted of simple protein precipitation using acetonitrile. Stable isotope labeled analogues for each antihypertensive were obtained for internal standardization and quantitative analysis ([2H7]-MET, ([13C6]-AML, [2H4]-CAN, [13C6]-HCT). Calibrators and quality controls were prepared in plasma matrix of normal individuals. Sample preparation: protein precipitation with acetonitrile and addition of internal standard-mix. RESULTS: All analytes were eluted within a runtime of 2.5 min. Linearity experiments were demonstrated in plasma over following concentration ranges: MET: 5-750 µg/l, AML: 1-50 µg/l, CAN: 10-500 µg/l, HCT: 5-500 µg/l (R2 > 0.993). Chromatographic separation was achieved using a C18 column (50 × 2.1 mm, 1.9 µm particle size) and an isocratic elution. LC-MS/MS analyses were performed on a triple quadrupole mass spectrometer using positive and negative electrospray ionization in selected reaction monitoring (SRM) mode. Ion transitions monitored for quantitation were m/z 268.2 → 74.1 for MET, m/z 409.1 → 238.0 for AML, m/z 341.2 → 91.0 for CAN and m/z 296.0 → 205.1 for HCT. For all analytes, inter- and intra-day precision (CV, %) varied between 1.7 and 14.0 and inter- and intra-day accuracy values ranged from -2.5 to 7.1%. The lower limits of detection and quantification were: 0.08 and 0.23; 0.05 and 0.15; 2.82 and 8.54; and 0.02 and 0.05 µg/l for MET, AML, CAN and HCT, respectively. Results of stability experiments were within the required range of +/- 15%. CONCLUSIONS: Although the level of recommendation of TDM of antihypertensive drugs in patients with refractory hypertension is not yet established, the present LC-MS/MS-method can serve as an effective tool for detection of PK-alterations/nonadherence and may help to monitor antihypertensive pharmacotherapy.


Assuntos
Anti-Hipertensivos/sangue , Monitoramento de Medicamentos/métodos , Resistência a Medicamentos , Hipertensão/tratamento farmacológico , Anlodipino/sangue , Anlodipino/farmacocinética , Anlodipino/uso terapêutico , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/uso terapêutico , Canrenona/sangue , Canrenona/farmacocinética , Canrenona/uso terapêutico , Isótopos de Carbono , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Deutério , Monitoramento de Medicamentos/instrumentação , Humanos , Hidroclorotiazida/sangue , Hidroclorotiazida/farmacocinética , Hidroclorotiazida/uso terapêutico , Hipertensão/sangue , Hipertensão/patologia , Limite de Detecção , Masculino , Metoprolol/sangue , Metoprolol/farmacocinética , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/instrumentação , Espectrometria de Massas em Tandem/métodos
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