RESUMO
Heart failure (HF) is associated with disabling symptoms, poor quality of life, and a poor prognosis with substantial excess mortality in the years following diagnosis. Overactivation of the sympathetic nervous system is a key feature of the pathophysiology of HF and is an important driver of the process of adverse remodelling of the left ventricular wall that contributes to cardiac failure. Drugs which suppress the activity of the renin-angiotensin-aldosterone system, including ß-blockers, are foundation therapies for the management of heart failure with reduced ejection fraction (HFrEF) and despite a lack of specific outcomes trials, are also widely used by cardiologist in patients with HF with preserved ejection fraction (HFpEF). Today, expert opinion has moved away from recommending that treatment for HF should be guided solely by the LVEF and interventions should rather address signs and symptoms of HF (e.g. oedema and tachycardia), the severity of HF, and concomitant conditions. ß-blockers improve HF symptoms and functional status in HF and these agents have demonstrated improved survival, as well as a reduced risk of other important clinical outcomes such as hospitalisation for heart failure, in randomised, placebo-controlled outcomes trials. In HFpEF, ß-blockers are anti-ischemic and lower blood pressure and heart rate. Moreover, ß-blockers also reduce mortality in the setting of HF occurring alongside common comorbid conditions, such as diabetes, CKD (of any severity), and COPD. Higher doses of ß-blockers are associated with better clinical outcomes in populations with HF, so that ensuring adequate titration of therapy to their maximal (or maximally tolerated) doses is important for ensuring optimal outcomes for people with HF. In principle, a patient with HF could have combined treatment with a ß-blocker, renin-angiotensin-aldosterone system inhibitor/neprilysin inhibitor, mineralocorticoid receptor antagonist, and a SGLT2 inhibitor, according to tolerability.
Assuntos
Insuficiência Cardíaca , Humanos , Qualidade de Vida , Volume Sistólico , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/farmacologia , Sistema Renina-Angiotensina , Anti-Hipertensivos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêuticoRESUMO
Stress substantially increases the risk of developing painful temporomandibular disorders (TMDs) by influencing the release of endogenous catecholamines. Propranolol, an antagonist of ß-adrenergic receptors, has shown potential in alleviating TMD-associated pain, particularly when the level of catecholamines is elevated. The aim of this study was to explore whether intra-articular propranolol administration is effective in diminishing temporomandibular joint (TMJ) pain during repeated stress situations. Additionally, we investigated the effect of repeated stress on the expression of genes encoding ß-adrenoceptors in the trigeminal ganglion. In the present study, rats were exposed to a stress protocol induced by sound, then to the administration of formalin in the TMJ (to elicit a nociceptive response), followed immediately afterward by different doses of propranolol, after which the analgesic response to propranolol was evaluated. We also assessed the levels of beta-1 and beta-2 adrenergic receptor mRNAs (Adrb1 and Adrb2, respectively) using reverse transcription-quantitative PCR (RT-qPCR). Our findings revealed that propranolol administration reduces formalin-induced TMJ nociception more effectively in stressed rats than in non-stressed rats. Furthermore, repeated stress decreases the expression of the Adrb2 gene within the trigeminal ganglion. The findings of this study are noteworthy as they suggest that individuals with a chronic stress history might find potential benefits from ß-blockers in TMD treatment.
Assuntos
Propranolol , Articulação Temporomandibular , Ratos , Animais , Propranolol/efeitos adversos , Articulação Temporomandibular/metabolismo , Ratos Wistar , Dor , Catecolaminas/metabolismo , Catecolaminas/farmacologia , Catecolaminas/uso terapêutico , Formaldeído/efeitos adversos , Formaldeído/metabolismoRESUMO
Human performance enhancing drugs (PEDs), frequently used in sport competitions, are strictly prohibited by the World Anti-Doping Agency (WADA). Biological samples collected from athletes and regular patients are continuously tested regarding the identification and/or quantification of the banned substances. Current work is focused on the application of a new analytical method, molecularly imprinted nanoparticles (nanoMIPs), to detect and determine concentrations of certain prohibited drugs, such as ß-blockers, in water and human urine samples. These medications are used in the treatment of cardiovascular conditions, negative effects of adrenaline (helping to relief stress), and hypertension (slowing down the pulse and softening the arteries). They can also significantly increase muscle relaxation and improve heart efficiency. The new method of the detection and quantification of ß-blockers is based on synthesis, characterization, and implementation of nanoMIPs (so-called plastic antibodies). It offers numerous advantages over the traditional methods, including high binding capacity, affinity, and selectivity for target molecules. Additionally, the whole process is less complicated, cheaper, and better controlled. The size and shape of the nanoMIPs is evaluated by dynamic light scattering (DLS) and transmission electron microscope (TEM). The affinity and selectivity of the nanoparticles are investigated by competitive pseudo enzyme-linked immunosorbent assay (pseudo-ELISA) similar to common immunoassays employing natural antibodies. To provide reliable results towards either doping detection or therapeutic monitoring using the minimal invasive method, the qualitative and quantitative analysis of these drugs is performed in water and human urine samples. It is demonstrated that the assay can detect ß-blockers in water within the linear range 1 nmol·L-1-1 mmol·L-1 for atenolol with the detection limit 50.6 ng mL-1, and the linear range 1 mmol·L-1-10 mmol·L-1 for labetalol with the detection limit of 90.5 ng·mL-1. In human urine samples, the linear range is recorded in the concentration range 0.1 mmol·L-1-10 nmol·L-1 for atenolol and 1 mmol·L-1-10 nmol·L-1 for labetalol with a detection limit of 61.0 ng·mL-1 for atenolol and 99.4 ng·mL-1 for labetalol.
RESUMO
Fundamento: A cardiotoxicidade induzida por quimioterapia (CiC) é uma complicação importante entre os pacientes que recebem antraciclinas. Biomarcadores e parâmetros de imagem têm sido estudados por sua capacidade de identificar pacientes com risco de desenvolver essa complicação. O strain longitudinal global do ventrículo esquerdo (SLG-VE) tem sido descrito como um parâmetro sensível para detectar disfunção sistólica, mesmo na presença de fração de ejeção do ventrículo esquerdo (FEVE) preservada. Objetivo: avaliar o papel do SLG-VE como preditor de CiC. Métodos: O presente estudo consiste em uma análise post-hoc do estudo CECCY (Carvedilol for Prevention of ChemotherapyRelated Cardiotoxicity [Carvedilol para Prevenção da Cardiotoxicidade Relacionada à Quimioterapia]), que avaliou a prevenção primária de cardiotoxicidade com carvedilol durante quimioterapia com doxorrubicina em uma população com câncer de mama. Definiu-se cardiotoxicidade como uma redução >10% na FEVE. O SLG-VE foi obtido antes da quimioterapia em pacientes sem doença cardiovascular prévia ou anormalidades no ecocardiograma. Resultados: Trinta e um pacientes submetidos a estudo ecocardiográfico completo incluindo avaliação de SLG-VE antes da quimioterapia foram incluídos nesta análise. Um SLG-VE absoluto <16,9% antes da quimioterapia mostrou 100% de sensibilidade e 73% de especificidade para predizer cardiotoxicidade (AUC=0,85; IC 95% 0,6800,959, p<0,001). Nesta população, os valores de FEVE antes da quimioterapia não foram preditores de CiC (IC 95% 0,478 a -0,842, p=0,17). A associação de baixos níveis séricos de SLG-VE (<17%) e BNP (>17 pg/mL) dois meses após a quimioterapia aumentou a precisão para detectar CiC de início precoce (100% de sensibilidade, 88% de especificidade, AUC=0,94; IC 95% 0,7810,995, p<0,0001). Conclusões: Nossos dados sugerem que o SLG-VE é um possível preditor de cardiotoxicidade induzida por quimioterapia. São necessários estudos maiores para confirmar a relevância clínica desse parâmetro ecocardiográfico nesse cenário clínico. (AU)
Background: Chemotherapy-induced cardiotoxicity (ChC) is an important complication among patients receiving anthracyclines. Biomarkers and imaging parameters have been studied for their ability to identify patients at risk of developing ChC. Left ventricular global longitudinal strain (LV-GLS) is a sensitive parameter for detecting systolic dysfunction despite the presence of preserved left ventricular ejection fraction (LVEF). Objective: To evaluate the role of the LV-GLS as a predictor of ChC. Methods: This was a post-hoc analysis of the Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity trial, which evaluated the primary prevention of cardiotoxicity with carvedilol during doxorubicin chemotherapy in a population of patients with breast cancer. Cardiotoxicity was defined as a reduction ≥10% in LVEF. LV-GLS was determined before chemotherapy in patients with no prior cardiovascular disease or echocardiogram abnormalities. Results: Thirty-one patients for whom a complete echocardiography study including measurement of LV-GLS was performed before chemotherapy were included in this analysis. An absolute LV-GLS<16.9% before chemotherapy showed 100% sensitivity and 73% specificity for predicting cardiotoxicity (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.6800.959; p<0.001). In this population, LVEF values before chemotherapy did not predict ChC (95% CI, 0.478 to -0.842; p=0.17). The association of low LV-GLS (<17%) and brain-type natriuretic peptide serum levels (>17 pg/mL) at 2 months after chemotherapy increased the accuracy for detecting early-onset ChC (100% sensitivity, 88% specificity; AUC, 0.94; 95% CI, 0.7810.995; p<0.0001). Conclusions: Our data suggest that LV-GLS is a potential predictor of ChC. Larger studies are needed to confirm its clinical relevance in this clinical setting. (AU)
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/diagnóstico por imagem , Cardiotoxicidade/complicações , Deformação Longitudinal Global/efeitos dos fármacos , Neoplasias da Mama/diagnóstico , Ecocardiografia/métodos , Biomarcadores/análise , Doxorrubicina/uso terapêutico , Antraciclinas/administração & dosagem , Tratamento Farmacológico/métodos , Carvedilol/toxicidade , Insuficiência Cardíaca/prevenção & controleRESUMO
Memories of adverse events can be maladaptive when they lead to exaggerated fear, as observed in post-traumatic stress disorder (PTSD). Fear conditioning and fear sensitization are learning processes thought to play a role in fear-related disorders, and only few animal studies have evaluated the relationship between the associative and non-associative fear memory components on the development and maintenance of PTSD-like behavioral changes. Here we assessed the effects of a single dose of propranolol (10 mg/kg) or saline after fear memory retrieval on the long-term behavioral responses induced by severe stress in male rats. Animals were submitted to contextual fear conditioning (delayed shock group) or not (non-shock group) and underwent fear memory retrieval followed by propranolol or saline administration two weeks later. Rats were then evaluated in different behavioral tests to assess the expression of the conditioned fear response, anxiety-like and exploratory behaviors, and fear response after the presentation of unknown acoustic stimulus. Post-retrieval propranolol did not disrupt the subsequent expression of neither conditioned fear response nor the exploratory deficit and fear sensitization response, indicating that propranolol failed to mitigate long-term behavioral changes induced by severe stress in rats.
Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Propranolol/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Animais , Condicionamento Psicológico/fisiologia , Estimulação Elétrica/efeitos adversos , Comportamento Exploratório/fisiologia , Medo/fisiologia , Medo/psicologia , Masculino , Propranolol/farmacologia , Ratos , Ratos Wistar , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/prevenção & controle , Estresse Psicológico/psicologiaRESUMO
In this study, we describe the experimental variables influencing enantioseparation of twelve ß-blockers when analyzed under polar-organic, reversed-phase and hydrophilic interaction liquid chromatography conditions on a column with immobilized amylose tris(3-chloro-5-methylphenylcarbamate) as chiral stationary phase. Regarding polar-organic mode, two component mobile phases consisting of methanol, ethanol or acetonitrile with the addition of basic additives such as diethylamine, triethylamine, mono-ethanolamine, ethylendiamine or trifluoroacetic acid/diethylamine mixture were evaluated. Studies of retention at different temperatures were also performed. In reversed-phase mode, mixtures consisting of methanol or acetonitrile with either aqueous boric acid-borate buffer or sodium hydrogen carbonate-carbonate buffer solutions were compared aiming to study the influence of organic modifier as well as buffer type and pH on resolution. In addition, a systematic evaluation of the retention factors of ß-blockers enantiomers in hydro-organic eluents containing acetonitrile in presence of diethylamine as additive was carried out by increasing progressively the water content, in order to check for retention dependencies indicative of the interplay of both hydrophilic interaction liquid chromatography and reversed-phase modes.
Assuntos
Antagonistas Adrenérgicos beta/análise , Antagonistas Adrenérgicos beta/isolamento & purificação , Amilose/análogos & derivados , Cromatografia Líquida , Cromatografia de Fase Reversa , Fenilcarbamatos/química , Acetonitrilas/química , Amilose/química , Interações Hidrofóbicas e Hidrofílicas , Estereoisomerismo , Água/químicaRESUMO
Restricted-access nanoparticles (RANPs) were prepared from bovine serum albumin by coacervation. They have an average sized of 311 nm. They were characterized and used to capture the ß-blockers atenolol, metoprolol and propranolol from untreated biological samples. It is shown that both high protein affinity drugs (propranolol) and low protein affinity drugs (atenolol) could be rapidly extracted from plasma. This is revealed by kinetic and isothermal adsorption studies. On the other hand, almost all proteins from the sample were excluded. This demonstrates the efficiency of RANPs as restricted-access material. Sample preparation was carried out by solid phase microextraction using a probe obtained by the fixation of the RANPs at the end of a glass capillary. Atenolol (in concentrations from 100 to 1200 µg L-1), metoprolol (from 80 to 1000 µg L-1) and propranolol (from 15 to 200 µg L-1) were extracted from spiked plasma samples and analyzed by LC MS/MS without using a separation column. Correlation coefficients >0.99, good precision, accuracy, robustness, and lack of memory effects were observed for all of the analytes. The detection limits (at an S/N of 3) are 25.6, 14.6, and 3.8 µg L-1 for atenolol, metoprolol and propranolol, respectively. Ten samples can be simultaneously extracted within â¼15 min. Plasma samples of patients undergoing medical treatment were successfully analyzed with the method. Graphical abstract Schematic representation of a bovine serum albumin-based restricted access nanoparticle that exclude proteins from a human plasma sample but capture the small analytes.
Assuntos
Antagonistas Adrenérgicos beta/sangue , Nanopartículas/química , Soroalbumina Bovina/química , Animais , Bovinos , Cromatografia Líquida , Humanos , Tamanho da Partícula , Propriedades de Superfície , Espectrometria de Massas em TandemRESUMO
INTRODUCTION: Although main antihypertensive drugs are able to efficiently reduce blood pressure, only a third of treated hypertensive patients achieve optimal blood pressure control. Extensive interpatient variability on drug metabolism and oral disposition of blood pressure lowering drugs can contribute to this failure in hypertension management. Areas covered: The aim of the present review is to update the knowledge on the features of hepatic metabolism of the main antihypertensive agents, including ß-blockers, calcium channel blockers, angiotensin receptor blockers, and angiotensin converting enzyme inhibitors. The factors that contribute to the large interindividual variability of main antihypertensive drugs are also covered. Expert opinion: The variability of plasma concentration of antihypertensive drugs due to the involvement of hepatic metabolism can contribute to the inadequate control of blood pressure in the daily clinical practice. Genotype screening of specific hepatic drug-metabolizing enzymes may contribute to optimize dose selection and to increase the rate of blood pressure control in patients treated with specific ß-blockers, calcium channel blockers, and angiotensin receptor blockers.
Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/farmacocinética , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacocinética , Relação Dose-Resposta a Droga , Genótipo , HumanosRESUMO
AIM: To examine the interference of ß-blockers with the chemokine stromal cell-derived factor-1 (SDF-1) found in cell homing receptors, C-X-C chemokine receptor type 4 (CXCR-4) and CXCR-7, and regulatory proteins of homing pathways, we administered atenolol, carvedilol, metoprolol, and propranolol for 30 days using an orogastric tube to hypertensive rats. METHOD: We collected blood samples before and after treatment and quantified the levels of SDF-1 with enzyme-linked immunosorbent assay (ELISA). On day 30 of treatment, the spontaneously hypertensive rats (SHR) were euthanized, and heart, liver, lung, and kidney tissues were biopsied. Proteins were isolated for determining the expression of CXCR-4, CXCR-7, GRK-2 (G protein-coupled receptors kinase 2), ß-arrestins (ß1-AR and ß2-AR), and nuclear factor kappa B (NFκB). RESULTS: We found that the study drugs modulated these proteins, and metoprolol and propranolol strongly affected the expression of ß1-AR (P = .0102) and ß2-AR (P = .0034). CONCLUSION: ß-blockers modulated tissue expression of the proteins and their interactions following 30 days of treatment. It evidences that this class of drugs can interfere with proteins of cell homing pathways.