RESUMO
BACKGROUND: Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. ß-Adrenergic receptor antagonists (ß-blockers) are the first-line therapy for HCM. However, ß-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown. METHODS: We screened 21 ß-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM (Myh6R403Q/+ and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM (MYH7R403Q/+). RESULTS: We identified that carvedilol, a ß-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a ß1-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α1-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of ß-blocking effect, retains the ability to inhibit both α1-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In Myh6R403Q/+ mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in MYH7R403Q/+ iPSC-derived cardiomyocytes. CONCLUSIONS: R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α1-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.
Assuntos
Cardiomiopatia Hipertrófica , Metoprolol , Humanos , Camundongos , Animais , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Metoprolol/uso terapêutico , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/tratamento farmacológico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/uso terapêutico , Miócitos Cardíacos/metabolismo , Verapamil/uso terapêutico , Receptores Adrenérgicos/metabolismoRESUMO
RATIONALE: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain. OBJECTIVES: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota. METHODS: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST). The anti-depressive effect and fecal gut microbiota composition were studied in DPNP mice treated with carvedilol (10 mg/kg/day), and the relationships between them were analyzed by Spearman's correlation. RESULTS: Depression was successfully induced in DPNP mice. Carvedilol can reverse the decreased mechanical pain threshold and relieve the depressive behaviors of DPNP mice, while increasing the abundance of Prevotella, Ruminococcus, Helicobacter and Desulfovibrio, and decreasing the abundance of Akkermansia and Allobaculum. CONCLUSIONS: Carvedilol can alleviate the mechanical hyperalgesia and alter gut microbiota to ameliorate the depression-like behaviors which induced by DPNP.
Assuntos
Antidepressivos , Carvedilol , Depressão , Neuropatias Diabéticas , Microbioma Gastrointestinal , Estreptozocina , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Masculino , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Camundongos , Depressão/tratamento farmacológico , Depressão/microbiologia , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/microbiologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Experimental/microbiologia , Hiperalgesia/tratamento farmacológico , Camundongos Endogâmicos C57BLRESUMO
Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.
Assuntos
Doenças Cardiovasculares , Miócitos Cardíacos , Humanos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Miócitos Cardíacos/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Animais , Apoptose/efeitos dos fármacos , Transdução de Sinais , Fármacos Cardiovasculares/uso terapêutico , Fármacos Cardiovasculares/farmacologiaRESUMO
Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium-glucose cotransporter-2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon-like peptide-1 (GLP-1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase-4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Nefropatias Diabéticas , Quimioterapia Combinada , Antagonistas de Receptores de Mineralocorticoides , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Progressão da Doença , Sistema Renina-Angiotensina/efeitos dos fármacos , Resultado do Tratamento , Antagonistas de Receptores de Angiotensina/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Inibidores da Dipeptidil Peptidase IV/uso terapêuticoRESUMO
AIMS: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour ß-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. CONCLUSION: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent ß-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.
RESUMO
BACKGROUND: Pyroptosis is an inflammatory type of programmed cell death, and could overcome the drug-resistance induced by anti-apoptotic effect of cancers. Carvedilol (CVL), a ß-adrenergic receptors antagonist, has shown anti-inflammatory response and anti-cancer effect. The aim of this study is to investigate whether pyroptosis can be activated by CVL in prostate cancer (PCa). METHODS AND RESULTS: Datasets were used to analyze the expressions of pyroptosis-related proteins. Intracellular morphological change, cell viability, LDH and Il-1ß release by cells,, and Hoechst/PI staining were used to detect the occurrence of pyroptosis. Realtime-PCR, western blot, immunofluorescence, and immunohistochemistry (IHC) were used to investigate the expressions of pyroptosis-related proteins. Datasets analyze showed the expressions of NLRP3, Caspase 1, ASC and GSDMD were all decreased in PCa comparing with normal tissues, but without prognostic significance. CVL treatment weakened the viabilities of PCa cells. Cell morphology changing, cytoplasmic vacuole formation, membrane integrity loss, LDH and IL-1ß release and PI positive cells increasing were observed. NLRP3, Caspase 1, ASC, GSDMD and N-GSDMD expressions were elevated after CVL treatment, accompanied by a tendency of NF-κB transferring into nucleus. In vivo, CVL inhibited the growth of subcutaneous transplanted tumor. IHC showed CVL increased the expressions of NLRP3, ASC, and GSDMD, and decreased the expression of Ki-67 in transplanted tumor tissues. CONCLUSION: This study demonstrated that CVL could induce pyroptosis in PCa cells through NLRP3-caspase1-ASC inflammasome by promoting nuclear translocation of NF-κB, which would lay a foundation for the application of adrenergic receptor antagonist in PCa.
Assuntos
NF-kappa B , Neoplasias da Próstata , Masculino , Humanos , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Carvedilol , Piroptose , Caspase 1 , Neoplasias da Próstata/tratamento farmacológicoRESUMO
AIM: This study aimed to assess the prognostic significance of virtual portal pressure gradient (vPPG) response to carvedilol in patients with compensated cirrhosis (CC). METHODS: Compensated cirrhosis patients with high-risk varices were prospectively enrolled to receive carvedilol for prevention of first variceal hemorrhage (VH) and followed up for 1 year. The vPPG response was defined as a reduction of vPPG >10% from baseline after 1-month therapy. Logistic and Cox regression analyses were performed to identify independent predictors for vPPG response and first decompensation, respectively. Competitive risk models were constructed to predict disease progression, and validated using the C-index, Kaplan-Meier analysis, competitive risk analysis, and calibration curves. RESULTS: A total of 129 patients completed this study, of whom 56 (43.4%) achieved vPPG response and were referred as vPPG responders. Baseline vPPG, red color sign, Model for End-stage Liver Disease score, serum monocyte chemoattractant protein-1 (MCP-1), and laminin levels significantly correlated with vPPG response, which itself was further documented as an independent predictor of VH, ascites, and overall decompensation events in CC. Moreover, the red color sign or Child-Turcotte-Pugh score effectively predicted VH, while ascites correlated well with portal flow velocity or MCP-1. The predictive models for VH and ascites showed a good discrimination with C-index values of 0.747 and 0.689 respectively, and the high consistency on calibration curves. CONCLUSION: The vPPG response could be used as a noninvasive tool for prediction of disease progression in patients with CC.
RESUMO
PURPOSE: This study aimed to investigate the prescription of beta-blockers (ß-blockers) for patients with asthma. METHODS: In this retrospective cross-sectional study using the National Patient Sample (NPS) of the Health Insurance Review and Assessment Service (HIRA) of South Korea, ß-blockers and asthma medications were investigated using generic name codes provided by HIRA. Concomitant administration was identified when a ß-blocker and an asthma medication were co-prescribed in one billing statement or when separate ß-blocker and asthma prescriptions had overlapping dates of use. RESULTS: In the 1027 patients with asthma who were prescribed non-selective ß-blockers (non-SBs), 3087 non-SB prescriptions were identified, of which 62.3% and 37.3% were for carvedilol and propranolol, respectively. Of the 906 patients with asthma prescribed selective ß-blockers (SBs), 2942 SB prescriptions were identified, of which 48.5%, 28.3%, and 20.3% were for bisoprolol, atenolol, and nebivolol, respectively. Overall, 2149 non-SB and 2124 SB prescriptions with overlapping use dates with asthma medications were identified, which were prescribed to 726 and 657 patients, accounting for 70.7% and 72.5% of the patients receiving non-SBs and SBs, respectively. ß2-agonists accounted for 39.9% of the concomitant asthma medications with overlapping dates of use with non-SBs. Co-prescribing of bronchodilators occurred at a rate of 38.7% and 45.1% for the 3087 non-SB prescriptions and 2942 SB prescriptions, respectively. CONCLUSIONS: Carvedilol and propranolol accounted for half of all ß-blockers prescribed to asthma patients. Prescribing ß-blockers to patients with asthma requires caution to prevent exacerbation of asthma and drug interactions between ß-blockers and co-prescribed asthma medications.
Assuntos
Antagonistas Adrenérgicos beta , Asma , Humanos , Asma/tratamento farmacológico , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/administração & dosagem , Estudos Retrospectivos , Estudos Transversais , Masculino , Feminino , República da Coreia , Pessoa de Meia-Idade , Adulto , Idoso , Prescrições de Medicamentos/estatística & dados numéricos , Adulto Jovem , Antiasmáticos/uso terapêutico , Antiasmáticos/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos , AdolescenteRESUMO
The common antihypertensive drugs are B-blockers and diuretics. For the determination of beta-blocker medicines (bisoprolol fumarate and carvedilol) and diuretic drug (Furosemide), new and accurate chromatographic method has been developed. The separation was achieved using a developing system that includes chloroform:methanol:ethyl acetate:ammonia (6:2:2:0.2 by volume) as a mobile phase and the bands were detected at 240 nm. The concentration ranges were 5-25, 1-7, and 1-3.5 µg/band for bisoprolol fumarate, carvedilol, and furosemide, respectively. This chromatographic approach is the first methodology for simultaneously determining bisoprolol fumarate, carvedilol, and furosemide in their pure forms and in their pharmaceutical dosage forms. The advantages of using known analytical procedures are their simplicity, speed, cost effectiveness, lack of laboriousness, and ability to save time as the three tablets are determined in one step and can be used for routine analysis of the investigated combinations in quality control laboratories. According to International Conference of Harmonization guidelines, the established procedures have been validated, and the results were statistically compared to those obtained by the reported reversed-phase-high-performance liquid chromatography methods using Student's t-test and F-test, with no significant difference between them, indicating that the proposed methods can be used for routine drug quality control analysis.
Assuntos
Anti-Hipertensivos , Bisoprolol , Bisoprolol/análise , Furosemida , Cromatografia em Camada Fina/métodos , Carvedilol , Comprimidos , Densitometria/métodos , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos TestesRESUMO
ß-Adrenoceptors (ß-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three ß-ARs, ß1-AR, ß2-AR, ß3-AR are localized to the human heart. Activation of ß1-AR and ß2-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of ß1-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of ß1-AR is critical in the pathogenesis of cardiac arrhythmias while activation of ß2-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of ß2-AR in cardiovascular disease, particularly arrhythmia generation. All ß-blockers used therapeutically to treat cardiovascular disease block ß1-AR with variable blockade of ß2-AR depending on relative affinity for ß1-AR vs ß2-AR. Since the introduction of ß-blockers into clinical practice in 1965, ß-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. ß-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. ß-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The ß-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other ß-blockers and is used successfully in the treatment of heart failure. The discovery of ß3-AR in human heart created interest in the role of ß3-AR in heart failure but has not resulted in therapeutics at this stage.
RESUMO
Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.
Assuntos
Ascite , Cardiotoxicidade , Ratos , Animais , Carvedilol/farmacologia , NADP/metabolismo , Cardiotoxicidade/metabolismo , Ascite/patologia , Doxorrubicina/uso terapêutico , Miocárdio/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Ferro/metabolismo , Peroxidação de Lipídeos , Fígado/metabolismo , Transferrina/metabolismo , Peso CorporalRESUMO
Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). ß-adrenoceptor antagonist drugs (ß-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of ß-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind ß-blockers' anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed ß-blockers' cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC50 of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with ß-agonists, in comparison to the control. This effect might be attributed to ß-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR's multifaceted anticancer properties, implying that combining CAR with ß-agonists could be a useful strategy for lung cancer treatment.
RESUMO
For decades, non-selective beta-blockers (NSBBs) have been the standard of care for the primary and secondary prevention of bleeding from oesophageal varices. However, several questions regarding the best clinical use of NSBBs remain unanswered and new data continue to emerge. Herein, we aim to delineate the therapeutic window of NSBBs in cirrhosis from a more individualised perspective. We address the current controversy of widening the therapeutic window and prescribing NSBBs to all patients with clinically significant portal hypertension. Although transient elastography is useful to rule-in clinically significant portal hypertension, we lack robust data supporting the use of NSBBs in patients without varices. While most data are based on propranolol, accumulating evidence suggests that carvedilol is superior and should be the first-line treatment until the decompensated stage. The clinical risk-to-benefit ratio appears to deteriorate in advanced decompensated stages and the risk of harm is high in patients with refractory ascites, low blood pressure and renal impairment, which clinically define closure of the therapeutic window. We also critically review non-invasive surrogates and biomarkers for predicting the haemodynamic response to NSBBs and confirm that the absence of reliable non-invasive methods is one of the main challenges facing the field.
Assuntos
Varizes Esofágicas e Gástricas , Hipertensão Portal , Humanos , Medicina de Precisão , Hemorragia Gastrointestinal/prevenção & controle , Antagonistas Adrenérgicos beta/uso terapêutico , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Hipertensão Portal/etiologia , Hipertensão Portal/complicações , Varizes Esofágicas e Gástricas/tratamento farmacológico , Varizes Esofágicas e Gástricas/etiologiaRESUMO
An increasing number of studies have focus upon ß-adrenergic receptor blockers and their anti-tumor effects. However, the use of Carvedilol (CVD), the third generation ß-AR blocker, has not been explored for use against T-ALL. In this study, the level of ß-ARs was explored in pediatric T-ALL patients. Moreover, the antitumor effects of CVD against T-ALL were assessed in vitro and in vivo, and the underlying mechanisms were investigated. The viability of T-ALL cells following CVD treatment was detected using a CCK-8 assay, and the apoptotic and cell cycle effects were measured using flow cytometry. The protein levels of ß-ARs, cAMP, Epac, JAK2, STAT3, p-STAT3, PI3K, p-PI3K, AKT, p-AKT, mTOR, cyclin D1, PCNA, and cleaved caspase-3 were assessed by Western blotting. In vivo experiments were used to investigate the effect of CVD on T-ALL growth in mice. The results indicated that ß-ARs were highly expressed in the newly diagnosed T-ALL cells when compared to those in the control group (P < 0.05). In vitro, CVD significantly inhibited T-ALL cell viability, promoted apoptosis and blocked the G0/G1 phase of cell cycle. After CVD treatment, the protein levels of ß-ARs, cAMP, Epac, PI3K, p-PI3K, AKT, p-AKT, mTOR, JAK2, STAT3, p-STAT3, cyclin D1 and PCNA were significantly downregulated (P < 0.05); whereas cleaved caspase-3 was significantly upregulated (P < 0.05). In vivo, the volume and weight of the xenograft tumors were significantly decreased in the CVD group (P < 0.05). CVD promoted xenograft tumor apoptosis and reduced the proportion of CEM-C1 cells in murine peripheral blood and bone marrow (P < 0.05). Our results demonstrate that ß-ARs are expressed in T-ALL. CVD has a strong antitumor effect against T-ALL and inhibits ß-AR associated signaling pathways. Therefore, CVD may provide a potential therapy for T-ALL.
Assuntos
Doenças Cardiovasculares , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ciclina D1/metabolismo , Carvedilol/farmacologia , Carvedilol/uso terapêutico , Caspase 3/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Troca do Nucleotídeo Guanina , ApoptoseRESUMO
Cerebral ischemia is divided into local cerebral ischemia and diffuse cerebral ischemia. The etiology of localized cerebral ischemia includes middle cerebral artery embolism; stenosis, occlusion, or thrombosis of extracranial internal carotid artery or vertebral artery; and cerebral artery spasm. The causes of diffuse cerebral ischemia include cardiac arrest, hypotension, anemia, and hypoglycemia. However, the underlying mechanism is still unclear. In this study, we demonstrated that activator of transcription 3 (ATF3) is a hubgene in IS by bioinformatics analysis. The expression of ATF3 was increased in PC12 cells with oxygen-glucose deprivation/reoxygenation (OGD/R) treatment. ATF3 deficiency inhibited cell viability and induced cell apoptosis, whereas ATF3 overexpression showed the opposite role in cell viability and cell apoptosis. Moreover, Carvedilol as a compound targeting ATF3 also facilitated cell viability and reduced cell apoptosis. ATF3 deficiency retarded the increase in cell viability and inhibition of cell apoptosis in OGD/R-PC12 cells with Carvedilol treatment. Additionally, the decreased Bax and cleaved caspase-3 were released in OGD/R-PC12 cells with Carvedilol and siATF3 treatment, while Bcl-2 expression was inhibited in OGD/R-PC12 cells with Carvedilol and siATF3 treatment. In conclusion, Carvedilol may be a key compound targeting ATF3 in OGD/R-PC12 cells. Graphical Abstract: Carvedilol positively regulated cell viability and negatively regulated cell apoptosis in OGD/R-PC12 cells by inhibition of ATF3.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Ratos , Animais , AVC Isquêmico/tratamento farmacológico , Carvedilol/farmacologia , Apoptose , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Células PC12 , Oxigênio/metabolismo , Sobrevivência CelularRESUMO
AIM: The aim of this study was to investigate the potential cardioprotective and anti-cancer effects of carvedilol (CAR) either free or as loaded nano-formulated with or without doxorubicin (DOX) in solid Ehrlich carcinoma (SEC)-bearing mice. It focused on assessment of cardiac damage, drug resistance, apoptosis, oxidative stress status, angiogenesis and proliferation. METHODS: CAR was loaded into poly-D,L lactic-co-glycolic acid)PLGA(or Niosomes. SEC was induced in female albino mice as an experimental model of breast cancer. Seventy-two mice were randomly divided into 9 equal groups (Normal control, Untreated-SEC, SEC + DOX, SEC + CAR-free, SEC + CAR-PLGA, SEC + CAR-Niosomes, SEC + DOX + CAR-free, SEC + DOX + CAR-PLGA and SEC + DOX + CAR-Niosomes). Tumor volume and survival rate were recorded. On day 28 from tumor inoculation, mice were sacrificed, and blood samples were collected for determination of serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB). One part from tumor tissues was prepared for assessment of multidrug resistance protein-1 (MDR-1), caspase-3, reduced glutathione (GSH) and malondialdehyde (MDA), while the other part was processed for histopathological examination and immunohistochemical expression of vascular endothelial growth factor (VEGF) and Ki-67. RESULTS: There was non-significant difference between CAR-free, CAR-PLGA and CAR-Niosomes as anticancer either alone or when combined with DOX. However, CAR-free demonstrated potential cardioprotective effects against cardiac damage mediated by cancer or DOX that have been enhanced using CAR-PLGA or CAR-Niosomes, but that of Niosomes outperformed them both. CONCLUSION: CAR could be used as an adjuvant therapy with DOX, especially when nanoformualted with PLGA and even better with Niosomes, without compromising its cytotoxicity against cancer cells and preventing its cardiotoxic impacts.
Assuntos
Carcinoma , Nanopartículas , Camundongos , Feminino , Animais , Carvedilol/farmacologia , Lipossomos , Fator A de Crescimento do Endotélio Vascular , Doxorrubicina/farmacologia , Carcinoma/tratamento farmacológico , Ácido LácticoRESUMO
Portal hypertension (PH) is the most common complication ofcirrhosis and represents the main driver of hepatic decompensation. The overarching goal of PH treatments in patients with compensated cirrhosis is to reduce the risk of hepatic decompensation (i.e development of ascites, variceal bleeding and/or hepatic encephalopathy). In decompensated patients, PH-directed therapies aim at avoiding further decompensation (i.e. recurrent/refractory ascites, variceal rebleeding, recurrent encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome) and at improving survival. Carvedilol is a non-selective beta-blocker (NSBB) acting on hyperdynamic circulation/splanchnic vasodilation and on intrahepatic resistance. It has shown superior efficacy than traditional NSBBs in lowering PH in patients with cirrhosis and may be, therefore, the NSBB of choice for the treatment of clinically significant portal hypertension. In primary prophylaxis of variceal bleeding, carvedilol has been demonstrated to be more effective than endoscopic variceal ligation (EVL). In patients with compensated cirrhosis carvedilol achieves higher rate of hemodynamic response than propranolol, resulting in a decreased risk of hepatic decompensation. In secondary prophylaxis, the combination of EVL with carvedilol may prevent rebleeding and non-bleeding further decompensation better than that with propranolol. In patients with ascites and gastroesophageal varices, carvedilol is safe and may improve survival, as long as no impairment of the systemic hemodynamic or renal dysfunction occurs, with maintained arterial blood pressure as suitable safety surrogate. The target dose of carvedilol to treat PH should be 12.5 mg/day. This review summarizes the evidence behind Baveno-VII recommendations on the use of carvedilol in patients with cirrhosis.
Assuntos
Varizes Esofágicas e Gástricas , Hipertensão Portal , Humanos , Carvedilol/uso terapêutico , Propranolol , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/complicações , Ascite/etiologia , Ascite/complicações , Hemorragia Gastrointestinal/tratamento farmacológico , Hemorragia Gastrointestinal/etiologia , Antagonistas Adrenérgicos beta/uso terapêutico , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Cirrose HepáticaRESUMO
[Purpose] Beta blockers, commonly prescribed for older adults, affect heart rates and blood pressure and may reduce respiratory rates, which are used to evaluate patient status and predict outcomes. However, limited clinical evidence is available on the impact of beta blockers on respiratory rates. This study aimed to investigate the impact of beta blockers on respiratory rates in older adults. [Methods] This cross-sectional study included patients aged ≥60 years who underwent an annual checkup. Patients were excluded if they had a diagnosis of severe heart failure, chronic obstructive pulmonary disease, interstitial pneumonitis, severe anemia, or neurodegenerative disease. Doubly robust estimation with inverse probability weighting was applied to estimate the mean differences between beta blocker users and non-users. The dose-response relationship between the administered beta blockers and respiratory rates was examined using multivariable regression models. [Results] Of 637 participants, 108 had received beta blockers regularly. The adjusted mean differences (95% confidence interval, CI) in respiratory rates, pulse rates, systolic blood pressure, and diastolic blood pressure between beta blocker users and non-users were 0.35 (-0.68 to 1.37), -3.56 (-6.34 to -0.78), -5.53 (-8.53 to -2.52), and -4.70 (-8.27 to -1.14), respectively. The adjusted mean differences (95% CI) in respiratory rates per 1 mg of a carvedilol equivalent dose in all beta blocker users, liposoluble beta blocker users, and carvedilol users were -0.10 (-0.18 to -0.02), -0.35 (-0.59 to -0.11), and -0.29 (-0.54 to -0.06), respectively. [Conclusions] Beta blockers may dose-dependently reduce the respiratory rates of older adults. However, in clinical settings, the impact of beta-blocker use or non-use on the respiratory rate may not occur at a clinically important level. Clinicians should note the potentially suppressive impact of beta blockers on respiratory rates according to the situation.
Assuntos
Insuficiência Cardíaca , Doenças Neurodegenerativas , Humanos , Idoso , Carvedilol , Taxa Respiratória , Estudos Transversais , Antagonistas Adrenérgicos beta/farmacologiaRESUMO
PURPOSE: Carvedilol demonstrated therapeutic benefits in patients with heart failure and reduced ejection fraction (HFrEF). However, it had a short half-life time mandating twice a day administration. We investigated whether slow-release carvedilol (carvedilol-SR) is non-inferior to standard immediate-release carvedilol (carvedilol-IR) in terms of clinical efficacy in patients with HFrEF. METHODS: We randomly assigned patients with HFrEF to receive carvedilol-SR once a day or carvedilol-IR twice a day. The primary endpoint was the change in N-terminal pro B-natriuretic peptide (NT-proBNP) level from baseline to 6 months after randomization. The secondary outcomes were proportion of patients with NT-proBNP increment > 10% from baseline, mortality rate, readmission rate, changes in blood pressure, quality of life, and drug compliance. RESULTS: A total of 272 patients were randomized and treated (median follow-up time, 173 days). In each group of patients taking carvedilol-SR and those taking carvedilol-IR, clinical characteristics were well balanced. No patient died during follow-up, and there was no significant difference in the change of NT-proBNP level between two groups (-107.4 [-440.2-70.3] pg/mL vs. -91.2 [-504.1-37.4] pg/mL, p = 0.101). Change of systolic and diastolic blood pressure, control rate and response rate of blood pressure, readmission rate, and drug compliance rate were also similar. For safety outcomes, the occurrence of adverse reactions did not differ between carvedilol-SR group and carvedilol-IR group. CONCLUSION: Carvedilol-SR once a day was non-inferior to carvedilol-IR twice a day in patients with HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03209180 (registration date: July 6, 2017).
Assuntos
Insuficiência Cardíaca , Humanos , Carvedilol/efeitos adversos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Estudos Prospectivos , Qualidade de Vida , Volume Sistólico , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , BiomarcadoresRESUMO
Carvedilol, a highly protein-bound beta-blocker, is used in therapy as a racemic mixture of its two enantiomers that exhibit different pharmacological activity. The aim of this study was to evaluate the stereoselective nature of its binding to the two major plasma proteins: albumin and alpha-1-acid glycoprotein. The determination of the plasma protein-binding degree for carvedilol and its enantiomers was achieved using ultrafiltration for the separation of the free fraction, followed by LC-MS/MS quantification, using two different developed and validated methods in terms of stationary phase: achiral C18 type and chiral ovomucoid type. Furthermore, molecular docking methods were applied in order to investigate and to better understand the mechanism of protein-binding for S-(-)- and R-(+)-carvedilol. A difference in the binding behavior of the two enantiomers to the plasma proteins was observed when taken individually, with R-(+)-carvedilol having a higher affinity for albumin and S-(-)-carvedilol for alpha-1-acid glycoprotein. However, in the case of the racemic mixture, the binding of the S enantiomer to alpha-1-acid glycoprotein seemed to be influenced by the presence of its antipode, although no such influence was observed in the case of albumin. The results raise the question of a binding competition between the two enantiomers for alpha-1-acid glycoprotein.