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1.
Pharm Res ; 36(12): 170, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654151

RESUMO

PURPOSE: Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. METHODS: Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. RESULTS: The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. CONCLUSIONS: This newly demonstrated mode of "promiscuous inhibition" is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.


Assuntos
Sistema Enzimático do Citocromo P-450/química , Di-Hidropiridinas/química , Microssomos Hepáticos/metabolismo , Proteínas Recombinantes/química , Carvedilol/química , Carvedilol/metabolismo , Coloides/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Diclofenaco/química , Diclofenaco/metabolismo , Di-Hidropiridinas/metabolismo , Interações de Medicamentos , Ensaios de Triagem em Larga Escala/métodos , Humanos , Concentração Inibidora 50 , Cinética , Taxa de Depuração Metabólica/efeitos dos fármacos , Fenacetina/química , Fenacetina/metabolismo , Proteínas Recombinantes/metabolismo , Solventes/química , Tamoxifeno/química , Tamoxifeno/metabolismo
2.
Artigo em Inglês | MEDLINE | ID: mdl-31629310

RESUMO

In this paper we present an FDA validated method to analyze ten antiarrhythmic drugs (atenolol, bisoprolol, carvedilol, diltiazem, flecainide, lidocaine, metoprolol, propranolol, sotalol and verapamil). A simple and fast sample preparation protocol with protein precipitation followed by ultra performance liquid chromatography (UPLC) for chromatographic separation and mass spectrometric detection applying electrospray ionization (ESI+) and selected reaction monitoring mode (MS/MS) was used. Only 50 µl plasma sample is needed for the simultaneous quantification of all compounds within a 5 min run-to-run analysis time. Sotalol-D6, carvedilol-D5 and verapamil-D6 were used as internal standards. The method was validated according to the FDA guidelines. Correlation coefficients were higher than 0.998 for all compounds. Intra- and interday accuracies were within 15 CV(%) for all analytes. The method is currently successfully applied for routine analysis in our hospital.


Assuntos
Antiarrítmicos/sangue , Espectrometria de Massas em Tandem/métodos , Atenolol/sangue , Bisoprolol/sangue , Carvedilol/sangue , Cromatografia Líquida de Alta Pressão , Diltiazem/sangue , Flecainida/sangue , Ensaios de Triagem em Larga Escala/métodos , Humanos , Lidocaína/sangue , Metoprolol/sangue , Propranolol/sangue , Reprodutibilidade dos Testes , Sotalol/sangue , Espectrometria de Massas por Ionização por Electrospray , Verapamil/sangue
3.
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
4.
Phys Chem Chem Phys ; 21(35): 19686-19694, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31469369

RESUMO

In this study the glass transition temperatures (Tgα and Tgß) in mesoporous silica-based amorphous drugs were characterized. For this purpose, mesoporous silica Parteck SLC (MPS) was loaded with the drugs ibuprofen and carvedilol, either below, at, or above the monomolecular drug loading capacities, i.e. the concentration at which the entire MPS surface is covered with a monolayer of drug molecules. The resulting amorphous forms were analysed using X-ray powder diffraction and the thermal behaviour was characterised with differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). The drug monolayer did not contribute to the thermal signal in DSC. Using DMA however, it could be shown that the monolayer indeed exhibited a very weak Tgα, and that the temperature range of this transition did not differ from that of the quench cooled amorphous drugs. Theoretical ab initio molecular dynamics simulations revealed that the nature of hydrogen bonding geometry of the functional groups interacting with the MPS surface were similar to that of the respective crystalline drugs, which results in restricted molecular motions for those functional groups. On the other hand, the non-interacting parts of the molecules exhibited molecular motions similar to what is observed in pure amorphous drugs. As a result of the interactions of the monolayer with the MPS surface, the monomolecular drug layer did not reveal a Tgß. However, a Tgß was found at any drug-MPS ratios above the monomolecular drug loading capacity as a result of the excess drug which forms a "true" amorphous phase. Overall, this study demonstrated that drug molecules forming an amorphous monolayer on the surfaces of a mesoporous silica particle, even though they are restricted in their mobility, exhibit a Tgα, but lack a Tgß, whereas any excess drug confined in the MPS pores showed similar properties as the pure amorphous drug. These findings will help to increase the overall understanding of drug loaded MS systems, including their physical stability as well as release properties.


Assuntos
Vidro/química , Dióxido de Silício/química , Temperatura de Transição , Varredura Diferencial de Calorimetria , Carvedilol/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ibuprofeno/química , Simulação de Dinâmica Molecular
6.
Pharm Dev Technol ; 24(9): 1115-1124, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31282827

RESUMO

The objective of the present study was to enhance the dissolution rate of carvedilol (CA), a poorly water-soluble antihypertensive drug, using a co-grinding method in the presence of polyvinylpyrrolidone (PVP) and sodium lauryl sulfate (SLS). Various ratios of CA:PVP:SLS were ground by a planetary ball mill. They were studied in terms of dissolution, solubility, and particle size. The solid state and morphology of the intact drug and prepared samples were also characterized using differential scanning calorimetry (DSC), infrared spectroscopy (IR), X-ray diffraction (XRD), and scanning electron microscope (SEM). According to the results, co-grinding in the presence of PVP and SLS significantly increased CA dissolution rate. DE60 (dissolution efficiency) obtained for the best ternary ground mixture (89.31%) was 3.4 and 4.5 times higher than that of the related physical mixture (PM) and the intact drug, respectively. Further, the solubility of this formulation was about 10 times higher compared to that of the intact CA. A direct correlation was also observed between the chamber rotation speed of the planetary mill within the range of 100-400 rpm and CA dissolution rate. Finally, DSC, IR, and XRD analysis ruled out any polymorphic changes and chemical interactions during the grinding process.


Assuntos
Anti-Hipertensivos/química , Carvedilol/química , Excipientes/química , Povidona/química , Dodecilsulfato de Sódio/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Tamanho da Partícula , Difração de Pó , Solubilidade , Difração de Raios X
7.
Mol Med Rep ; 20(2): 1605-1612, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257490

RESUMO

Portal hypertension (PHT) is one of the most severe consequences of liver cirrhosis. Carvedilol is a first­line pharmacological treatment of PHT. However, the antifibrogenic effects of carvedilol on liver cirrhosis and the intrinsic mechanisms underlying these effects have not been thoroughly investigated. The present study aimed to investigate the antifibrogenic effects of carvedilol on liver cirrhosis in vivo and in vitro. Liver cirrhosis was induced in rats by carbon tetrachloride (CCl4) administration for 9 weeks; carvedilol was administered simultaneously in the experimental group. Blood samples were collected for serum biochemistry. Liver tissues were used for fibrosis evaluation, histological examination, immunohistochemistry and western blot analysis. The human hepatic stellate cell (HSC) line LX­2 was used for in vitro studies. The effects of carvedilol on LX­2 cell proliferation and invasion were evaluated by Cell Counting Kit­8 assay and Transwell invasion assays, respectively. The effect of carvedilol on transforming growth factor ß1 (TGFß1)­induced collagen synthesis in LX­2 cells and the molecular mechanisms were examined by western blot analysis. The results demonstrated that carvedilol improved CCl4­induced structural distortion and fibrosis in the liver. Carvedilol inhibited HSC activation, proliferation and invasion. Carvedilol inhibited HSC collagen synthesis through the TGFß1/SMAD pathway. In conclusion, carvedilol may alleviate liver cirrhosis in rats by inhibiting HSC activation, proliferation, invasion and collagen synthesis. Carvedilol may be a potential treatment of early­stage liver cirrhosis.


Assuntos
Antioxidantes/farmacologia , Carvedilol/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Administração Oral , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Tetracloreto de Carbono , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Regulação da Expressão Gênica , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Humanos , Hipertensão Portal/induzido quimicamente , Hipertensão Portal/genética , Hipertensão Portal/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Wistar , Transdução de Sinais , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Fator de Crescimento Transformador beta1/farmacologia
8.
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
9.
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
11.
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
12.
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
13.
Molecules ; 24(9)2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067732

RESUMO

Mesoporous carriers have been extensively applied to improve the dissolution velocity and bioavailability of insoluble drugs. The goal of this work was to compare the drug-loading efficiency (LE) and drug-dissolution properties of mesoporous silica nanoparticles (MSN) and mesoporous carbon nanoparticles (MCN) as drug vectors oral delivery of water-insoluble drugs. For this purpose, MSN and MCN with similar particle size, surface area, and mesoporous diameter were prepared to precisely evaluate the effects of different textures on the drug-loading and dissolution behavior of insoluble drugs. Carvedilol (CAR), a Bio-pharmaceutic Classification System (BCS) class II drug, was loaded in the MSN and MCN by the solvent adsorption method and solvent evaporation method with different carrier-drug ratios. The carboxylated MCN (MCN-COOH) had a higher LE for CAR than MSN for both the two loading methods due to the strong adsorption effect and π-π stacking force with CAR. In vitro drug dissolution study showed that both MSN and MCN-COOH could improve the dissolution rate of CAR compared with the micronized CAR. In comparison to MSN, MCN-COOH displayed a slightly slower dissolution profile, which may be ascribed to the strong interaction between MCN-COOH and CAR. Observation of cell cytotoxicity and gastrointestinal mucosa irritation demonstrated the good biocompatibility of both MSN and MCN-COOH. The present study encourages further research of different carriers to determine their potential application in oral administration.


Assuntos
Carbono/química , Carvedilol/química , Portadores de Fármacos/química , Dióxido de Silício/química , Administração Oral , Adsorção/efeitos dos fármacos , Disponibilidade Biológica , Células CACO-2 , Carbono/farmacologia , Carvedilol/efeitos adversos , Portadores de Fármacos/farmacologia , Composição de Medicamentos , Humanos , Nanopartículas/química , Nanopartículas/uso terapêutico , Dióxido de Silício/farmacologia , Solubilidade/efeitos dos fármacos , Água/química
14.
Int J Pharm ; 566: 89-100, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31129345

RESUMO

Self-(micro)emulsifying drug delivery systems (S(M)EDDS) have emerged as effective vehicles for enhancing bioavailability of poorly water soluble drugs, however solidification of the systems represents a major challenge. Objective of this study was development of carvedilol loaded liquid SMEDDS and transformation into solid pellets employing fluid-bed coating technologies. Carvedilol-loaded formulation of SMEDDS was comprised of Capmul® MCM EP, castor oil, Kolliphor® RH40 and PEG 400. The obtained liquid SMEDDS mixed with fillers and polymers was layered onto MCC pellets. Coating process was conducted in the modified, swirl-flow based fluid bed coating device, which was proved superior over the conventional Wurster fluid bed, with lower agglomeration rate. Use of polymer was essential for entrapping SMEDDS in the coating layer(s). Self-microemulsifying properties as well as fast drug release as one of main SMEDDS advantages were preserved in the solid products. Addition of lactose into the coating dispersion and applying intermediate and surface film coating to the pellets enabled higher drug loading and prevented sticking of the pellets during handling and storage. Present study indicates that the (swirling) fluid-bed pellet coating technology is a promising strategy for preparation of solid SMEDDS-coated pellets with adequate drug loading capacity and enhanced release of poorly water soluble drug.


Assuntos
Carvedilol/química , Sistemas de Liberação de Medicamentos , Tecnologia Farmacêutica/métodos , Emulsões
15.
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
16.
Eur J Pharmacol ; 855: 50-55, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31063774

RESUMO

Previous studies indicated that one of the action targets of carvedilol is the voltage-gated potassium (Kv) channel, which has a fundamental role in the control of electrical properties in excitable cells. It is not clear whether this compound exerts any actions specifically on delayed rectifier Kv2.1 channels. The present study is conducted on Kv2.1 currents heterologously expressed in HEK293 cells to characterize the block by carvedilol in detail, identifying molecular determinants and providing biophysical insights of the block. Macroscopic Kv2.1 currents obtained by whole-cell recording were substantially inhibited after addition of carvedilol with an IC50 value of 5.1 µM. This drug also led to a largely hyperpolarizing shift (30 mV) of the inactivation curve, which may contribute to the blocking action due to more inactivation of Kv2.1 currents occurred in depolarization potentials. Mutations at Y380 (a putative TEA binding site) and K356 (a K+ binding site) in the outer vestibule of Kv2.1 channels significantly eliminated the inhibitory effects of carvedilol and prevented the leftward shift of inactivation. Moreover, mutations at above positions modulated the effects of carvedilol on the deactivation but not activation kinetics of Kv2.1 channels. Collected data indicate that carvedilol can exert a blocking effect on the closed-state of Kv2.1 channels, and specific residues within the S5-P and P-S6 linkers in the outer vestibule may play crucial roles in carvedilol-induced blocking for Kv2.1 channels.


Assuntos
Carvedilol/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Shab/antagonistas & inibidores , Células HEK293 , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Canais de Potássio Shab/metabolismo
18.
Int J Biol Macromol ; 135: 246-260, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31128197

RESUMO

A major challenge associated with the oral delivery of anti-hypertensive drugs is their poor water solubility and low oral bioavailability. Carvedilol (CAR), a potential beta-blocker is hydrophobic drug that exhibit limited therapeutic effect through oral conventional drug delivery systems. For this reason, it is prerequisite to further investigate and develop an alternative drug delivery system so as to improve therapeutic efficacy of carvedilol as well as to minimize side effects of conventional treatment therapy. In the present study, it was aimed to develop nanoparticles (NPs) of a hydrophobic antihypertensive agent, Carvedilol by using chitosan (CS) as biodegradable polymer. Carvedilol chitosan nanoparticles (CAR-CS-NPs) were prepared by ionic gelation technique using sodium tripolyphosphate (TPP) as a crosslinking agent. The NPs were optimized and validated by Box-Behnken design (BBD). The optimized formulation showed particle size 102.12 nm and drug entrapment efficiency 71.26 ±â€¯1.16%. The drug release profile of CAR-CS NPs showed biphasic release pattern with an initial burst release in the first 2 h followed by a controlled release over a period of 72 h. The pharmacokinetic results revealed that the optimized chitosan nanoparticles formulation have higher bioavailability than marketed tablet formulation which indicates CAR-CS NPs as an effective strategy to delivery poorly water soluble drugs.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/farmacocinética , Carvedilol/administração & dosagem , Carvedilol/farmacocinética , Quitosana , Portadores de Fármacos , Nanopartículas , Administração Oral , Antagonistas Adrenérgicos beta/química , Animais , Disponibilidade Biológica , Carvedilol/química , Química Farmacêutica , Quitosana/química , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Estrutura Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos , Solubilidade , Análise Espectral
19.
Eur J Pharmacol ; 854: 159-166, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30991047

RESUMO

After acute myocardial infarction (AMI), reactive oxygen species and oxidative stress have important roles in the progression to heart failure. As a therapeutic alternative, thyroid hormones (TH) revealed cardioprotective effects after AMI, including decreasing oxidative stress. Carvedilol beta-blocker, already used in the clinical treatment of AMI, also mitigate cardiac pathological remodelling. This study assessed the effects of post-AMI carvedilol and TH co-administration on oxidative stress and cardiac function as well as whether those effects were synergistic. Male Wistar rats were divided into five groups: sham-operated (SHAM), infarcted (MI), infarcted + TH (MI + TH), infarcted + carvedilol (MI + C) and infarcted + C + TH (MI + C + TH). Two days post-surgery, the SHAM and MI groups received saline, and treated groups received their respective treatments by gavage for 12 days. The animals were submitted to echocardiographic evaluation, ventricular catheterization and euthanized for heart collection to perform oxidative stress analysis. Treated groups improved for ejection fraction compared to the MI group. Carvedilol decreased the positive chronotropic TH effects in the MI + C + TH group. The MI and MI + C groups had increased reactive oxygen species and reduced sulfhydryl levels. Carvedilol and TH co-administration showed synergic effects in the MI + C + TH group, reducing reactive oxygen species levels and improving GSH/GSSG ratio. Moreover, co-treatment attenuated NADPH oxidase activity in the MI group. Therefore, this study showed for the first time that carvedilol and TH co-administration may improve redox balance and cardiac function after AMI. Such co-administration could represent a therapeutic strategy capable of preventing cardiac dysfunction and redox unbalance after AMI.


Assuntos
Carvedilol/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Infarto do Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Animais , Antioxidantes/metabolismo , Sinergismo Farmacológico , Eletrocardiografia/efeitos dos fármacos , Dissulfeto de Glutationa/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Infarto do Miocárdio/sangue , Infarto do Miocárdio/fisiopatologia , NADPH Oxidases/metabolismo , Oxirredução , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Compostos de Sulfidrila/metabolismo , Tireotropina/sangue
20.
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
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