Extemporaneous combination therapy with nebivolol/ramipril for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVES: To describe the clinical characteristics and treatment adherence in European adult hypertensive patients starting treatment with the extemporaneous combination of nebivolol and ramipril (NR-EXC). METHODS: Retrospective database analysis of patients receiving NR-EXC treatment across five European countries (Italy, Germany, France, Poland, Hungary) over a period ranging from 3 to 9 years (until 30 June 2020) according to data availability for the different data sources. Patient demographics, comorbidities, and treatment adherence were evaluated. RESULTS: We identified 592,472 patients starting NR-EXC. Most of them were over 60 years of age, with ramipril most commonly prescribed at 5 mg (from 30.0 to 57.2% of patients across the databases). Notable comorbidities included diabetes (19.2%) and dyslipidemia (18.2%). The study population was also highly subjected to polytherapy with antithrombotics, lipid-lowering agents, and other lowering blood pressure agents as the most co-prescribed medications, as resulted from Italian database. Up to 59% of the patients did not request a cardiologic visit during the study period. Adherence to therapy was low in 56.3% of the patients, and it was high only in 11.1% of them. CONCLUSIONS: The combination of nebivolol and ramipril is frequently prescribed in Europe, but adherence to treatment is suboptimal. The transition to a single pill combination could enhance treatment adherence and streamline regimens, potentially leading to significant benefits. Improved adherence not only correlates with better blood pressure control but also reduces the risk of cardiovascular events, underscoring the importance of this development.

Nebivolol ameliorates sepsis-evoked kidney dysfunction by targeting oxidative stress and TGF-ß/Smad/p53 pathway.

Sepsis is a potential fetal organ destruction brought on through an overzealous immunologic reaction to infection, causing severe inflammation, septic shock, and damage to different organs. Although there has been progress in the identification and controlling of clinical sepsis, the fatality rates are still significant. This study, for the first time, intended to examine the possible ameliorative impact of Nebivolol, a ß1-adrenergic antagonist antihypertensive drug, against nephrotoxicity resulted from cecal ligation and puncture (CLP)-induced sepsis in rats, on molecular basis. Sixty male Wistar albino rats were chosen. Oxidative stress indicators and biochemical markers of kidney activity were evaluated. Inflammatory mediators, fibrosis- and apoptosis-related proteins and gene expressions were investigated. Moreover, renal histopathological investigation was performed. CLP-induced nephrotoxicity characterized by markedly elevated serum levels of creatinine, blood urea nitrogen, uric acid, and renal malondialdhyde. On the other hand, it decreased serum total protein level, renal superoxide dismutase activity and reduced glutathione level. Additionally, it significantly elevated the renal inflammatory mediators (tumor necrosis factor-alpha, ilnerlukin (IL)-6, and IL-1ß) and Caspase-3 protein, reduced IL-10 level, amplified the expression of transforming growth factor-beta 1 (TGF-ß1), p-Smad2/3 and alpha-smooth-muscle actin proteins, downregulated the B cell lymphoma-2 (Bcl-2) gene and elevated the transcription of Bcl-2-associated X-protein (Bax), p53 and Nuclear factor-kappa B (NF-κB) genes. Furtheremor, kidney tissues exhibited significant histopathological changes with CLP. On the contrary, Nebivolol significantly improved all these biochemical changes and enhanced the histopathological alterations obtained by CLP. This research showed, for the first time, that Nebivolol effectively mitigated the CLP-induced kidney dysfunction via its antioxidant, antifibrotic and anti-apoptotic activity through modulation of oxidative stress, TGF-ß/NF-κB and TGF-ß/Smad/p53 signaling pathways.

Extemporaneous combination therapy with nebivolol/valsartan for the treatment of hypertension: a study of real-world evidence in Europe.

OBJECTIVE: To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe. METHODS: Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until 30 June 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated. RESULTS: The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51 to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2 to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC. CONCLUSIONS: The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.

Physicians' attitudes toward beta-blockers for the treatment of hypertension in Italy, Poland, and Turkey.

Despite substantial progress in understanding the complex pathophysiology, hypertension remains a serious public health challenge affecting over 1.2 billion adults aged 30-79 years worldwide. Appropriate knowledge of the different pharmaceutical classes of antihypertensive agents and an understanding of the characteristics of individual molecules are essential to optimize clinical outcomes in patients with hypertension. We conducted a computer-assisted web interviewing (CAWI) quantitative survey in Italy, Poland, and Turkey to investigate physicians' prescriptions, knowledge, and perceptions of antihypertensive drugs with a focus on ß-blockers, to assess antihypertensive usage patterns and the reasons underlying prescription choices. The survey findings show that ß-blockers retain a pivotal role in the management of hypertension and are prescribed more often for patients with cardiovascular comorbidities than for patients with diabetic comorbidities. In all three countries, nebivolol is the only ß-blocker among the ones analyzed which is consistently prescribed to 20% or more of patients and is overall the most prescribed one for the population with comorbid diabetes. In terms of specific ß-blockers' features, this study revealed knowledge gaps that underline the need for educational activities focused on the differences among ß-blockers, which are important in choosing the most suitable agent for individualized antihypertensive therapy.

Nebivolol, an antihypertensive agent, has new application in inhibiting melanoma.

Repurposing existing drugs for cancer therapy has become an important strategy because of its advantages, such as cost reduction, effect and safety. The present study was designed to investigate the antimelanoma effect and possible mechanisms of action of nebivolol, which is an approved and widely prescribed antihypertensive agent. In this study, we explored the effect of nebivolol on cell proliferation and cell activity in melanoma in vitro and the potential antimelanoma mechanism of nebivolol through a series of experiments, including the analysis of the effects with regard to cell apoptosis and metastasis. Furthermore, we evaluated the antimelanoma effect on xenograft tumor models and inspected the antimelanoma mechanism of nebivolol in vivo using immunohistochemical and immunofluorescence staining assays. As results in this work, in vitro , nebivolol possessed a strong activity for suppression proliferation and cell cycle arrest on melanoma. Moreover, nebivolol significantly induced cell apoptosis in melanoma through a mitochondrial-mediated endogenous apoptosis pathway. Additionally, nebivolol inhibited melanoma cell metastasis. More importantly, nebivolol exhibited significantly effective melanoma xenograft models in vivo , which related to the mechanism of apoptosis induction, proliferation inhibition, metastasis blocking and angiogenesis arrest. Overall, the data of the present study recommend that nebivolol holds great potential in application as a novel agent for the treatment of melanoma.

Modulation of TNF-α, interleukin-6, and interleukin-10 by nebivolol-valsartan and nebivolol-lisinopril polytherapy in SHR rats.

Antihypertensive drug therapies have demonstrated their capacity to modulate the inflammatory processes associated with hypertension, leading to improvements in disease progression. Given the prevalent use of polytherapy in treating most hypertensive patients, comprehending the time-dependent effects of combination treatments on inflammation becomes imperative. In this study, spontaneously hypertensive rats (SHR) were divided into seven groups (n = 6): (i) SHR + vehicle, (ii) SHR + nebivolol, (iii) SHR + valsartan, (iv) SHR + lisinopril, (v) SHR + nebivolol-valsartan, (vi) SHR + nebivolol-lisinopril, and (vii) WKY + vehicle. Blood pressure was measured using the tail-cuff method. Temporal alterations in inflammatory cytokines TNF-α, IL-6, and IL-10 were assessed in serum through ELISA and mRNA expression in aortic tissue via qPCR after 1, 2, and 4 weeks of treatment with nebivolol, lisinopril, valsartan, and their respective combinations. Histological alterations in the aorta were assessed. The findings indicated that combined treatments reduced systolic and diastolic blood pressure in SHR. The nebivolol and lisinopril combination demonstrated a significant decrease in IL-6 serum and mRNA expression at both 1 week and 4 weeks into the treatment. Additionally, TNF-α mRNA expression also showed a reduction with this combination at the same time points. Particularly, nebivolol-valsartan significantly decreased TNF-α serum and mRNA expression after one and four weeks of treatment. Furthermore, an elevation in serum IL-10 levels was observed with both combination treatments starting from the second week onwards. This study provides compelling evidence that concurrent administration of nebivolol with lisinopril or valsartan exerts time-dependent effects, reducing proinflammatory cytokines TNF-α and IL-6 while modifying IL-10 levels in an experimental hypertensive model.

Extemporaneous combination therapy with nebivolol/amlodipine for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVE: The investigation of the real-world use of the extemporaneous combination of nebivolol and amlodipine (NA-EXC) in adult patients diagnosed with hypertension in Europe. METHODS: Retrospective analysis of data extracted from seven databases of patient medical records and prescriptions from Italy, Germany, France, Hungary, and Poland, to determine the prevalence and incidence of NA-EXC use and to estimate the number of patients potentially eligible for a single-pill combination of the two antihypertensives. Secondary objectives included: the description of the population of NA-EXC users and the assessment of their adherence to treatment based on the proportion of days covered. RESULTS: The use of NA-EXC was found to be common in Europe and ranged between 2.9% to 9.9% of all patients identified in the databases with a prescription of nebivolol and/or amlodipine. The estimated numbers of patients potentially eligible in 2019 for a single-pill combination of nebivolol and amlodipine in Italy and Germany were, respectively, 178,133 and 113,240. Users of NA-EXC were mostly aged 70-79 years, had metabolic disorders and other comorbidities; >70% of them had received ≥2 concomitant medications before starting NA-EXC. Adherence to NA-EXC was defined as high only in 15.6% to 35% of patients. CONCLUSIONS: The extemporaneous combination of nebivolol and amlodipine is commonly prescribed in Europe, however adherence to the therapy is poor. The development of a single-pill combination of nebivolol and amlodipine may improve adherence by reducing the number of pills administered to patients and thus simplifying treatment regimens.

Ameliorative effect of nebivolol in doxorubicin-induced cardiotoxicity.

This study aimed to investigate the potential of nebivolol in preventing doxorubicin-induced cardiotoxicity by targeting the inflammatory, oxidative, and apoptotic pathways. Twenty-eight male rats were randomly divided into four groups, each consisting of seven rats. The control group received standard diets and unrestricted access to water. The rats in the normal saline (N/S) group were administered a 0.9% normal saline solution for two weeks. The doxorubicin group (the "induced group") received doxorubicin at a dosage of 2.5 mg/kg three times per week for two weeks. The nebivolol group received an oral dose of 4 mg/kg of nebivolol for the same duration. The cardiac tissues of rats treated with doxorubicin exhibited increased levels of tumor necrosis factor, interleukin-1, malondialdehyde, and caspase-3 compared to the normal saline control group (p<0.05), along with decreased levels of total antioxidant capacity and Bcl-2. These results show that doxorubicin is harmful to the heart. The administration of nebivolol significantly reduced the cardiotoxic effects induced by doxorubicin, as indicated by a statistically significant decrease in the levels of inflammatory markers, specifically tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß) (p<0.05). The nebivolol group exhibited a significant decrease in malondialdehyde levels, which serves as a signal of oxidation, in cardiac tissue compared to the doxorubicin-only group (p<0.05). Additionally, the nebivolol group showed a significant increase in overall antioxidant capacity. Nebivolol dramatically attenuated doxorubicin-induced cardiotoxicity in rats, likely by interfering with oxidative stress, the inflammatory response, and the apoptotic pathway.

Relationship Between Hypertension, Antihypertensive Drugs and Sexual Dysfunction in Men and Women: A Literature Review.

Sexual dysfunction pertains to any issue that hinders an individual from attaining sexual contentment. This health issue can have a significant impact on the quality of life and psychological health of affected individuals. Sexual dysfunction can generate stress, anxiety, depression, and low self-esteem, which can lead to a reduction in overall life satisfaction and the quality of interpersonal relationships. Sexual dysfunction can manifest as erectile dysfunction in men or lack of sexual desire in women. Although both sexes can experience sexual problems, there are some significant differences in the manifestation of sexual dysfunction between men and women. In men, sexual dysfunction is usually physical and associated with problems such as erectile dysfunction, while in women, sexual dysfunction is usually related to psychological factors. Additionally, there was an association between hypertension and sexual dysfunction in both the sexes. In men, hypertension can cause erection problems, whereas in women, it can cause vaginal dryness and a decrease in sexual desire. Furthermore, antihypertensive drugs can negatively impact sexual function, which can decrease adherence to drug treatment. However, nebivolol, an antihypertensive drug, has beneficial effects on erectile dysfunction in men. This is believed to be because nebivolol improves blood flow to the penis by producing nitric oxide, which can help improve erections.

Therapeutic Effects of Combination of Nebivolol and Donepezil: Targeting Multifactorial Mechanisms in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in the spinal cord. Although the disease's pathophysiological mechanism remains poorly understood, multifactorial mechanisms affecting motor neuron loss converge to worsen the disease. Although two FDA-approved drugs, riluzole and edaravone, targeting excitotoxicity and oxidative stress, respectively, are available, their efficacies are limited to extending survival by only a few months. Here, we developed combinatorial drugs targeting multifactorial mechanisms underlying key components in ALS disease progression. Using data analysis based on the genetic information of patients with ALS-derived cells and pharmacogenomic data of the drugs, a combination of nebivolol and donepezil (nebivolol-donepezil) was identified for ALS therapy. Here, nebivolol-donepezil markedly reduced the levels of cytokines in the microglial cell line, inhibited nuclear factor-κB (NF-κB) nucleus translocation in the HeLa cell and substantially protected against excitotoxicity-induced neuronal loss by regulating the PI3K-Akt pathway. Nebivolol-donepezil significantly promoted the differentiation of neural progenitor cells (NPC) into motor neurons. Furthermore, we verified the low dose efficacy of nebivolol-donepezil on multiple indices corresponding to the quality of life of patients with ALS in vivo using SOD1G93A mice. Nebivolol-donepezil delayed motor function deterioration and halted motor neuronal loss in the spinal cord. Drug administration effectively suppressed muscle atrophy by mitigating the proportion of smaller myofibers and substantially reducing phospho-neurofilament heavy chain (pNF-H) levels in the serum, a promising ALS biomarker. High-dose nebivolol-donepezil significantly prolonged survival and delayed disease onset compared with vehicle-treated mice. These results indicate that the combination of nebivolol-donepezil efficiently prevents ALS disease progression, benefiting the patients' quality of life and life expectancy.

Clinical pharmacokinetics of nebivolol: a systematic review.

Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.

Role of p38 MAPK, Akt and NFκB in renoprotective effects of nebivolol on renal ischemia-reperfusion injury in rats.

Renal ischemia-reperfusion (I-R) injury is a complex pathophysiologic condition characterized by oxidative stress, inflammation and apoptosis. We investigated the potential renoprotective effect of nebivolol, a ß1 adrenergic receptor blocker, against renal I-R injury. We focused on the role of nebivolol in activating p38 mitogen-activated protein kinase (MAPK) signaling, Akt (protein kinase B) and nuclear factor-κB (NFκB) transcription factors, which contribute to oxidative stress, inflammation and apoptosis during renal I-R. We divided 20 adult male Wistar albino rats into three experimental groups. Group 1 was a sham control in which only laparotomy was performed. Group 2 was the I-R group in which both kidneys were made ischemic for 45 min, then reperfused for 24 h. Group 3 was the I-R + nebivolol group in which 10 mg/kg nebivolol was administrated by gavage for 7 days before I-R. We measured Inflammation, oxidative stress and active caspase-3 as well as activation of p38 MAPK, Akt (protein kinase B) and NFκB transcription factor. Nebivolol significantly reduced oxidative stress and increased superoxide dismutase levels during renal I-R. We found that nebivolol significantly decreased interstitial inflammation, and TNF-α and interleukin-1ß mRNA expression. Nebivolol significantly reduced active caspase-3 and kidney injury molecule-1 (KIM-1) expressions. Nebivolol also significantly decreased activation of p38 MAPK signaling and NFκB, and induced Akt activation during renal I-R. Our findings suggest that nebivolol may be useful for management of renal I-R injury.

Nebivolol Sensitizes BT-474 Breast Cancer Cells to FGFR Inhibitors.

BACKGROUND/AIM: The fibroblast growth factor receptor (FGFR) signaling pathway is abnormally activated in human cancers, including breast cancer. Therefore, targeting the FGFR signaling pathway is a potent strategy to treat breast cancer. The purpose of this study was to find drugs that could increase sensitivity to FGFR inhibitor effects in BT-474 breast cancer cells, and to investigate the combined effects and underlying mechanisms of these combinations for BT-474 breast cancer cell survival. MATERIALS AND METHODS: Cell viability was measured by MTT assay. Protein expression was determined by western blot analysis. mRNA expression was detected by Real-time PCR. Drug synergy effect was determined by isobologram analysis. RESULTS: Nebivolol, a third generation ß1-blocker, synergistically increased the sensitivity of BT-474 breast cancer cells to the potent and selective FGFR inhibitors erdafitinib (JNJ-42756493) and AZD4547. A combination of nebivolol and erdafitinib markedly reduced AKT activation. Suppression of AKT activation using specific siRNA and a selective inhibitor further enhanced cell sensitivity to combined treatment with nebivolol and erdafitinib, whereas SC79, a potent activator of AKT, reduced cell sensitivity to nebivolol and erdafitinib. CONCLUSION: Enhanced sensitivity of BT-474 breast cancer cells to nebivolol and erdafitinib was probably associated with down-regulation of AKT activation. Combined treatment with nebivolol and erdafitinib is a promising strategy for breast cancer treatment.

Nebivolol Alleviates Vascular Endothelial Insulin Resistance by Inhibiting Endoplasmic Reticulum Stress.

Vascular endothelial insulin resistance (IR) is an important risk factor in the development of vascular complications in diabetes. Prolonged endoplasmic reticulum stress (ERS) contributes to the development and progression of endothelial IR. The current study assessed the effects and mechanism of nebivolol on vascular IR in Goto-Kakizaki (GK) rats and endothelial IR induced by high glucose (33.3 mmol/L) associated with high insulin (10-7 mol/L) in human aortic endothelial cells (HAECs). Rats were divided into Wistar, Wistar + Neb (Wistar rats treated with nebivolol, 10 mg/kg, ig), GK, and GK + Neb (GK rats treated with nebivolol, 10 mg/kg, ig). GK rats showed hyperglycemia, dyslipidemia, impaired glucose homeostasis, metabolic IR, reduced relaxation to insulin, and lower serum nitric oxide (NO) level. Treatment with nebivolol for 4 months ameliorated insulin's vasorelaxation and NO production, and relieved dyslipidemia in GK rats. Additionally, nebivolol increased glucose uptake and NO level in the endothelial IR group in vitro. Nebivolol increased aortic expressions of IRS-1/PI3K/Akt/eNOS relative proteins and GLUT4 and reduced expressions of ERS markers (ATF6, GRP78, and CHOP, p-JNK/JNK). Furthermore, both nebivolol and TUDCA (ERS inhibitor) alleviated the attenuated IRS-1PI3K/Akt/eNOS pathway and enhanced ERS in HAECs IR. Tunicamycin (ERS inducer) not only induced endothelial IR but also blocked nebivolol's alleviation on the IRS-1PI3K/Akt/eNOS pathway and ERS. Nebivolol ameliorated endothelial IR partially by inhibiting ERS and then regulating the IRS-1/PI3K/Akt/eNOS signal.

Green fluorometric strategy for simultaneous determination of the antihypertensive drug telmisartan (A tentative therapeutic for COVID-19) with Nebivolol in human plasma.

Telmisartan (TEL) and Nebivolol (NEB) are frequently co-formulated in a single dosage form that is frequently prescribed for the treatment of hypertension, moreover, telmisartan is currently proposed to be used to treat COVID19-induced lung inflammation. Green rapid, simple, and sensitive synchronous spectrofluorimetric techniques for simultaneous estimation of TEL and NEB in their co-formulated pharmaceutical preparations and human plasma were developed and validated. Synchronous fluorescence intensity at 335 nm was used for TEL determination (Method I). For the mixture, the first derivative synchronous peak amplitudes (D1) at 296.3 and 320.5 nm were used for simultaneous estimation of NEB and TEL, respectively (Method II). The calibration plots were rectilinear over the concentration ranges of 30-550 ng/mL, and 50-800 ng/mL for NEB and TEL, respectively. The high sensitivity of the developed methods allowed for their analysis in human plasma samples. NEB`s Quantum yield was estimated by applying the single-point method. The greenness of the proposed approaches was evaluated using the Eco-scale, National Environmental Method Index (NEMI), and Green Analytical Procedure Index (GAPI) methods.

Protective role of nebivolol via AKT1/Hif-1α/eNOS signaling pathway: nephrotoxicity caused by methotrexate in a rat model.

Methotrexate (MTX) is an antineoplastic and anti-inflammatory agent, which is used in severe diseases. Its use should be limited due to side effects such as nephrotoxicity, myelotoxicity, and hepatotoxicity. Nebivolol (NBV), which is a beta-blocker used in the treatment of hypertension, also contributes to vasodilation in tissues by activating the endothelial nitric oxide synthase (eNOS) enzyme. The purpose of this study is to research the effect of NBV on MTX-induced nephrotoxicity through the AKT1/hypoxia-inducible factor 1-alpha (Hif-1α)/eNOS signaling pathway. The rats were randomly divided into three groups of eight each. The groups were control, MTX, and MTX + NBV. A single dose of 20 mg/kg MTX was given intraperitoneally to the rats on the first day of the study and 10 mg/kg NBV was given orally to the treatment group for 7 days. At the end of the study, rats' blood and kidney tissues were taken for histopathological, immunohistochemical, and biochemical examinations. MTX administration significantly decreased the expression levels of AKT1, eNOS, and Hif-1α compared with the control group (p < 0.001 for all), and NBV treatment increased these values compared with the MTX group (p < 0.001 for all). In conclusion, NBV treatment ameliorated the MTX-induced nephrotoxicity via AKT1/Hif-1α/eNOS signaling pathway.

The Safety and Tolerability of Nebivolol in Hypertensive Patients with Coronary Artery Disease and Left Ventricular Ejection Fraction ≥ 40%: A Population-Based Cohort Study (Nebivolol-TR Study).

BACKGROUND: This study aimed to assess the safety and tolerability of nebivolol in hypertensive patients with coronary artery disease and left ventricular ejection fraction ≥ 40% in a Turkish cohort. METHODS: A total of 1015 hypertensive patients and coronary artery disease with left ventricular ejection fraction ≥ 40% were analyzed from 29 different centers in Turkey. Primary outcomes were the mean change in blood pressure and heart rate. Secondary outcomes were to assess the rate of reaching targeted blood pressure (<130/80 mmHg) and heart rate (<60 bpm) and the changes in the clinical symptoms (angina and dyspnea). Adverse clinical events and clinical outcomes including cardiovascular mortality, cardiovascular hospital admissions, or acute cardiac event were recorded. RESULTS: The mean age of the study population was 60.3 ± 11.5 years (male: 54.2%). During a mean follow-up of 6 months, the mean change in blood pressure was -11.2 ± 23.5/-5.1 ± 13.5 mmHg, and the resting heart rate was -12.1 ± 3.5 bpm. Target blood pressure and heart rate were achieved in 76.5% and 37.7% of patients. Angina and functional classifications were improved by at least 1 or more categories in 31% and 23.2% of patients. No serious adverse events related to nebivolol were reported. The most common cardiovascular side effect was symptomatic hypotension (4.2%). The discontinuation rate was 1.7%. Cardiovascular hospital admission rate was 5% and hospitalization due to heart failure was 1.9% during 6 months' follow-up. Cardiovascular mortality rate was 0.1%. CONCLUSION: Nebivolol was well tolerated and safe for achieving blood pressure and heart rate control in hypertensive patients with coronary artery disease and heart failure with preserved or mildly reduced ejection fraction.

Extemporaneous combination therapy with nebivolol/zofenopril in hypertensive patients: usage in Italy.

OBJECTIVE: Clinically describing hypertensive patients initiating nebivolol/zofenopril extemporaneous combination (NZ-EXC) and estimating the number of patients currently receiving NZ-EXC and of those potentially eligible for the fixed-dose combination of the two molecules (NZ-FDC) in Italy. METHODS: This retrospective observational study used data from IQVIA Italian Longitudinal Patient Database (LPD). Adult hypertensive patients firstly prescribed NZ-EXC between 1 July 2011 and 30 June 2020 were identified and their demographic and clinical characteristics were extracted. Treatment adherence was evaluated as proportion of days covered (PDC) and classified as low (PDC <40%), intermediate (PDC ≥40% and <80%) or high (PDC ≥80%). Two additional cohorts were identified in 2019 to provide the national-level yearly estimates of patients prescribed NZ-EXC and of patients eligible for NZ-FDC. RESULTS: In total 1745 patients were prescribed NZ-EXC: 60% were women; mean age was 65 years. The most frequent comorbidities were dyslipidemia (19.0%), diabetes (15.5%) and thyroid diseases (13.1%); the most common co-prescribed treatments were antithrombotics (29.1%), lipid-lowering agents (28.8%), nonsteroidal anti-inflammatory drugs (26.1%) and antihyperglycemic agents (13.5%). Mean PDC was 39%, and 57% of the patients had a PDC < 40%. The yearly estimate of patients prescribed NZ-EXC in 2019 was 59,000, while potential users of NZ-FDC were estimated to be 29,000. CONCLUSIONS: NZ-EXC in hypertensive patients is a common practice in Italy and the development of a NZ-FDC can be a viable treatment option for hypertensive patients who are already receiving nebivolol and zofenopril through the concomitant assumption of two distinct pills. As supported by scientific literature, FDCs of antihypertensive drugs could simplify treatment, improve adherence and potentially reduce health-care costs as related to a better control of blood pressure.

Nebivolol and incident cardiovascular events in hypertensive patients compared with nonvasodilatory beta blockers.

OBJECTIVE: Nonvasodilatory beta blockers are associated with inferior cardiovascular event reduction compared with other antihypertensive classes, and there is uncertainty about first-line use of beta blockers for hypertension in guidelines. The third generation vasodilatory beta blocker nebivolol has unique beneficial effects on central and peripheral vasculature. Our objective was to compare longitudinal cardiovascular outcomes of hypertensive patients taking nebivolol with those taking the nonvasodilatory beta blockers metoprolol and atenolol. METHODS: We performed a retrospective cohort analysis of hypertensive adults in the University of Colorado health system, without preceding diagnosis of cardiovascular or cerebrovascular disease. The primary outcome was composite incident heart failure, stroke, myocardial infarction, angina, or coronary revascularization. Mahalanobis 1:2 distance matching and Cox proportional hazards regression was used. Matching and regression variables included baseline demographics, socioeconomic factors, medical insurance type, prescribing provider type, cardiovascular risk factors, Charlson comorbidity index, other medications, and follow-up duration. RESULTS: After matching, patients were predominantly women (54%, 3085 of 5705) and non-Hispanic Caucasian (79%, 4534 of 5705), with median age of 58. In matched Cox regression analysis, nebivolol was associated with 17% reduction in incident cardiovascular events compared with all nonvasodilatory beta blockers [hazard ratio 0.83, 95% confidence interval (CI) 0.74-0.94, P  = 0.004], and 24% reduction compared with metoprolol (hazard ratio 0.76, CI 0.66-0.87, P = 0.0001). CONCLUSION: The vasodilatory beta blocker nebivolol was associated with reduced incident cardiovascular events compared with nonvasodilatory beta blockers. Additional study of other beta blockers is necessary to determine if this is a vasodilatory beta blocker class effect or is specific to nebivolol.http://links.lww.com/HJH/B916.

Comparative beneficial effects of nebivolol and nebivolol/valsartan combination against mitochondrial dysfunction in angiotensin II-induced pathology in H9c2 cardiomyoblasts.

OBJECTIVES: Considering the complementary nature of signalling mechanisms and the therapeutic effects of nebivolol, a ß1-adrenoreceptor antagonist, and valsartan, an angiotensin receptor blocker (ARB), here we aimed to investigate whether nebivolol/valsartan combination would complement the cardioprotective effects of nebivolol on angiotensin II (ANG II)-induced pathology in H9c2 cardiomyoblasts. METHODS: H9c2 cardiomyoblasts were used to investigate the protective effects of nebivolol and nebivolol and valsartan combination against ANG II-induced pathology. Reactive oxygen species (ROS) generation was determined by 2',7'-dichlorofluorescein diacetate (DCFDA) and MitoSOX Red staining. Real-time PCR and immunoblotting were employed to quantify the changes in mRNA and protein expression levels, respectively. KEY FINDINGS: Our data revealed that pretreatment with nebivolol and nebivolol/valsartan combination significantly reduced ANG II-induced oxidative stress and mTORC1 signalling. Concurrently, ANG II-induced activation of inflammatory cytokines and fetal gene expressions were significantly suppressed by nebivolol and nebivolol/valsartan combination. Pretreatment with nebivolol and nebivolol/valsartan combination alleviated ANG II-induced impairment of mitochondrial biogenesis by restoring the gene expression levels of PGC-1α, TFAM, NRF-1 and SIRT3. Our data further show that nebivolol and nebivolol/valsartan combination mediated up-regulation in mitochondrial biogenesis is accompanied by decrease in ANG II-stimulated mitochondrial ROS generation as well as increase in expression of mitochondrial fusion genes MFN2 and OPA1, indicative of improved mitochondrial dynamics. SUMMARY: These findings suggest that both nebivolol and nebivolol/valsartan combination exert protective effects on ANG II-induced mitochondrial dysfunction by alleviating its biogenesis and dynamics. Moreover, addition of valsartan to nebivolol do not produce any additive effects compared with nebivolol alone on ANG II-induced cardiac pathology.