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European Journal of Internal Medicine Jun 2021β-blockers represent a mainstay in the pharmacological approach to patients affected by heart failure with reduced ejection fraction (HFrEF). However, underuse of this... (Review)
Review
β-blockers represent a mainstay in the pharmacological approach to patients affected by heart failure with reduced ejection fraction (HFrEF). However, underuse of this class of drugs is still reported, especially in the presence of cardiovascular and non-cardiovascular comorbidities, even if they are not contraindications for prescription of a β-blocker. The prognostic benefit of β-blockers is relevant in the presence of comorbidities, and achievement of the maximum tolerated dose is an important goal to increase their favorable prognostic role. The aim of the present review is to analyze the available evidence on the use of β-blockers in HFrEF patients with the most common comorbidities. In particular, we will discuss the role and most appropriate beta-blocker in patients with pulmonary disease (bisoprolol, metoprolol, nebivolol), diabetes (carvedilol and nebivolol), atrial fibrillation (all indicated for rate control, with metoprolol as the first choice followed by bisoprolol, nebivolol, and carvedilol), erectile dysfunction (bisoprolol and nebivolol), peripheral arterial disease (nebivolol), and other conditions, in order to clarify the correct use of this class of drugs in the clinical practice.
Topics: Adrenergic beta-Antagonists; Carbazoles; Heart Failure; Humans; Male; Propanolamines; Stroke Volume
PubMed: 33941435
DOI: 10.1016/j.ejim.2021.03.035 -
Cardiovascular Drugs and Therapy Oct 2022Bisoprolol and nebivolol are highly selective β-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with... (Review)
Review
Therapeutic Properties of Highly Selective β-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.
Bisoprolol and nebivolol are highly selective β-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of "second generation" and "third generation" β-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.
Topics: Adrenergic beta-Antagonists; Benzopyrans; Bisoprolol; Cardiovascular Diseases; Ethanolamines; Heart Failure; Humans; Hypertension; Myocardial Ischemia; Nebivolol; Stroke Volume; Vasodilator Agents; Ventricular Function, Left
PubMed: 34106365
DOI: 10.1007/s10557-021-07205-y -
Nature Communications Oct 2021Abnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to...
Abnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we show that F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation, resulting in suppression of EGFR-driven NSCLC growth. Reduced FBXL2 expression is associated with poor clinical outcomes of NSCLC patients. Furthermore, we show that glucose-regulated protein 94 (Grp94) protects EGFR from degradation via blockage of FBXL2 binding to EGFR. Moreover, we have identified nebivolol, a clinically used small molecule inhibitor, that can upregulate FBXL2 expression to inhibit EGFR-driven NSCLC growth. Nebivolol in combination with osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates that the FBXL2-Grp94-EGFR axis plays a critical role in NSCLC development and suggests that targeting FBXL2-Grp94 to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.
Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; F-Box Proteins; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Membrane Glycoproteins; Mice; Mice, Nude; Nebivolol; Protein Kinase Inhibitors; Signal Transduction; Survival Analysis; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 34635651
DOI: 10.1038/s41467-021-26222-x -
Frontiers in Medicine 2022
PubMed: 36388886
DOI: 10.3389/fmed.2022.1011957 -
Basic & Clinical Pharmacology &... Sep 2019This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third-generation beta-adrenoceptor antagonist (BAA) nebivolol.... (Review)
Review
This MiniReview reports the current knowledge about the treatment of arterial hypertension with the third-generation beta-adrenoceptor antagonist (BAA) nebivolol. Furthermore, it reviews the advantages of nebivolol compared to the earlier generation of BAAs with respect to their different pharmacological properties. Beta-adrenoceptor antagonists are a class of drugs applied for several different conditions, including hypertension and heart failure. They differ significantly in their pharmacological properties, including varying β /β -selectivity and/or exertion of additive effects on the heart and circulation. Although these drugs have been a part of hypertensive therapy for about 40 years, the outcome of large clinical trials has put the role of BAAs into question. However, most of these results were based on first- and second-generation BAAs and cannot be translated directly into third-generation drugs. The third-generation BAA nebivolol has the highest β -selectivity seen so far, together with additional vasodilating and anti-oxidative properties. It is currently applied in the treatment of hypertension and congestive heart failure. Nebivolol has a unique pharmacological profile, despite showing similar blood pressure-lowering effects, and has certain advantages in the treatment of hypertension compared to the previous generations of BAAs. This includes significant improvements in endothelial dysfunction, central haemodynamics and the degree of erectile dysfunction in men, a neutral/beneficial metabolic profile and lastly a more favourable side effect profile. It is widely beneficial for, for example, sexually active men and patients with comorbidities such as type II diabetes mellitus, metabolic syndrome and chronic obstructive lung disorders. Whether the advantages translate to an improved long-term clinical outcome remains to be clarified, and ongoing prospective studies will show this in the future.
Topics: Adrenergic beta-1 Receptor Antagonists; Blood Pressure; Clinical Trials as Topic; Comorbidity; Diabetes Mellitus, Type 2; Endothelium, Vascular; Erectile Dysfunction; Humans; Hypertension; Male; Metabolic Syndrome; Nebivolol; Pulmonary Disease, Chronic Obstructive; Treatment Outcome; Vasodilation
PubMed: 31066991
DOI: 10.1111/bcpt.13248 -
Pharmacology Research & Perspectives Aug 2019The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state... (Review)
Review
The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state pharmacokinetic studies from the literature. PubMed was searched for pharmacokinetic studies of beta-adrenergic blocking agents, both single-dose and steady-state studies. The studies included reported maximum plasma concentration (C) and/or area under the concentration curve (AUC). The coefficient of variation (CV%) was calculated for all studies, and a CV% <40% was considered low or moderate variability, and a CV% >40% was considered high variability. The C and AUC were reported a total of 672 times in 192 papers. Based on AUC, metoprolol, propranolol, carvedilol, and nebivolol showed high pharmacokinetic variability (highest first), whereas bisoprolol, atenolol, sotalol, labetalol, nadolol, and pindolol showed low to moderate variability (lowest first). We have shown a high interindividual pharmacokinetic variability that varies markedly in different beta-adrenergic blocking agents; the extreme being steady state ratios as high as 30 in metoprolol. A more personalized approach to the medical treatment of patients may be obtained by combining known pharmacokinetic information about variability, pharmaco-genetics and -dynamics, and patient characteristics, to avoid adverse events or lack of treatment effect.
Topics: Adrenergic beta-Antagonists; Area Under Curve; Biological Availability; Carvedilol; Healthy Volunteers; Humans; Male; Metoprolol; Propranolol
PubMed: 31338197
DOI: 10.1002/prp2.496 -
Drug Design, Development and Therapy 2020We evaluated the efficacy and safety of nebivolol and rosuvastatin combination treatment in patients with hypertension and hyperlipidemia. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We evaluated the efficacy and safety of nebivolol and rosuvastatin combination treatment in patients with hypertension and hyperlipidemia.
PATIENTS AND METHODS
Eligible patients, after more than 4 weeks of therapeutic lifestyle change, were randomly assigned to three groups: 5 mg nebivolol plus 20 mg rosuvastatin (NEBI/RSV), 20 mg rosuvastatin (RSV), or 5 mg nebivolol (NEBI). Treatments lasted 8 weeks.
RESULTS
Efficacy was analyzed using data from 276 patients. Sitting systolic and diastolic blood pressures differed between the NEBI/RSV and RSV groups (LSmean difference = -5.89 and -5.99 mmHg; 95% confidence interval [CI] = -9.88 to -1.90 mmHg and -8.13 to -3.84 mmHg, respectively). Reductions in the two pressures did not differ between the NEB/RSV and NEB groups. The percent reduction in low-density lipoprotein (LDL) cholesterol differed between the NEBI/RSV and NEBI groups (LSmean difference = -47.76%, 95% CI = -52.69 to -42.84%) but not between the NEBI/RSV and RSV groups. The blood pressure (BP) control rate was higher in the NEBI/RSV group than in the RVS group (51.09% vs 29.67%, = 0.003). The LDL cholesterol goal achievement rate was higher in the NEBI/RSV group than in the NEBI group (85.87% vs 11.83%, < 0.001). The incidence of adverse drug reactions in the NEBI/RSV, RSV, and NEBI groups was 8.51%, 7.45%, and 8.60%, respectively ( = 0.950).
CONCLUSION
Nebivolol plus rosuvastatin treatment is effective in reducing BP and LDL cholesterol levels and is safe in patients with hypertension and hypercholesterolemia without the loss of BP or the LDL cholesterol-lowering effect of each drug.
TRIAL REGISTRATION
CRIS registration number KCT0002148.
Topics: Adult; Aged; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Nebivolol; Rosuvastatin Calcium; Young Adult
PubMed: 33235439
DOI: 10.2147/DDDT.S280055