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1.
Arq Bras Cir Dig ; 33(3): e1525, 2020.
Artigo em Inglês, Português | MEDLINE | ID: mdl-33331427

RESUMO

BACKGROUND: Portal hypertension (PH) can be measured indirectly through a hepatic vein pressure gradient greater than 5 mmHg. Cirrhosis is the leading cause for PH and can present as complications ascites, hepatic dysfunction, renal dysfunction, and esophagogastric varices, characterizing gastropathy. AIM: To evaluate the use of carvedilol as primary prophylaxis in the development of collateral circulation in rats submitted to the partial portal vein ligament (PPVL) model. METHOD: This is a combined qualitative and quantitative experimental study in which 32 Wistar rats were divided into four groups (8 animals in each): group I - cirrhosis + carvedilol (PPVL + C); group II - cirrhosis + vehicle (PPVL); group III - control + carvedilol (SO-sham-operated + C); group IV - control + vehicle (SO-sham-operated). After seven days of the surgical procedure (PPVL or sham), carvedilol (10 mg/kg) or vehicle (1 mL normal saline) were administered to the respective groups daily for seven days. RESULTS: The histological analysis showed no hepatic alteration in any group and a decrease in edema and vasodilatation in the PPVL + C group. The laboratory evaluation of liver function did not show a statistically significant change between the groups. CONCLUSION: Carvedilol was shown to have a positive effect on gastric varices without significant adverse effects.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Carvedilol/administração & dosagem , Hemorragia Gastrointestinal/prevenção & controle , Hipertensão Portal/complicações , Animais , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/prevenção & controle , Hemorragia Gastrointestinal/etiologia , Ratos , Ratos Wistar
3.
Medicine (Baltimore) ; 99(39): e22301, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991436

RESUMO

RATIONALE: Cardiotoxicity related to osimertinib, including cardiac failure, QT prolongation, and atrial fibrillation, has been reported as an extremely rare incidence in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the occurrence of osimertinib-induced cardiomyopathy. PATIENT CONCERNS: A 76-year old woman was treated with afatinib (40 mg/day) as the 1st line treatment due to recurrence after surgical resection for pulmonary adenocarcinoma. However, she experienced recurrence with positive T790 M, and osimertinib (80 mg/day) was administered as the 2nd line therapy. DIAGNOSIS: Four months after osimertinib initiation, she complained of fever and progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating osimertinib-induced cardiomyopathy. INTERVENTIONS AND OUTCOMES: She was treated with furosemide, carvedilol, and enalapril, and her cardiac function, her symptoms, and condition improved 3 weeks after the withdrawal of osimertinib. LESSONS: Physicians should be alert of the cardiomyopathy-causing potential of osimertinib in advanced NSCLC patients.


Assuntos
Acrilamidas/efeitos adversos , Compostos de Anilina/efeitos adversos , Cardiomiopatias/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Afatinib/uso terapêutico , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Compostos de Anilina/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/fisiopatologia , Carvedilol/uso terapêutico , Diuréticos/uso terapêutico , Enalapril/uso terapêutico , Feminino , Furosemida/uso terapêutico , Humanos , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Resultado do Tratamento , Suspensão de Tratamento
4.
Bioessays ; 42(11): e2000094, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32815593

RESUMO

More than 15 million people have been affected by coronavirus disease 2019 (COVID-19) and it has caused 640 016 deaths as of July 26, 2020. Currently, no effective treatment option is available for COVID-19 patients. Though many drugs have been proposed, none of them has shown particular efficacy in clinical trials. In this article, the relationship between the Adrenergic system and the renin-angiotensin-aldosterone system (RAAS) is focused in COVID-19 and a vicious circle consisting of the Adrenergic system-RAAS-Angiotensin converting enzyme 2 (ACE2)-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (which is referred to as the "ARAS loop") is proposed. Hyperactivation of the ARAS loop may be the underlying pathophysiological mechanism in COVID-19, and beta-adrenergic blockers are proposed as a potential treatment option. Beta-adrenergic blockers may decrease the SARS-CoV-2 cellular entry by decreasing ACE2 receptors expression and cluster of differentiation 147 (CD147) in various cells in the body. Beta-adrenergic blockers may decrease the morbidity and mortality in COVID-19 patients by preventing or reducing acute respiratory distress syndrome (ARDS) and other complications. Retrospective and prospective clinical trials should be conducted to check the validity of the hypothesis. Also see the video abstract here https://youtu.be/uLoy7do5ROo.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Infecções por Coronavirus/epidemiologia , Reposicionamento de Medicamentos/métodos , Humanos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pandemias , Papaína/antagonistas & inibidores , Papaína/metabolismo , Peptidil Dipeptidase A/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/epidemiologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Embolia Pulmonar/prevenção & controle , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Insuficiência Respiratória/prevenção & controle , Choque Séptico/prevenção & controle , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Internalização do Vírus/efeitos dos fármacos
6.
Cochrane Database Syst Rev ; 7: CD007037, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32700759

RESUMO

BACKGROUND: Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial in children. However, congestive heart failure in children differs from that in adults in terms of characteristics, aetiology, and drug clearance. Therefore, paediatric needs must be specifically investigated. This is an update of a Cochrane review previously published in 2009. OBJECTIVES: To assess the effect of beta-adrenoceptor-blockers (beta-blockers) in children with congestive heart failure. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS up to November 2015. Bibliographies of identified studies were checked. No language restrictions were applied. SELECTION CRITERIA: Randomised, controlled, clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and assessed data from the included trials. MAIN RESULTS: We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block. A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement with beta-blockers. However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure; heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in meta-analyses. AUTHORS' CONCLUSIONS: There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future trials.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Adolescente , Carbazóis/uso terapêutico , Carvedilol , Criança , Pré-Escolar , Insuficiência Cardíaca/mortalidade , Transplante de Coração/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Metoprolol/uso terapêutico , Propanolaminas/uso terapêutico , Propranolol/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Volume Sistólico
7.
Chem Biol Interact ; 327: 109181, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32569593

RESUMO

Acute pancreatitis (AP) is a sudden pancreatic inflammation accompanied by an excessive reactive oxygen species production that provokes inflammation. The present study investigated whether carvedilol can protect against l-arginine induced AP in a rat model and studied the mechanisms associated with its protection. Rats were divided into four groups: a control group, an AP group (injected with 2 doses of l-arginine 250 mg/100 g body weight at 1 h interval, intraperitoneally) on the 22nd day of the experiment, a carvedilol group (10 mg/kg, orally) for 21 successive days, and finally a carvedilol + AP group. It was found that pretreatment with carvedilol decreased α-amylase and lipase activities as well as C-reactive protein (CRP) and malondialdehyde levels; on the other hand, it improved the reduced glutathione (GSH) level and catalase (CAT) activity. In addition, carvedilol markedly decreased all of the following biomarkers: nuclear factor kappa B (NF-κB p65), p38 mitogen-activated protein kinases (P38-MAPK), signal transducer and activator of transcription 1 (STAT1-α), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), myeloperoxidase (MPO), and phospholipase A2 (PLA2) levels that was induced by l-arginine. Finally, carvedilol noticeably down regulated the pancreatitis associated protein (PAP2) and the pancreas platelets activating factor (PAF) genes expression. In conclusion: carvedilol protected against l-arginine induced AP in rats, via the inhibition of cellular oxidative stress and inflammatory pathways that contributed to pancreas injury.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Carvedilol/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Animais , Arginina , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Glutationa/metabolismo , Hidrolases/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdeído/metabolismo , Pancreatite/induzido quimicamente , Pancreatite/metabolismo , Peroxidase/metabolismo , Ratos , Fator de Necrose Tumoral alfa/metabolismo
8.
Proc Natl Acad Sci U S A ; 117(22): 12435-12443, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32414934

RESUMO

A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a ß2-adrenergic receptor (ß2AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in ß-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of ß2AR agonists. Carvedilol, classically defined as a ßAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a ß-arrestin-biased ligand for the ß2AR, stimulating ß-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via ß-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other ß-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by ß-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with ßAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Carvedilol/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , beta-Arrestina 1/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/fisiologia , beta-Arrestina 1/genética
9.
Vascular ; 28(6): 765-774, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32408854

RESUMO

BACKGROUND: The major mechanisms of arteriovenous graft (AVG) failure due to intimal hyperplasia (IH) are smooth muscle cell proliferation and inflammation. Therefore, carvedilol may improve AVG primary patency because of its anti-proliferative and anti-inflammatory activities. METHODS: The data of end-stage renal disease patients receiving regular hemodialysis were collected from the National Health Insurance Research database. The end point was the first percutaneous transluminal angioplasty (PTA) for AVG failure or death during a follow-up period of two years or the end of 2013. The analysis was calculated with Cox proportional hazard model. RESULTS: There were 3028 patients treated with carvedilol and 13,704 patients not treated with carvedilol. According to a univariate analysis, the carvedilol group was younger, received more anti-hypertensive medications and platelet aggregation inhibitors, and had higher rates of diabetes mellitus and hyperlipidemia but had lower rates of hypotension and smoking. According to a multivariate analysis, after controlling for covariates, the use of carvedilol for more than 84 days reduced the probability of a first PTA for AVG failure by 9% compared with no use of carvedilol (p = 0.021), but the use of carvedilol for 1 to 84 days did not. CONCLUSION: The results of this study indicate that the use of carvedilol for more than 84 days improves the primary patency of AVGs, but the use of carvedilol for less than 84 days does not.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/administração & dosagem , Derivação Arteriovenosa Cirúrgica , Carvedilol/administração & dosagem , Oclusão de Enxerto Vascular/prevenção & controle , Falência Renal Crônica/terapia , Diálise Renal , Grau de Desobstrução Vascular/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Idoso , Angioplastia , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Carvedilol/efeitos adversos , Bases de Dados Factuais , Feminino , Oclusão de Enxerto Vascular/diagnóstico por imagem , Oclusão de Enxerto Vascular/etiologia , Oclusão de Enxerto Vascular/fisiopatologia , Humanos , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taiwan , Fatores de Tempo , Resultado do Tratamento
10.
AAPS PharmSciTech ; 21(5): 146, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32435989

RESUMO

The objective of this work was to study the effect of the physiologically relevant enzymes pepsin, pancreatin, and the synthetic surfactant sodium lauryl sulfate (SLS) on the surface tension of the dissolution media and the solubility and dissolution of the weakly basic drug carvedilol. Compendial dissolution media and buffer solutions that simulate the gastrointestinal fluid, prepared with and without the addition of SLS, were used in this study. The surface tension of the dissolution media; critical micelle concentration (CMC) of SLS in buffer solutions; and size, polydispersity index, and zeta potential of SLS micelles loading carvedilol were determined. The solubility and dissolution of carvedilol were investigated and compared with those of the corresponding media prepared without the addition of pepsin, pancreatin, and SLS. Results showed that the addition of pepsin, pancreatin, and SLS lowered the surface tension of the dissolution media to 54.8, 55.7, and ~ 30 mN/m, respectively. The solubility of carvedilol was significantly enhanced with pepsin and SLS; however, no significant difference was found with pancreatin. The dissolution rate of carvedilol was fast in simulated gastric fluid with and without pepsin. The dissolution was further enhanced in media with pancreatin and SLS. The dissolution data were corroborated with the molar micellar solubilization (X) of SLS, ranging between 0.02 and 3.09. Understanding the effect of pepsin, pancreatin, and SLS on the surface tension of the dissolution media and the solubility and dissolution of poorly soluble drugs can improve our knowledge of the performance of these drugs in vivo.


Assuntos
Carvedilol/química , Dodecilsulfato de Sódio/farmacologia , Tensoativos/farmacologia , Micelas , Pancreatina/química , Pepsina A/química , Solubilidade , Tensão Superficial
11.
Sci Rep ; 10(1): 7101, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345990

RESUMO

Alveolar ß2-receptor blockade worsens lung diffusion in heart failure (HF). This effect could be mitigated by stimulating alveolar ß2-receptors. We investigated the safety and the effects of indacaterol on lung diffusion, lung mechanics, sleep respiratory behavior, cardiac rhythm, welfare, and exercise performance in HF patients treated with a selective (bisoprolol) or a non-selective (carvedilol) ß-blocker. Study procedures were performed before and after indacaterol and placebo treatments according to a cross-over, randomized, double-blind protocol in forty-four patients (27 on bisoprolol and 17 on carvedilol). No differences between indacaterol and placebo were observed in the whole population except for a significantly higher VE/VCO2 slope and lower maximal PETCO2 during exercise with indacaterol, entirely due to the difference in the bisoprolol group (VE/VCO2 31.8 ± 5.9 vs. 28.5 ± 5.6, p < 0.0001 and maximal PETCO2 36.7 ± 5.5 vs. 37.7 ± 5.8 mmHg, p < 0.02 with indacaterol and placebo, respectively). In carvedilol, indacaterol was associated with a higher peak heart rate (119 ± 34 vs. 113 ± 30 bpm, with indacaterol and placebo) and a lower prevalence of hypopnea during sleep (3.8 [0.0;6.3] vs. 5.8 [2.9;10.5] events/hour, with indacaterol and placebo). Inhaled indacaterol is well tolerated in HF patients, it does not influence lung diffusion, and, in bisoprolol, it increases ventilation response to exercise.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Antagonistas Adrenérgicos beta/administração & dosagem , Bisoprolol/administração & dosagem , Carvedilol/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Indanos/administração & dosagem , Quinolonas/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Antagonistas Adrenérgicos beta/efeitos adversos , Idoso , Bisoprolol/efeitos adversos , Carvedilol/efeitos adversos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Indanos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Quinolonas/efeitos adversos , Receptores Adrenérgicos beta 2/metabolismo
12.
Am J Physiol Heart Circ Physiol ; 318(5): H1245-H1255, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275472

RESUMO

Carvedilol is an FDA-approved ß-blocker commonly used for treatment of high blood pressure, congestive heart failure, and cardiac tachyarrhythmias, including atrial fibrillation. We investigated at the cellular level the mechanisms through which carvedilol interferes with sarcoplasmic reticulum (SR) Ca2+ release during excitation-contraction coupling (ECC) in single rabbit atrial myocytes. Carvedilol caused concentration-dependent (1-10 µM) failure of SR Ca2+ release. Failure of ECC and Ca2+ release was the result of dose-dependent inhibition of voltage-gated Na+ (INa) and L-type Ca2+ (ICa) currents that are responsible for the rapid depolarization phase of the cardiac action potential (AP) and the initiation of Ca2+-induced Ca2+ release from the SR, respectively. Carvedilol (1 µM) led to AP duration shortening, AP failures, and peak INa inhibition by ~80%, whereas ICa was not markedly affected. Carvedilol (10 µM) blocked INa almost completely and reduced ICa by ~40%. No effect on Ca2+-transient amplitude, ICa, and INa was observed in control experiments with the ß-blocker metoprolol, suggesting that the carvedilol effect on ECC is unlikely the result of its ß-blocking property. The effects of carvedilol (1 µM) on subcellular SR Ca2+ release was spatially inhomogeneous, where a selective inhibition of peripheral subsarcolemmal Ca2+ release from the junctional SR accounted for the cell-averaged reduction in Ca2+-transient amplitude. Furthermore, carvedilol significantly reduced the probability of spontaneous arrhythmogenic Ca2+ waves without changes of SR Ca2+ load. The data suggest a profound antiarrhythmic action of carvedilol in atrial myocytes resulting from an inhibitory effect on the SR Ca2+ release channel.NEW & NOTEWORTHY Here we show that the clinically widely used ß-blocker carvedilol has profound effects on Ca2+ signaling and ion currents, but also antiarrhythmic effects in adult atrial myocytes. Carvedilol inhibits sodium and calcium currents and leads to failure of ECC but also prevents spontaneous Ca2+ release from cellular sarcoplasmic reticulum (SR) Ca2+ stores in form of arrhythmogenic Ca2+ waves. The antiarrhythmic effect occurs by carvedilol acting directly on the SR ryanodine receptor Ca2+ release channel.


Assuntos
Potenciais de Ação , Antagonistas Adrenérgicos beta/farmacologia , Sinalização do Cálcio , Carvedilol/farmacologia , Acoplamento Excitação-Contração , Miócitos Cardíacos/efeitos dos fármacos , Animais , Células Cultivadas , Masculino , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/fisiologia , Coelhos
13.
Eur J Med Chem ; 193: 112235, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32203789

RESUMO

Cytochrome P450 1B1 (CYP1B1) is a promising target for prevention and therapy of cancer, particularly those with drug resistance, stimulating cancer cell survival, and promoting cancer resistance. In view of the extreme complexity and high risk in drug discovery and development, a drug repurposing strategy was applied in the present study to find potential CYP1B1 inhibitors through structure-based virtual screening in the FDA database. Intriguingly, after a thorough assessment of docking scores, binding affinities, as well as binding modes, six compounds were highlighted for further verification. In fact, both carvedilol and indacaterol showed inhibitory activity towards human CYP1B1 with the IC50 of 1.11 µM and 59.52 µM, respectively, according to EROD assay; however, neither docking score nor the detailed binding mode of carvedilol in the hit pose dictated to be a superior CYP1B1 inhibitor to indacaterol, which called for the necessity to re-access the binding mode of carvedilol. Thus, the top two representative docking poses of carvedilol were re-assessed. Indeed, compared to the one hit in the virtual screening (due to a false positive Glide gscore), the other docking pose exhibited ideal performance in both molecular dynamics (MD) simulation, binding free energy, and density functional theory (DFT) calculation evaluations. This identification of the exact binding pose of carvedilol is not only essential for a better understanding of the mechanism underlying its activity, but also contributes to uncovering the structure-activity relationship of CYP1B1 inhibitors. Of note, carvedilol exhibited direct cytotoxicity against both human lung adenocarcinoma epithelial cell line A459 and its Taxol-resistant subline (A549/Taxol). In particular, it showed superior toxicity towards A549/Taxol cells that overexpressed CYP1B1, which further supported its potential to be an effective CYP1B1 inhibitor.


Assuntos
Carvedilol/farmacologia , Citocromo P-450 CYP1B1/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Células A549 , Carvedilol/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocromo P-450 CYP1B1/química , Citocromo P-450 CYP1B1/metabolismo , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas
14.
Am J Cardiol ; 125(7): 1069-1076, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32000982

RESUMO

This study compared the survival and the risk of heart failure (HF), chronic obstructive pulmonary disease (COPD), diabetes mellitus (DM), hypoglycemia, and renal failure (RF) hospitalizations in geriatric patients exposed to carvedilol or metoprolol. Data sources were Danish administrative registers. Patients aged ≥65 and having HF, COPD, and DM were followed for 1 year from the first ß-blocker prescription redemption. Patients' characteristics were used to 1:1 propensity score match carvedilol and metoprolol users. A Cox regression model was used to compute the hazard ratio (HR) of study outcomes. For statistically significant associations, a conditional inference tree was used to assess predictors most associated with the outcome. In total, 1,424 patients were included. No statistically significant differences were observed for survival (HR 0.86; 95% confidence interval [CI] 0.67 to 1.11, p = 0.240) between carvedilol/metoprolol users. The same applied to COPD (HR 0.88; 95% CI 0.75 to 1.05, p = 0.177), DM (HR 0.95; 95% CI 0.82 to 1.10, p = 0.485), hypoglycemia (HR 0.88; 95% CI 0.47 to 1.67, p = 0.707), and RF (HR 1.25; 95% CI 0.93 to 1.69, p = 0.142) hospitalizations. Carvedilol users had a 38% higher hazard then metoprolol users of HF hospitalization during the follow-up period (HR 1.38; 95% CI 1.19 to 1.60, p <0.001). Artificial intelligence identified carvedilol exposure as the most important predictor for HF hospitalization. In conclusion, we found an increased risk of HF hospitalization for carvedilol users with this triad of diseases but no statistically significant differences in survival or risk of COPD, DM, hypoglycemia, and RF hospitalizations.


Assuntos
Carvedilol/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Metoprolol/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Insuficiência Renal/epidemiologia , Doença Aguda , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Idoso , Comorbidade , Dinamarca/epidemiologia , Feminino , Seguimentos , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Estudos Retrospectivos , Taxa de Sobrevida/tendências
15.
Trials ; 21(1): 137, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32019575

RESUMO

BACKGROUND: Anthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a ß-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the ß-blocker effect, could prevent related cardiotoxicity. However, carvedilol's antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo. METHODS/DESIGN: We designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing. DISCUSSION: We expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN69560410. Registered on 8 June 2016.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Antibióticos Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carvedilol/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Doxorrubicina/efeitos adversos , Precondicionamento Isquêmico Miocárdico/métodos , Adolescente , Adulto , Idoso , Antibióticos Antineoplásicos/uso terapêutico , Biomarcadores/sangue , Neoplasias da Mama/sangue , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Método Duplo-Cego , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Volume Sistólico , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Adulto Jovem
17.
BMJ Case Rep ; 13(2)2020 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-32094236

RESUMO

A 62-year-old woman with chronic kidney disease stage 4, sleep apnoea on continuous positive airway pressure and recent admission for acute-on-chronic diastolic heart failure presented to emergency room with weakness. She was hypotensive and had symptomatic bradycardia in the 30 s secondary to hyperkalaemia and beta-blockers, raising concern for BRASH syndrome. Antihypertensives were immediately held. Potassium-lowering agents (with calcium gluconate for cardiac stability) were begun, as were fluids and dopamine for vasopressor support. The patient was admitted to intensive care unit and electrophysiology was consulted. Over the next 2 days, the patient clinically improved: she remained off dopamine for over 24 hours; potassium levels and renal function improved; and heart rate stabilised in 60 s. The patient was eventually discharged and advised to avoid metolazone, bumetanide and carvedilol, with primary care provider and cardiology follow-up.


Assuntos
Bloqueio Atrioventricular , Bradicardia , Hiperpotassemia , Insuficiência Renal , Choque , Anti-Hipertensivos/efeitos adversos , Bumetanida/efeitos adversos , Carvedilol/efeitos adversos , Feminino , Humanos , Metolazona/efeitos adversos , Pessoa de Meia-Idade , Síndrome , Vasoconstritores/uso terapêutico
18.
J Cardiovasc Pharmacol Ther ; 25(4): 354-363, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32052660

RESUMO

BACKGROUND: Insulin resistance (IR) is a well-known risk factor for cardiovascular complications. This study aimed to investigate the effect of a dietary model of IR in mice on cardiac remodeling, cardiac ß-arrestin2 signaling, and the protective effects of carvedilol as a ß-arrestin-biased agonist. METHODS AND RESULTS: Insulin resistance was induced by feeding mice high-fructose/high-fat diet (HFrHFD) for 16 weeks. Carvedilol was adiministered for 4 weeks starting at week 13. At the end of the experiment, body weight, heart weight, left and right ventricular thickness, visceral fat weight, fasting blood glucose (FBG), serum insulin, IR index, and serum endothelin-1 were measured. In addition, cardiac tissue samples were histopathologically examined. Also, cardiac levels of cardiotrophin-1, ß-arrestin2, phosphatidylinositol 4,5 bisphosphate (PIP2), diacylglycerol (DAG), and phosphoserine 473 Akt (pS473 Akt) were measured. Results showed significant increases in the FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, cardiac fibrosis, and degenerated cardiac myofibrils in HFrHFD-fed mice associated with a significant reduction in cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. On the other hand, carvedilol significantly reduced the heart weight, FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, left ventricular thickness, right ventricular fibrosis, and degeneration of cardiac myofibrils. In addition, carvedilol significantly increased cardiac levels of cardiotrophin-1, ß-arrestin2, PIP2, and pS473 Akt. CONCLUSION: Carvedilol enhances cardiac ß-arrestin2 signaling and reduces cardiac remodeling in HFrHFD-fed mice.


Assuntos
Cardiomegalia/prevenção & controle , Carvedilol/farmacologia , Resistência à Insulina , Miócitos Cardíacos/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , beta-Arrestina 2/agonistas , Animais , Cardiomegalia/etiologia , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatologia , Citocinas/metabolismo , Dieta Hiperlipídica , Açúcares da Dieta , Modelos Animais de Doenças , Fibrose , Frutose , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Remodelação Ventricular/efeitos dos fármacos , beta-Arrestina 2/metabolismo
19.
Int J Mol Sci ; 21(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991834

RESUMO

The ß-blocker carvedilol prevents ultraviolet (UV)-induced skin cancer, but the mechanism is unknown. Since carvedilol possesses antioxidant activity, this study investigated whether carvedilol prevents oxidative photodamage of skin, a precursor event in skin carcinogenesis. The effects of carvedilol, metoprolol (a ß-blocker without antioxidant property), and 4-hydroxycarbazole (4-OHC, a carvedilol synthesis intermediate and a free radical scavenger) were compared on UV- or H2O2-induced cell death and reactive oxygen species (ROS) production in murine epidermal JB6 P+ cells. Although carvedilol attenuated cell death, metoprolol and 4-OHC failed to show protective effects. As expected, increased cellular ROS induced by H2O2 or UV was abolished by carvedilol and 4-OHC, but not by metoprolol. Consistently, carvedilol attenuated the formation of UV-induced cyclobutane pyrimidine dimers (CPDs) and release of prostaglandin E2 in JB6 P+ cells. Carvedilol's activity was further confirmed in full thickness 3D human reconstituted skin, where carvedilol attenuated UV-mediated epidermal thickening, the number of Ki-67 and p53 positive cells as well as CPD formation. Based on pathway-specific Polymerase Chain Reaction (PCR) Array analysis, carvedilol treatment in many cases normalized UV-induced expression changes in DNA repair genes. Thus, carvedilol's photoprotective activity is not attributed to ß-blockade or direct ROS-scavenging capacity, but likely via DNA repair regulation.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Carvedilol/farmacologia , Células Epidérmicas/efeitos dos fármacos , Células Epidérmicas/efeitos da radiação , Raios Ultravioleta/efeitos adversos , Animais , Técnicas de Cultura de Células , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/efeitos da radiação , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Dinoprostona/metabolismo , Células Epidérmicas/metabolismo , Humanos , Peróxido de Hidrogênio , Mediadores da Inflamação , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
J Pharm Pract ; 33(1): 96-98, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29916290

RESUMO

Beta-blockers such as metoprolol, carvedilol, and bisoprolol are indicated for the treatment of patients with reduced ejection fraction heart failure. Heart failure treatment guidelines call for titration of these medications to specific target doses for morbidity and mortality benefit. Hepatic enzymes are responsible for metabolizing these medications; however, these enzymes are subject to genetic variations (polymorphisms) that can increase or decrease enzyme activity. Metoprolol relies almost exclusively on this enzyme for degradation to inactive metabolites, whereas carvedilol relies on this enzyme only partially for metabolism, and the portion of drug that is metabolized by CYP2D6 becomes active metabolites. The clinical significance of genetic variations in CYP2D6 in heart failure patients requiring treatment with carvedilol and metoprolol remains unclear, and further research is needed before any strong recommendations on treatment approach can be made. However, based on what is known regarding the incidence of genetic variations of this enzyme, it is reasonable to conclude that heart failure patients of European and Asian ancestry may be at a greater risk of intolerance to guideline-directed doses of metoprolol. Patients of North African ancestry may be at a lower risk of intolerance to metoprolol, although limited data are available to conclude. Additionally, due to the significant prevalence of CYP2D6 enzyme variations among all ethnicities, it may be reasonable to consider switching to carvedilol for patients who are unable to fully titrate metoprolol.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Citocromo P-450 CYP2D6/genética , Variação Genética/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas Adrenérgicos beta/administração & dosagem , Bisoprolol/uso terapêutico , Carvedilol/uso terapêutico , Humanos , Metoprolol/uso terapêutico , Projetos de Pesquisa , Resultado do Tratamento
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