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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(8): 796-800, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31416505

RESUMO

OBJECTIVE: To study the clinical effect of carvedilol in the treatment of children with severe hand-foot-mouth disease (HFMD) caused by enterovirus 71 (EV71) infection. METHODS: A retrospective analysis was performed for the clinical data of 86 children with severe HFMD caused by EV71 infection who were admitted to the hospital from April 2016 to August 2017. According to whether carvedilol was used, the children were divided into conventional treatment group with 51 children and carvedilol treatment group with 35 children. A total of 56 healthy children who underwent physical examination at the outpatient service during the same period were enrolled as the control group. The two treatment groups were compared in terms of clinical features and levels of catecholamines (norepinephrine, adrenaline and dopamine), and the levels of catecholamines were compared between these two treatment groups and the control group. RESULTS: Before treatment, the conventional treatment group and the carvedilol treatment group had significantly higher levels of norepinephrine and adrenaline than the control group (P<0.05). After treatment, both the conventional treatment group and the carvedilol treatment group had significant reductions in norepinephrine, adrenaline, blood glucose, systolic pressure, diastolic pressure, heart rate, body temperature and leukocyte count (P<0.05). Compared with the conventional treatment group, the carvedilol treatment group had significantly lower dopamine level, blood glucose, heart rate and respiratory rate after treatment (P<0.05). CONCLUSIONS: Changes in norepinephrine and adrenaline might be involved in the pathogenesis of severe HFMD caused by EV71 infection. Carvedilol, in addition to the conventional treatment, can improve respiration, heart rate and blood glucose in children with severe HFMD caused by EV71 infection.


Assuntos
Carvedilol/uso terapêutico , Enterovirus Humano A , Infecções por Enterovirus , Doença de Mão, Pé e Boca , Criança , China , Infecções por Enterovirus/complicações , Doença de Mão, Pé e Boca/tratamento farmacológico , Doença de Mão, Pé e Boca/etiologia , Humanos , Estudos Retrospectivos
2.
Environ Toxicol Pharmacol ; 70: 103198, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154273

RESUMO

Cadmium (Cd) is a highly toxic heavy metal with several harmful effects including cardiotoxicity. For the first time, we aimed to evaluate the possible cardioprotective effect of carvedilol (CAR) in Cd induced cardiotoxicity and study the mechanisms involved in such protection including endothelial nitric oxide synthase (eNOS) and HO1/Nrf2 pathway. CAR (1,10 mg/kg/d) was administered orally for 4 weeks with Cd induced cardiac injury (3 mg/kg/d) orally for 4 weeks. We measured cardiac enzymes, mean arterial pressure changes, heme oxygenase-1 (HO1) and total antioxidant capacity (TAC). Moreover; cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), western blotting of caspase3 and eNOS levels and histopathology were evaluated. Immunoexpression of eNOS in cardiac tissue, gene expression changes of HO1, and nuclear factor erythroid 2-related factor 2 (Nrf2) using real time polymerase chain reactions (rtPCR) were detected. Our results showed that CAR could significantly decrease Cd induced cardiotoxicity.


Assuntos
Cádmio/toxicidade , Cardiotônicos/farmacologia , Cardiotoxicidade/metabolismo , Carvedilol/farmacologia , Animais , Cardiotônicos/uso terapêutico , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/genética , Carvedilol/uso terapêutico , Heme Oxigenase (Desciclizante)/genética , Masculino , Malondialdeído/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos
3.
J Immunol Res ; 2019: 3019794, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31183386

RESUMO

Liver cirrhosis is the result of an uncontrolled fibrogenetic process, due to the activation and subsequent differentiation into myofibroblasts of the hepatic stellate cells (HSC). It is known that HSC express adrenoreceptors (AR), and the use of AR antagonists protects experimental animals from cirrhosis. However, several studies suggest that the toxicity generated by metabolism of these antagonists would hinder its use in cirrhotic patients. In addition, liver fibrosis may be associated with a decrease of the antioxidant response of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and the overregulation of the proinflammatory pathway of nuclear factor kappa B (NF-κB). Therefore, in the present work, the capacity of doxazosin (α1 antagonist), carvedilol (nonselective beta-adrenoceptor blocker with alpha 1-blocking properties), and curcumin (antioxidant and anti-inflammatory compound) to reverse liver cirrhosis and studying the possible modulation of Nrf-2 and NF-κB were evaluated. Hamsters received CCl4 for 20 weeks, and then treatments were immediately administered for 4 weeks more. The individual administration of doxazosin or carvedilol showed less ability to reverse cirrhosis in relation to concomitantly curcumin administration. However, the best effect was the combined effect of doxazosin, carvedilol, and curcumin, reversing liver fibrosis and decreasing the amount of collagen I (Sirius red stain) without affecting the morphology of hepatocytes (hematoxylin and eosin stain), showing normal hepatic function (glucose, albumin, AST, ALT, total bilirubin, and total proteins). In addition, carvedilol treatment and the combination of doxazosin with curcumin increased Nrf-2/NF-κB mRNA ratio and its protein expression in the inflammatory cells in the livers, possibly as another mechanism of hepatoprotection. Therefore, these results suggest for the first time that α/ß adrenergic blockers with curcumin completely reverse hepatic damage, possibly as a result of adrenergic antagonism on HSC and conceivably by the increase of Nrf-2/NF-κB mRNA ratio.


Assuntos
Antagonistas Adrenérgicos alfa/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Curcumina/uso terapêutico , Células Estreladas do Fígado/fisiologia , Cirrose Hepática/tratamento farmacológico , Fígado/patologia , Miofibroblastos/fisiologia , Animais , Tetracloreto de Carbono , Carvedilol/uso terapêutico , Diferenciação Celular , Cricetinae , Modelos Animais de Doenças , Doxazossina/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Fibrose , Humanos , Fígado/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo
4.
Biomed Pharmacother ; 117: 109106, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31200253

RESUMO

Carvedilol, a third generation beta blocker, is in clinical use for heart failure patients. However, besides adrenergic receptor blockade, the pharmacological effects of carvedilol on cardiomyocytes remain unknown. AMP-activated protein kinase (AMPK) is an emerging target recognized for heart failure treatment. The mechanical properties and intracellular Ca2+ properties were measured in isolated cardiomyocyte contractile functions in response to ischemic stress. Treatment of cardiomyocytes with carvedilol augmented phosphorylation of AMPK and downstream acetyl CoA carboxylase (ACC), and ameliorated hypoxia-induced impairment in maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt), and the impaired peak height and peak shortening (PS) amplitude caused by hypoxia. Carvedilol treatment improved calcium homeostasis with rescuing the peak Ca2+ signal, the maximum rate of Ca2+ change during contraction (+dF/dt) and the maximum rate of Ca2+ change during relaxation (-dF/dt) under hypoxia conditions. In mouse hearts perfused ex vivo with carvedilol, the function of post-ischemia left ventricle was improved and an augmentation in myocardial glucose uptake and glucose oxidation, and inhibition of fatty acid oxidation during ischemia and reperfusion. The protective effect of carvedilol was further supported in an in vivo regional ischemia model by ligation of left anterior descending coronary artery (LAD), mice treated with carvedilol followed by LAD occlusion and reperfusion showed significant size reduction in infarcted myocardium and improved cardiac functions. Therefore, Carvedilol as a clinical drug can modulate cardiac AMPK signaling pathway to reduce ischemic insults by ischemia and reperfusion.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Cardiotônicos/uso terapêutico , Carvedilol/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/enzimologia , Transdução de Sinais , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cardiotônicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Testes de Função Cardíaca , Camundongos Endogâmicos C57BL , Contração Miocárdica/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosforilação
5.
Tokai J Exp Clin Med ; 44(2): 29-30, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31250422

RESUMO

The newer generation non selective vasodilating beta adrenergic blocking agent Carvedilol, also has an alpha 1 adrenoceptor antagonistic effect and is widely used in treating various cardiovascular diseases. It is a selective alpha and non-selective beta blocker. It's side effects are vast and not limited to any particular organ system, the neuropsychiatric adverse effects include; somnolence, nervousness, sleep disorder, aggravated depression, vivid dreams, delirium, psychosis, impaired concentration, abnormal thinking, paroniria, and emotional lability. Hallucinations are rarely reported and as far as we know the only reported couple of cases were on metoprolol and propranolol, none has been reported with Carvedilol.


Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1/efeitos adversos , Antagonistas Adrenérgicos beta/efeitos adversos , Carvedilol/efeitos adversos , Alucinações/induzido quimicamente , Antagonistas de Receptores Adrenérgicos alfa 1/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Carvedilol/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico
6.
Medicine (Baltimore) ; 98(18): e15403, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045794

RESUMO

BACKGROUND: Clinical trials examining the therapeutic benefit of carvedilol on patients with dilated cardiomyopathy have reported inconsistent results. The aim of this study was to evaluate the clinical efficacy of carvedilol on patients with dilated cardiomyopathy. METHODS: PubMed, Embase, Cochrane Library, web of science, China National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Scientific and Technological Journal (VIP) databases were searched for randomized controlled trials (RCTs) before March 2018. Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were used to evaluate the effects of carvedilol on patients with dilated cardiomyopathy. RESULTS: Twenty one studies including 1146 participants were included. There were significant improvements on heart rate (HR) (WMD = -14.18, 95% CI: -17.72 to -10.63, P < .001), LVEF (WMD = 7.28, 95% CI: 6.53-8.03, P < .001), SBP (WMD = -10.74, 95% CI: -12.78 to -8.70, P < .001), DBP (WMD = -4.61, 95% CI: -7.32 to -1.90, P = .001), LVEDD (WMD = -2.76, 95% CI: -4.89 to -0.62, P = .011), LVESD (WMD = -3.63, 95% CI: -6.55 to -0.71, P = .015), LVEDV (WMD = -9.30, 95% CI: -11.89 to -6.71, P < .001), LVESV (WMD = -12.28, 95% CI: -14.86 to -9.70, P < .001) under carvedilol treatment compared with control. CONCLUSION: This meta-analysis demonstrates that carvedilol significantly improves cardiac function on patients with dilated cardiomyopathy. Further large scale, high-quality and multicenter RCTs are still required to confirm the impacts of carvedilol on patients with dilated cardiomyopathy.


Assuntos
Cardiomiopatia Dilatada/tratamento farmacológico , Carvedilol/uso terapêutico , Vasodilatadores/uso terapêutico , Pressão Sanguínea , Frequência Cardíaca , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Volume Sistólico
7.
J Vet Med Sci ; 81(5): 734-738, 2019 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-30944272

RESUMO

Beta-blockers are used to treat cats with hypertrophic obstructive cardiomyopathy (HOCM). However, there are various hemodynamic responses to beta-blockers. This retrospective study aimed to explore the relationship between the response to carvedilol and the presence of geometric abnormalities. Medical records were reviewed for 16 cats diagnosed with HOCM. Cats were divided into two groups based on the velocity of the left-ventricular outflow-tract after carvedilol treatment (responder: eight cats, non-responder: eight cats). Baseline intergroup comparison revealed that anterior mitral valve leaflet length and diastolic left-ventricular posterior-wall thickness were significantly greater in the non-responder group. Longer anterior mitral valve leaflet and thicker left-ventricular posterior-wall may cause poor response to carvedilol. Thus, these properties may predict a lack of response to carvedilol therapy.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Cardiomiopatia Hipertrófica/veterinária , Carvedilol/uso terapêutico , Doenças do Gato/tratamento farmacológico , Valva Mitral/patologia , Animais , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/patologia , Gatos , Ecocardiografia/veterinária , Feminino , Masculino , Estudos Retrospectivos
8.
Life Sci ; 222: 175-182, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30826497

RESUMO

AIM: An experimental study of the effect of two vasodilators, carvedilol (B blocker with alpha-antagonist) and nicorandil (NO donor) on nonalcoholic fatty liver (NAFLD) induced by hypercholesterolemia and fatty diet in rats through studying the possible anti-inflammatory and antioxidant mechanisms. MAIN METHODS: The rats were divided into 4 groups (6 rats each): The first (negative control group). The second, third and fourth groups were fed with cholesterol and fat- enriched diet for one month that stopped and continued on the standard diet for another month without treatment in the second group but treated with carvedilol and nicorandil in the third and fourth group respectively. KEY FINDINGS: They revealed that both improved NAFLD especially nicorandil treated proved by the reduction of liver enzymes (AST, ALT), the fatty infiltration determined histologically and biochemically (decrease liver triglycerides). This may be due to either being antioxidants (reduced malondialdehyde and elevated reduced glutathione) or anti-inflammatory (decreased of TNF-α) together with the reduction of insulin resistance and adiponectin elevation or gene expression (increased liver NF-κB and decreased eNOS expression) and finally maybe by their obvious effect on improvements of lipid parameters. SIGNIFICANCE: Carvedilol and nicorandil improved NAFLD through the interrelationship between inflammatory cytokines, antioxidants and insulin resistance.


Assuntos
Carvedilol/uso terapêutico , Fígado/irrigação sanguínea , Fígado/efeitos dos fármacos , Nicorandil/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Vasodilatadores/uso terapêutico , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Animais , Carvedilol/farmacologia , Fígado/metabolismo , Masculino , Nicorandil/farmacologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Ratos Sprague-Dawley , Vasodilatadores/farmacologia
9.
Front Biosci (Landmark Ed) ; 24: 1037-1049, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844728

RESUMO

An autoimmune reaction directed against the cardiac b1-adrenergic receptor (beta1-ADR) leading to the generation of autoantibodies (AA) against this G-coupled receptor has been described in patients with heart failure (HF). Agonist-like beta1-ADR-AA are associated with morbidity in HF patients and even predict mortality. Standardised and valid diagnostic tools to detect beta 1-ADR-AA in clinical routine are lacking. We used a novel ELISA approach to investigate beta 1-ADR-AA in a cohort of 574 HF patients of the CIBIS-ELD trial with follow up. The CIBIS-ELD trial compared the titration of bisoprolol and carvedilol to recommended target doses in regard to BB tolerability in patients aged 65 years and older. Patient with left ventricular (LV) ejection fraction (EF) less than 50% or LV diameter end diastolic (DED) more than 55 cm showed significantly higher levels of beta1-ADR-AA. Although not yet fully validated, this ELISA allowed for a negative correlation of beta1-ADR-AA with the EF at baseline and at the follow up, beta1-ADR-AA further correlated positively with basal heart rate at follow up 12 weeks later. beta1-ADR-AA levels thus determined  significantly increased under titration with beta-blockers (pless  than 0.01). Changes in beta1-ADR-AA between F-Up and baseline were significantly higher in patients who used beta blockers (p=0.016) before study inclusion. The type of beta-blocker titrated in this study did not affect log beta1-ADR-AA levels at baseline (p=0.132), follow-up (p=0.058), nor the change (p=0.426). beta1-ADR-AA levels were estimated using a novel, commercially available ELISA. Although not yet fully validated, this ELISA allowed for pathophysiological insights: beta1-ADR-AA levels thus determined significantly increased under titration with beta-blockers (pless  than 0.01), irrespective of type of BB. Higher levels of beta1-ADR-AA at baseline are associated with higher heart rates, lower ejection fraction and enlarged left ventricles. The relevance of the beta1-ADR-AA biomarker should be further evaluated.


Assuntos
Autoanticorpos/sangue , Insuficiência Cardíaca/imunologia , Receptores Adrenérgicos beta 1/imunologia , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Bisoprolol/uso terapêutico , Carvedilol/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Taxa de Filtração Glomerular , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca , Humanos , Masculino , Resultado do Tratamento , Função Ventricular Esquerda
10.
Carbohydr Polym ; 210: 274-288, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30732764

RESUMO

This investigation was undertaken to unveil the controlled drug delivery and preclinical anti-hypertensive potential of a novel interpenetrating biopolymer-based network of karaya gum and carboxymethyl locust bean gum (CLBG). The Williamson synthesis of CLBG was confirmed after analyzing FTIR spectra, degree of O-carboxymethyl group substitution and viscosity. The hydrogel particles (HPs) were developed using aluminium chloride solution as cross-linker. A full 32 factorial design approach was adopted for the optimization of two responses: drug entrapment efficiency and drug release (%) in simulated gastrointestinal conditions at 10 h. FE-SEM images and EDX spectra supported the formation of spherical HPs and successful entrapment of the drug in the HPs. Depending upon formulation variables, the drug entrapment efficiency of the HPs lied in the range of 84-98%. The HP matrix was chemically compatible for carvedilol phosphate as was suggested by infrared, thermal and x-ray analyses. The swelling kinetics of HPs corroborated well with the pH-dependent in vitro drug discharge characteristics. The drug release from HPs was found to follow anomalous transport mechanism with varying contribution of simple diffusion and polymer relaxation as was elucidated by Peppas-Sahlin model equation. Preclinical data suggested that the optimized HPs had an excellent blood pressure lowering activity in male Swiss albino mice up to 10 h.


Assuntos
Anti-Hipertensivos/química , Portadores de Fármacos/química , Galactanos/química , Hidrogéis/química , Hipertensão/tratamento farmacológico , Goma de Karaya/química , Mananas/química , Gomas Vegetais/química , Animais , Anti-Hipertensivos/uso terapêutico , Carvedilol/química , Carvedilol/uso terapêutico , Desenho de Drogas , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Tamanho da Partícula , Viscosidade
11.
Int Immunopharmacol ; 70: 47-55, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30785090

RESUMO

Silicosis is a well acknowledged occupational lung disorder with considerable negative impact on the patients' quality of life. Various signaling pathways have been reported to interplay in the pathogenesis of pulmonary fibro-proliferative disorders; of which, P-AKT/mTOR signaling pathway. The current study highlights the potential pulmonary protective effect of carvedilol; a non-selective α/ß blocker against experimental silicosis-induced in rats by the intranasal installation of silica (50 mg/rat, 1 ml 0.9% NaCl). Carvedilol (20 mg/kg, orally) was administered for 8 weeks post intranasal silica installation. Carvedilol significantly attenuated silica-induced pulmonary damage on all the investigated scales. Inflammatory, oxidative/anti-oxidative and fibrotic incidences significantly improved with a significant histopathological restoration of lung architecture and attenuation of inflammatory and fibrotic biomarkers expression. Carvedilol significantly reduced lung contents of P-AKT and mTOR which, appears to be the main mechanism underlying the pulmonary protective effect of carvedilol. In conclusion; carvedilol attenuated silica-induced pulmonary fibrosis by modulating P-AKT/mTOR/TGFß1 signaling and underlying inflammatory and fibrotic sequel.


Assuntos
Anti-Inflamatórios/uso terapêutico , Carvedilol/uso terapêutico , Pulmão/efeitos dos fármacos , Silicose/tratamento farmacológico , Animais , Humanos , Pulmão/imunologia , Masculino , NF-kappa B/metabolismo , Proteína Oncogênica v-akt/metabolismo , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
12.
Heart Vessels ; 34(6): 957-964, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30604188

RESUMO

Resting heart rate (HR) plus 20 or 30 beats per minute (bpm), i.e., a simplified substitute for HR at the anaerobic threshold (AT), is used as a tool for exercise prescription without cardiopulmonary exercise testing data. While resting HR plus 20 bpm is recommended for patients undergoing beta-blocker therapy, the effects of specific beta blockers on HR response to exercise up to the AT (ΔAT HR) in patients with subacute myocardial infarction (MI) are unclear. This study examined whether carvedilol treatment affects ΔAT HR in subacute MI patients. MI patients were divided into two age- and sex-matched groups [carvedilol (+), n = 66; carvedilol (-), n = 66]. All patients underwent cardiopulmonary exercise testing at 1 month after MI onset. ΔAT HR was calculated by subtracting resting HR from HR at AT. ΔAT HR did not differ significantly between the carvedilol (+) and carvedilol (-) groups (35.64 ± 9.65 vs. 34.67 ± 11.68, P = 0.604). Multiple regression analysis revealed that old age and heart failure after MI were significant predictors of lower ΔAT HR (P = 0.039 and P = 0.013, respectively), but not carvedilol treatment. Our results indicate that carvedilol treatment does not affect ΔAT HR in subacute MI patients. Therefore, exercise prescription based on HR plus 30 bpm may be feasible in this patient population, regardless of carvedilol use, without gas-exchange analysis data.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Carvedilol/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/reabilitação , Idoso , Limiar Anaeróbio , Estudos Transversais , Teste de Esforço , Terapia por Exercício , Tolerância ao Exercício , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/fisiopatologia , Análise de Regressão , Estudos Retrospectivos
13.
Oncol Rep ; 41(2): 811-818, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30483797

RESUMO

Reactive oxygen species (ROS) cause oncogenic mutations through direct interaction with DNA. Carvedilol (CAR) exhibits antioxidative activity, and pre­clinical studies have identified that CAR may prevent malignant transformation in certain carcinogenic models. This suggests that CAR may be a potential agent in cancer prevention. In the present study, non­cancerous MCF­10A cells were used as a model to investigate the chemopreventive effect of CAR on benzo(a)pyrene (BaP)­induced cellular carcinogenesis. It was identified that CAR had the ability to eliminate BaP­induced ROS production and subsequent DNA damage. CAR/BaP activated the ROS­mediated phosphoinositide 3­kinase (PI3K)/protein kinase B (AKT)Thr308 signaling pathway, whereas the effectors of the PI3K/AKT signaling pathway, murine double minute 2 (MDM2) and p53Ser15, served important functions in the BaP/CAR­mediated MCF10A cellular transformation. The results of the present study indicated that CAR may be a novel chemopreventive agent, notably in the prevention of estrogen receptor­negative breast cancer. The antioxidant effects of CAR may contribute to its chemopreventive activity.


Assuntos
Antioxidantes/farmacologia , Neoplasias da Mama/prevenção & controle , Carvedilol/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antioxidantes/uso terapêutico , Benzo(a)pireno/toxicidade , Mama/citologia , Neoplasias da Mama/patologia , Carvedilol/uso terapêutico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo
14.
Clin Cardiol ; 42(2): 299-304, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30592068

RESUMO

BACKGROUND: The effects of carvedilol and metoprolol succinate on appropriate and inappropriate implantable cardioverter defibrillator (ICD) therapy in patients with heart failure with reduced ejection fraction (HFrEF) are not fully understood. HYPOTHESIS: The hypothesis of our study is possible carvedilol superiority over metoprolol in patients with ICD. METHODS: All patients with ICD registered to a single device clinic between 1/2012 and 6/2017 (n = 569) were identified. Patients with systolic heart failure (left ventricular ejection fraction ≤40%) treated with carvedilol vs metoprolol succinate were compared. Primary endpoint was difference in survival free of appropriate device therapy (shock or anti-tachycardia pacing, ATP). Secondary endpoints were freedom from inappropriate therapy (shock or ATP) and all cause death. RESULTS: A total of 225 patients were included in the analysis with median follow up of 57 months (IQR 33.7-90). The 2 groups were comparable in the baseline characteristics. Carvedilol was superior to metoprolol succinate in improving survival free of appropriate ICD therapy (HR 0.42; 95% CI 0.24-0.72, P = 0.01). This difference was driven by reduction in survival free of appropriate shocks (HR 0.30; 95% CI 0.15-0.63, P = -0.01) while there was no significant difference in appropriate ATP (HR 0.55; 95% CI 0.28-1.1, P = 0.12). There was no significant difference in time to inappropriate shocks (HR 1.02; 95% CI 0.19-5.6, P = 0.97), inappropriate ATP (HR 0.93, OR 0.24-3.5, p value 0.9) or all cause death (HR 0.8; 95% CI 0.42-1.5, P = 0.52). CONCLUSIONS: This study suggests that carvedilol use was associated with improved survival free of appropriate ICD therapy compared to metoprolol succinate in patients with HFrEF.


Assuntos
Carvedilol/uso terapêutico , Desfibriladores Implantáveis , Insuficiência Cardíaca/terapia , Metoprolol/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Antiarrítmicos/uso terapêutico , Arkansas/epidemiologia , Causas de Morte/tendências , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/prevenção & controle , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
15.
Cochrane Database Syst Rev ; 10: CD011510, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30372514

RESUMO

BACKGROUND: Non-selective beta-blockers are recommended for the prevention of bleeding in people with cirrhosis, portal hypertension and gastroesophageal varices. Carvedilol is a non-selective beta-blocker with additional intrinsic alpha1-blocking effects, which may be superior to traditional, non-selective beta-blockers in reducing portal pressure and, therefore, in reducing the risk of upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of carvedilol compared with traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices. SEARCH METHODS: We combined searches in the Cochrane Hepato-Biliary's Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, and Science Citation Index with manual searches. The last search update was 08 May 2018. SELECTION CRITERIA: We included randomised clinical trials comparing carvedilol versus traditional, non-selective beta-blockers, irrespective of publication status, blinding, or language. We included trials evaluating both primary and secondary prevention of upper gastrointestinal bleeding in adults with cirrhosis and verified gastroesophageal varices. DATA COLLECTION AND ANALYSIS: Three review authors (AZ, RJ and LH), independently extracted data. The primary outcome measures were mortality, upper gastrointestinal bleeding and serious adverse events. We undertook meta-analyses and presented results using risk ratios (RR) or mean differences (MD), both with 95% confidence intervals (CIs), and I2 values as a marker of heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary domains and the quality of the evidence with GRADE. MAIN RESULTS: Eleven trials fulfilled our inclusion criteria. One trial did not report clinical outcomes. We included the remaining 10 randomised clinical trials, involving 810 participants with cirrhosis and oesophageal varices, in our analyses. The intervention comparisons were carvedilol versus propranolol (nine trials), or nadolol (one trial). Six trials were of short duration (mean 6 (range 1 to 12) weeks), while four were of longer duration (13.5 (6 to 30) months). Three trials evaluated primary prevention; three evaluated secondary prevention; while four evaluated both primary and secondary prevention. We classified all trials as at 'high risk of bias'. We gathered mortality data from seven trials involving 507 participants; no events occurred in four of these. Sixteen of 254 participants receiving carvedilol and 19 of 253 participants receiving propranolol or nadolol died (RR 0.86, 95% CI 0.48 to 1.53; I2 = 0%, low-quality evidence). There appeared to be no differences between carvedilol versus traditional, non-selective beta-blockers and the risks of upper gastrointestinal bleeding (RR 0.77, 95% CI 0.43 to 1.37; 810 participants; 10 trials; I2 = 45%, very low-quality evidence) and serious adverse events (RR 0.97, 95% CI 0.67 to 1.42; 810 participants; 10 trials; I2 = 14%, low-quality evidence). Significantly more deaths, episodes of upper gastrointestinal bleeding and serious adverse events occurred in the long-term trials but there was not enough information to determine whether there were differences between carvedilol and traditional, non-selective beta-blockers, by trial duration. There was also insufficient information to detect differences in the effects of these interventions in trials evaluating primary or secondary prevention. There appeared to be no differences in the risk of non-serious adverse events between carvedilol versus its comparators (RR 0.55, 95% CI 0.23 to 1.29; 596 participants; 6 trials; I2 = 88%; very low-quality evidence). Use of carvedilol was associated with a greater reduction in hepatic venous pressure gradient than traditional, non-selective beta-blockers both in absolute (MD -1.75 mmHg, 95% CI -2.60 to -0.89; 368 participants; 6 trials; I2 = 0%; low-quality evidence) and percentage terms (MD -8.02%, 95% CI -11.49% to -4.55%; 368 participants; 6 trials; I2 = 0%; low-quality evidence). However, we did not observe a concomitant reduction in the number of participants who failed to achieve a sufficient haemodynamic response (RR 0.76, 95% CI 0.57 to 1.02; 368 participants; 6 trials; I2 = 42%; very low-quality evidence) or in clinical outcomes. AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effects of carvedilol versus traditional, non-selective beta-blockers on mortality, upper gastrointestinal bleeding, serious or non-serious adverse events despite the fact that carvedilol was more effective at reducing the hepatic venous pressure gradient. However, the evidence was of low or very low quality, and hence the findings are uncertain. Additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, which evaluate both clinical and haemodynamic outcomes.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Carvedilol/uso terapêutico , Varizes Esofágicas e Gástricas/tratamento farmacológico , Hemorragia Gastrointestinal/prevenção & controle , Cirrose Hepática/tratamento farmacológico , Nadolol/uso terapêutico , Propranolol/uso terapêutico , Antagonistas Adrenérgicos beta/efeitos adversos , Adulto , Carvedilol/efeitos adversos , Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/mortalidade , Hemorragia Gastrointestinal/mortalidade , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/mortalidade , Nadolol/efeitos adversos , Prevenção Primária , Propranolol/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Prevenção Secundária
16.
Biomed Pharmacother ; 108: 1617-1627, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30372864

RESUMO

Carvedilol has been identified as a promising agent for the treatment of liver fibrosis. Meanwhile, autophagy and apoptosis have been reported to play key roles in the activation of hepatic stellate cells (HSCs), which can contribute to the progression of liver fibrosis. However, the effects of carvedilol on autophagy and apoptosis in HSCs remain unclear. Our study aimed to detect these effects and identify the underlying mechanisms by which carvedilol mediates HSC autophagy and apoptosis. For this purpose, the LX-2 cell line was used in this study, and the cells were exposed to various concentrations of carvedilol for specific times. First, we found that carvedilol increased autophagic marker levels, the number of GFP-LC3-containing puncta and LC3B-II levels in LX-2 cells. Interestingly, the addition of chloroquine (CQ) failed to enhance the effects on GFP-LC3 puncta and LC3B-II levels, and carvedilol treatment resulted in a significant increase in p62 protein levels. Moreover, carvedilol treatment led to the accumulation of yellow dots only in GFP-RFP-LC3-LX-2 cells, similar to the results following CQ treatment, indicating that carvedilol inhibited autophagic flux. Next, we found evidence that carvedilol inhibited autophagic flux by increasing lysosomal pH and not by impairing the fusion of autophagosomes with lysosomes. Moreover, carvedilol substantially reduced the viability of LX-2 cells and noticeably induced cell apoptosis, as observed by flow cytometry. In addition, increased levels of cleaved caspase-3, cleaved caspase-8 and cleaved PARP, increased Bax activity and decreased Bcl-2 expression were detected in LX-2 cells. Finally, the carvedilol treatment inhibited autophagy and subsequently induced apoptosis in vitro. In conclusion, carvedilol suppresses autophagy and promotes apoptosis in HSCs and the late-stage inhibition of autophagy preceded the induction of apoptosis.


Assuntos
Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Carvedilol/uso terapêutico , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Antioxidantes/farmacologia , Apoptose/fisiologia , Autofagia/fisiologia , Carvedilol/farmacologia , Linhagem Celular , Relação Dose-Resposta a Droga , Células Estreladas do Fígado/metabolismo , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia
17.
Am J Cardiol ; 122(11): 1959-1964, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30292333

RESUMO

Anthracycline is a commonly prescribed antineoplastic agent. As a consequence of the growing number of cancer survivors, the incidence of anthracycline-induced cardiotoxicity is increasing. However, the optimal primary preventive strategy is lacking. Therefore, we conducted a meta-analysis of all randomized controlled trials to evaluate the efficacy of carvedilol for the primary prevention of anthracycline-induced cardiotoxicity. A comprehensive search of electronic databases was conducted. The primary and secondary outcomes were the occurrence of low left ventricular ejection fraction, and the absolute change in left ventricular ejection fraction (LVEF), respectively. We calculated the odds ratios for the primary outcome and the weighted mean differences for the secondary outcomes using a random-effects model. We included 8 randomized controlled trials (633 total patients). Our results showed significantly reduced rates of low LVEF favoring the carvedilol group (3.2% vs 5.8%; odds ratios: 0.42; 95% confidence interval: 0.18 to 0.99; p = 0.05). Furthermore, there were significantly smaller reductions in LVEF in carvedilol-treated patients than in placebo-treated patients (mean differences: 2.41%; 95% confidence interval: 0.01 to 4.81; p = 0.05). In conclusion, prophylactic administration of carvedilol in anthracycline-treated cancer patients may reduce the early onset of left ventricular dysfunction compared with placebo.


Assuntos
Antraciclinas/efeitos adversos , Carvedilol/uso terapêutico , Cardiopatias/prevenção & controle , Antioxidantes/uso terapêutico , Cardiotoxicidade , Cardiopatias/induzido quimicamente , Humanos , Neoplasias/tratamento farmacológico
18.
Pharm Res ; 35(11): 204, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30191328

RESUMO

PURPOSE: The organic cation transporters (OCTs) and multidrug and toxin extrusions (MATEs), located in the basolateral and apical membrane of proximal tubular cells respectively, are crucial determinants of renal elimination and/or toxicity of cationic drugs such as cisplatin. The purpose of this study was to discover selective OCT inhibitors over MATEs, and explore their potential to protect against cisplatin-induced nephrotoxicity that is clinically common. METHODS: The inhibition by select compounds on the uptake of the probe substrate metformin was assessed in HEK293 cells overexpressing human OCT2, OCT1, MATE1, MATE2-K, and mouse Oct2, Oct1, and Mate1. Furthermore, the effects of carvedilol on organic cation transporter-mediated cellular and renal accumulation of metformin and cisplatin, and particularly the toxicity associated with cisplatin, were investigated in HEK293 cells and mice. RESULTS: Five selective OCT inhibitors were identified through the screening of forty-one drugs previously reported as the inhibitors of OCTs and/or MATEs. Among them, carvedilol showed the most selectivity on OCTs over MATEs (IC50: 3.6 µM for human OCT2, 103 µM for human MATE1 and 202 µM for human MATE2-K) in the cellular assays in vitro, with the selectivity in mice as well. Moreover, carvedilol treatment could significantly decrease cisplatin accumulation and ameliorate its toxicity both in vitro in cells and in vivo in mouse kidney. CONCLUSIONS: Our data indicate that selective inhibition of OCTs by carvedilol may protect from cisplatin-induced nephrotoxicity by restraining the cellular entry of cisplatin via OCTs, while having no impact on its elimination through MATEs.


Assuntos
Antineoplásicos/toxicidade , Carvedilol/farmacologia , Cisplatino/toxicidade , Nefropatias/tratamento farmacológico , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Animais , Carvedilol/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Masculino , Metformina/metabolismo , Camundongos Endogâmicos C57BL , Substâncias Protetoras/uso terapêutico
19.
Sci Rep ; 8(1): 14327, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254303

RESUMO

Circulating microRNAs (miRNAs) play a role in modulating the prevalence of fibrosis and have been a target of the cardiac anti-fibrotic effect of Carvedilol. However, the impact of miRNAs on the hepatoprotective effect of this non-selective ß-blocker has not been yet elucidated. Hence, the current goal is to evaluate the potential role of circulating miR-200a in the hepatic anti-fibrotic pathway of Carvedilol. Male Wistar rats were randomized into normal, CCl4 (2 ml/kg, i.p, twice weekly for 8 weeks), and CCl4 + Carvedilol (10 mg/kg, p.o, daily). Carvedilol over-expressed the circulating miR-200a to modulate epithelial mesenchymal transition (EMT) markers (vimentin, E-Cadherin). In turn, Carvedilol increased SMAD7 gene expression and protein content to attenuate the pro-fibrogenic marker transforming growth factor ß1 (TGF-ß1) and the inflammatory markers (p-38 MAPK and p-S536-NF-κB p65). The anti-fibrotic potential was reflected on the decreased expression of the mesenchymal product and EMT marker α-SMA, besides the improved histopathological examination, and the fibrosis scores/collagen quantification to enhance liver functions (AST, ALT, ALP, and AST/platelet ratio index; APRI). In conclusion, circulating miR-200a/SMAD7/TGF-ß1/EMT/MAPK axis is crucial in the hepatic anti-fibrotic mechanism of Carvedilol.


Assuntos
Carvedilol/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , MicroRNAs/sangue , Proteína Smad7/sangue , Fator de Crescimento Transformador beta1/metabolismo , Animais , Biomarcadores/metabolismo , Tetracloreto de Carbono/efeitos adversos , Carvedilol/uso terapêutico , Colágeno/metabolismo , Modelos Animais de Doenças , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Wistar
20.
PLoS One ; 13(8): e0199347, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30153268

RESUMO

BACKGROUND: Despite its recommendation by the current guidelines, the role of long-term oral beta-blocker therapy has never been evaluated by randomized trials in uncomplicated ST-segment elevation myocardial infarction (STEMI) patients without heart failure, left ventricular dysfunction or ventricular arrhythmia who underwent primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: In a multi-center, open-label, randomized controlled trial, STEMI patients with successful primary PCI within 24 hours from the onset and with left ventricular ejection fraction (LVEF) ≥40% were randomly assigned in a 1-to-1 fashion either to the carvedilol group or to the no beta-blocker group within 7 days after primary PCI. The primary endpoint is a composite of all-cause death, myocardial infarction, hospitalization for heart failure, and hospitalization for acute coronary syndrome. Between August 2010 and May 2014, 801 patients were randomly assigned to the carvedilol group (N = 399) or the no beta-blocker group (N = 402) at 67 centers in Japan. The carvedilol dose was up-titrated from 3.4±2.1 mg at baseline to 6.3±4.3 mg at 1-year. During median follow-up of 3.9 years with 96.4% follow-up, the cumulative 3-year incidences of both the primary endpoint and any coronary revascularization were not significantly different between the carvedilol and no beta-blocker groups (6.8% and 7.9%, P = 0.20, and 20.3% and 17.7%, P = 0.65, respectively). There also was no significant difference in LVEF at 1-year between the 2 groups (60.9±8.4% and 59.6±8.8%, P = 0.06). CONCLUSION: Long-term carvedilol therapy added on the contemporary evidence-based medications did not seem beneficial in selected STEMI patients treated with primary PCI. TRIAL REGISTRATION: CAPITAL-RCT (Carvedilol Post-Intervention Long-Term Administration in Large-scale Randomized Controlled Trial) ClinicalTrials.gov.number, NCT 01155635.


Assuntos
Carvedilol/uso terapêutico , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Idoso , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
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