Effects Of Nebivolol Research Articles

Effect of nebivolol monotherapy or combination therapy on blood pressure levels in patients with hypertension: an updated systematic review and multilevel meta-analysis of 91 randomized controlled trials.

To systematically appraise and summarize the available evidence from published randomized controlled trials considering the effect of nebivolol on blood pressure in patients with hypertension. Literature search was performed through Medline (via PubMed), Cochrane Library and Scopus until December 15, 2023. Double-independent study selection, data extraction and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. In total, 7,737 participants with hypertension, who were treated with nebivolol, were analyzed across 91 RCTs. Nebivolol was associated with significantly greater reduction in office systolic and diastolic BP compared to placebo (MD = - 6.01 mmHg; 95% CI = [- 7.46, - 4.55] and MD = - 5.01 mmHg; 95% CI = [- 5.91, - 4.11], respectively). Moreover, resulted a similar reduction in systolic BP (MD = - 0.22 mmHg; 95% CI = [- 0.91, 0.46]) and a significantly greater reduction in diastolic BP compared to the active comparator (MD = - 0.71 mmHg; 95% CI = [- 1.27, - 0.16]). When considering the effect of nebivolol on 24-hour ambulatory BP, notable reductions were observed compared to placebo. In contrast, compared to the active comparators, there was no significant difference in systolic BP reduction, but a significant reduction in diastolic BP favoring nebivolol. Based on moderator analyses, the impact of nebivolol on the pooled estimates remained independent of the dose of nebivolol, age, male sex, trial duration, body mass index (BMI), baseline diabetes, heart failure, and baseline systolic and diastolic BP. Nebivolol, compared to placebo, showed a significant BP reduction and was non-inferior to other active comparators in terms of BP reduction.

The Effects of Nebivolol-Gefitinib-Loratadine Against Lung Cancer Cell Lines.

Non-small-cell lung cancer (NSCLC) is the most frequently diagnosed malignancy and the first cause of cancer-related death. Thus, finding alternative therapeutic options is crucial. Drug repurposing offers therapeutic options in a simplified and affordable manner, especially to cancer patients in developing countries. Several drugs including antihistamines and beta-adrenergic receptor blockers (beta-blockers) display antiproliferative properties on cancer cells. Interestingly, NSCLC patients who had used either antihistamines or beta-blockers showed improved response to chemotherapy or reduced mortality in comparison to non-users of any of these drugs. However, combination therapy is gaining substantial interest in many cancers including non-EGFR mutated NSCLC. Here, we investigated the antineoplastic effect of the combination of the antihistamine loratadine, the beta-blocker nebivolol, and the tyrosine-kinase inhibitor gefitinib on NSCLC cell lines. A-549 and NCI-H1975 cell lines were used. The effect of nebivolol, gefitinib, and loratadine on the metabolic activity was studied using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated and used in the drug-combination experiments. Apoptosis was investigated using flow cytometry; and cell survival using the colony formation assay. The combination nebivolol-loratadine-gefitinib produced a significant synergistic effect on inhibiting the metabolic activity and colony formation, as well as on promoting apoptosis in both cell lines. Noteworthy, the effect on the cell line carrying the EGFR mutation (NCI-H1975) was very similar to the cell line that does not exhibit such mutation (A-549 cells). The nebivolol-gefitinib-loratadine combination may be a promising alternative for lung cancer treatment.

The β2-adrenergic biased agonist nebivolol inhibits the development of Th17 and the response of memory Th17 cells in an NF-κB-dependent manner.

Adrenergic receptors regulate metabolic, cardiovascular, and immunological functions in response to the sympathetic nervous system. The effect of β2-adrenergic receptor (AR) as a high expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional β2-AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4+ T (Th1, Th2, Th17) cells and polarized naive Th17 cells, highlighting its potential for IL-17A suppression via a non-canonical β2-AR cell signaling pathway. The effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naive Th17 cells activated with anti-CD3/anti-CD28/anti-CD2 ImmunoCult reagent. IFN-γ, IL-4, and IL-17A, which are primarily derived from Th1, Th2, and Th17 cells, respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR/Cas9. Protein expression of phosphorylated serine133-CREB and phosphorylated NF-κB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry. Nebivolol treatment decreased IL-17A and IFN-γ secretion by activated memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A+ Th cells and downregulated RORC expression. Unlike the β2-AR agonist terbutaline, nebivolol inhibited the shift of naive CD4+ T cells toward the Th17 phenotype. IL-10 and the proliferation index remained unchanged. Nebivolol-treated β2-knockout memory Th cells showed significant inhibition of β2-AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-κB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control. The findings demonstrate that nebivolol acts through a β2-AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing the phosphorylation of NF-κB. This highlights nebivolol's potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.

Multichannel 3D-printed bionanoparticles-loaded tablet (M3DPBT): designing, development, and in vitro functionality assessment

BackgroundThe intersubject variability which was related to the genetic makeup was the major cause of change in pharmacological and pharmacokinetic behavior of same dosage form in varied human being. 3D printing technology will help therapy evolve and eliminate the limitations of conventional technologies. Nebivolol's (NBL)-limited oral bioavailability is mainly due to its poor aqueous solubility. The research aims to combine advanced 3D printing technology and nanotechnology to design customized therapy and enhance the functionality of NBL using a statistical approach.Results and discussionThe results of the phase solubility indicated that NBL was a poorly aqueous soluble drug. Its solubility was increased by employing nanoparticle drug delivery, which is a promising solubility enhancement technique. The 32 full factorial design was employed to develop and optimize bionanoparticles (BNPs) by solvent evaporation technique using poly (lactic-co-glycolic acid 50:50) (PLGA 50:50) and poloxamer-407 as a surfactant. The BNPs were characterized by % encapsulation efficiency (% EE), Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimeter (DSC), transmission electron microscope (TEM), zeta potential, polydispersity index (PDI), particle size, in vitro drug release, etc. The BNPs loaded of NBL were further incorporated into the multichannel 3D-controlled release tablets made by PVA filaments employing fused deposition modeling (FDM) technology optimized by central composite design (CCD). Multichannel 3D-printed bionanoparticles-loaded tablet (M3DPBT) was optimized using CCD. All designed M3DPBTs were evaluated for post-fabrication parameters. The optimized M3DPBT could release more than 85% NBL within 10 h.ConclusionsThe newly fabricated M3DPBT was found stable. The amount of PLGA 50:50 and Polaxomer was significant for developing BNPs. % infill and layer height were observed as critical for the designing M3DPBT. The combined novel 3D printing and nanotechnology technology will open a new direction for patient compliance and better therapeutic effects.Graphical abstractDesigning and developing of M3DPBT is substantially improve the patient compliance and therapeutic effectiveness of Nebivolol.

Enhanced eNOS/nitric oxide production by nebivolol interferes with TGF-β1/Smad3 signaling and collagen I deposition in the kidney after prolonged tacrolimus administration

AimsTacrolimus is an effective immunosuppressant commonly used post-transplantation and in certain autoimmune diseases. However, its long-term administration is associated with renal fibrosis through transforming growth factor-beta/suppressor of mother against decapentaplegic (TGF-β/Smad) signaling that could be partly attributed to endothelial dysfunction alongside decreased nitric oxide (NO) release. Our study aimed to investigate the prospective renal anti-fibrotic effect of enhanced NO production by nebivolol against tacrolimus-stimulated TGF-β1/Smad3 signaling. Materials and methodsTo illustrate the proposed mechanism of nebivolol, Nω-nitro-L-arginine methyl ester (L-NAME); nitric oxide synthase inhibitor; was co-administered with nebivolol. Rats were treated for 30 days as control, tacrolimus, tacrolimus/nebivolol, tacrolimus/L-NAME, and tacrolimus/nebivolol/L-NAME groups. Key findingsOur results revealed that renal NO content was reduced in tacrolimus-treated rats, while treatment with tacrolimus/nebivolol enhanced NO content via up-regulated endothelial nitric oxide synthase (eNOS), but down-regulated inducible nitric oxide synthase (iNOS) expression. That participated in the inhibition of TGF-β1/Smad3 signaling induced by tacrolimus, where the addition of L-NAME abolished the defensive effects of nebivolol. Subsequently, the deposition of collagen I and alpha-smooth muscle actin (α-SMA) was retarded by nebivolol, emphasized by reduced Masson's trichrome staining. In accordance, there was a strong negative correlation between eNOS and both TGF-β1 and collagen I protein expression. The protective effects of nebivolol were further confirmed by the improvement in kidney function biomarkers and histological features. SignificanceIt can be suggested that treatment with nebivolol along with tacrolimus could effectively suppress renal TGF-β1/Smad3 fibrotic signaling via the enhancement of endothelial NO production, thus curbing renal fibrosis development.

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.

Histopathological and Immunological Effects of Nebivolol 5% Topical Cream in Mice Model of Imiquimod-Induced Psoriasis

Background: Psoriasis is a chronic inflammatory skin condition that affects multiple systems. Topical therapy is one of the most important modalities in the treatment of this disease, and efforts are directed toward developing more effective topical therapies. Objective: To investigate the possible anti-psoriatic effect of Nebivolol 5% topical cream in mice based on observational, histopathological, and biochemical outcomes. Methods: Forty-five male Swiss Albino mice were divided into five groups; each group contained nine mice with shaved dorsal skin. Group I remained as the control group while the rest of the groups were induced psoriasis by Imiquimod (IMQ) for six consecutive days and underwent different interventions for each group for eight consecutive days, including administering Nebivolol 5% topical cream. The clinical, pathological and laboratory effects were then measured. Results: Topical nebivolol significantly reduced the inflammatory signs of the psoriatic lesions, and these findings were supported by the histopathological examination. Topical Nebivolol also significantly decreased IL-17 levels, as well as Tumor Necrosis Factor-alpha (TNF-α) levels and Vascular Endothelial Growth Factor (VEGF) levels, in comparison with the non-treated Imiquimod-induced psoriatic mice group. Conclusions: Nebivolol has a comparable anti-psoriatic effect to the effect of clobetasol due to its anti-inflammatory and antioxidant effects. It could be a promising future treatment for psoriasis as an alternative to steroids.

Contrastive analysis on the safety of brand and generic nebivolol: a real-world pharmacovigilance study based on the FDA adverse event reporting system.

Background: The equivalence of generic drugs to their brand-name counterparts is a controversial issue. Current literature indicates disparities between the generic nebivolol (GN) and the brand nebivolol (BN). Aim: The study is designed to investigate the safety difference between GN and BN and provide reference information for clinical practice. Methods: We reviewed adverse event (AE) reports that recorded nebivolol as the primary suspect drug in the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2022, conducted a disproportional analysis to detect signals for the GN and BN respectively, and compared the AE heterogeneity between them using the Breslow-Day test. Results: A total of 2613 AE reports of nebivolol were recorded in the FAERS database from 2004 to 2022, of which 2,200 were classified as BN, 346 as GN, and 67 unclassifiable AE reports were excluded. The signals of 37 AEs distributed in cardiac, gastrointestinal, psychiatric, and nervous systems were detected in disproportional analysis. 33 out of 37 AEs were positive signals, with 21 not previously listed on the drug label, indicating an unrecognized risk with nebivolol. In the heterogeneity analysis of AE signals between GN and BN, the GN generally showed a higher AE signal value than BN, especially 15 AEs distributed in the cardiac, neurological, and psychiatric systems that showed statistically significantly higher risk by taking GN. Conclusion: Our study shows some previously overlooked adverse effects of nebivolol. It suggests that the risk of GN's adverse effects may be higher than those in BN, which deserves further attention and investigation by healthcare professionals, regulators, and others.

Comparison of anticonvulsant activity of nebivolol with sodium valproate in Swiss albino mice

Background: Antiepileptic activity was observed with an antiarrhythmic beta-blocker. In this context, the present study was designed to demonstrate the effects of nebivolol on the epilepsy experimental model. Aim and Objective: This study aimed to compare the anticonvulsant activity of sodium valproate and nebivolol on pentylenetetrazole-induced seizure model of Swiss albino mice. Materials and Methods: Twenty-four male Swiss strain albino mice of either sex were used in this study. The efficacy of nebivolol and sodium valproate was evaluated against pentylenetetrazole-induced seizure model of Swiss albino mice. Results: The latency of seizure and duration of seizure in rats of Group 1 and Group 2 was significantly higher compared with Group 3 control rats. There was no significant difference in the latency period of Group 1 and Group 2 rats. Conclusion: Nebivolol exhibited anti-epileptic activity against the pentylenetetrazole mice model.

Comparison of the Protective Effects of Nebivolol and Metoprolol against LPS-Induced Injury in H9c2 Cardiomyoblasts.

Here, we, for the first time, compared the cardioprotective effects of third-generation vasodilating beta-blocker nebivolol (Neb) and conventional beta-blocker metoprolol (Met) on LPS-induced injury in H9c2 cardiomyoblasts. Our findings denoted that Neb and Met pretreatment diminish LPS-mediated cytotoxicity and oxidative stress. Concomitantly, LPS-triggered inflammatory cytokines activation was significantly suppressed by Neb but not by Met. Pretreatment with either Neb or Met alleviated LPS-mediated mitochondrial impairment by enhancing the expression of genes related to its biogenesis such as PGC-1α, NRF1, and TFAM. On the contrary, Neb but not Met-upregulated mitochondrial fusion-related genes such as OPA, and MFN2. In summary, our findings suggest that Neb and Met treatment significantly ameliorated the LPS-induced cytotoxicity and oxidative stress. Additionally, these findings suggest that Neb but not Met significantly down-regulates LPS-induced proinflammatory factors, probably by enhancing mitochondrial biogenesis and fusion.

Nebivolol in oral subacute treatment prevents cardiac post-ischemic dysfunction in rats, but hyperthyroidism reduces this protection: mechanisms involved.

Nebivolol could prevent dysfunction in patients suffering myocardial ischemia. However, influence of hyperthyroidism is not known. Consequences and mechanisms of nebivolol treatment were investigated in isolated hearts from euthyroid (EuT) and hyperthyroid (HpT) rats. Rats were orally treated during 1 week with 20 mg/kg/day nebivolol (O-Neb), 30 mg/kg/day atenolol (O-Ate), or not treated (C). Isolated perfused hearts were exposed to global ischemia and reperfusion (I/R) inside a flow calorimeter. Left diastolic ventricular pressure, developed contractile pressure (P), and total heat rate (Ht) were continuously measured, while infarct size was measured after 2-h R. EuT-C and HpT-C hearts developed similarly low post-ischemic contractile recovery and economy (P/Ht). Nebivolol totally prevented dysfunction and reduced infarction size in EuT hearts, but partially improved recovery in HpT rat hearts. Contrarily, oral atenolol totally prevented dysfunction in HpT hearts but partially in EuT hearts. Nebivolol effects were reversed by perfusing L-NAME in both conditions, but partially reduced by aminoguanidine in HpT. However, L-NAME increased P and P/Ht recoveries in EuT-C and HpT-C rat hearts, as well as melatonin. Oral nebivolol prevented post-ischemic dysfunction and infarction in EuT hearts due to adrenergic β1 blockade and activation of iNOS and/or eNOS, but the effect was attenuated in HpT hearts by excessive iNOS-dependent nitrosative pathways.

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-1β) (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.

Effect of Fixed-dose Combination Amlodipine/Valsartan in Comparison to Two Drug Combination Nebivolol/Valsartan on 24-Hour Ambulatory Blood Pressure.

Nebivolol has a dual mechanism of action, exerting a moderate b- blockade effect and reducing peripheral arterial resistance, as a result, the antihypertensive effect of nebivolol may be higher than that of a potent vasodilator CCB such as amlodipine. The study evaluated the effect of two nebivolol/valsartan on 24 hour ambulatory blood pressure versus amlodipine/valsartan in grade II or III hypertension patients or having uncontrolled BP despite treatment. Ambulatory blood pressure monitoring is a powerful method to monitor the changes in blood pressure over the 24 hour. A total of 74 from 90 patients continued the study. Fourty patients received amlodipine 10 mg/valsartan 160 mg (group I), and thirty-four patients received nebivolol 5 mg/ valsartan 160 mg (group II). Peripheral blood pressure readings were measured at randomization at 6 and 12 weeks. Ambulatory blood pressure was measured at randomization and 12 weeks. Both drug combinations showed high efficacy in reducing peripheral and 24 hour ambulatory BP. There was no statistically significant difference between the groups in lowering peripheral systolic and diastolic blood pressure at 6 and 12 weeks. Furthermore, both groups failed to show any significant difference in reducing 24 hour SBP and DBP. Regarding day SBP, the blood pressure dropped by -5.63 ± 14.87 in group I and -6.25 ± 11.59 in group II (p = 0.844). Also, group I reduced the day DBP average by -2.53 ± 9.83 and group II by -3.61 ± 9.78 (p = 0.640). In addition, both drug combinations had no statistically significant difference in lowering night SBP and DBP average. Both treatment groups reached the target ambulatory blood pressure, and there was no statistically significant difference between both groups as a regard reduction in all ambulatory blood pressure readings.

Comparative effects of nebivolol and carvedilol on left ventricular diastolic function in older patients with heart failure and preserved ejection fraction

BackgroundAlthough many studies have compared carvedilol and nebivolol in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF), such comparative studies for the elderly have not been reported yet. Nebivolol is known to be effective for improving diastolic function of elderly patients with HF. Thus, this study aimed to determine whether nebivolol could improve LV diastolic function to a greater extent than carvedilol in older patients aged over 70 years. MethodsThis trial was a prospective, randomized, open-label, single-center, active-controlled study that enrolled 62 patients with class II or III HF over 70 years of age with an LVEF ≥40%. Patients were randomized into a carvedilol group or a nebivolol group. Transthoracic echocardiography was performed at baseline and 12 months by the same investigator who was blinded to clinical data. The primary endpoint was E/e′ measured by echocardiographic evaluation 12 months after treatment. ResultsThe median duration of follow-up was 24 months. Baseline clinical characteristics and echocardiographic parameters, such as LV diastolic function indices, did not differ significantly between carvedilol and nebivolol groups. Twelve-month follow-up echocardiography data showed no significant difference in E/e′ or other LV diastolic function indices between the two groups. There were no significant changes in echocardiographic parameters over 12 months in either group. ConclusionsThere was no difference between carvedilol and nebivolol for improving diastolic function of elderly HF patients with LVEF ≥40%. This study showed no superiority of nebivolol over carvedilol in elderly patients with HF.

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

ABSTRACT 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 β1 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-1β 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.

Abstract P6-10-19: Screening of GPCR-targeting drugs for repositioning in breast cancer

Abstract Drug repositioning can overcome both substantial costs and the long process of new drug discovery and development in cancer treatment. Some FDA-approved drugs have been found to have the potential to be repositioned as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repositioning potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repositioning potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of anti-HER2 therapies. We identified 7 drugs/compounds as potential hits, out of which 4 were FDA-approved drugs. We focused on beta-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of β3 receptors and nitric oxide (NO) production. Nebivolol reduced invasion and migration potentials which may suggest its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset found a reduced but not statistically significant risk of all-cause mortality in the nebivolol group. In-depth future analyses including detailed in vivo studies and real-world data analysis with more patients are needed to investigate further the potential of nebivolol as a repositioned therapy for BC. Citation Format: Noor Abdulkareem, Raksha Bhat, Reid Powell, Soumya Chikermane, Soham Yande, Lisa Trinh, Hala Abdelnasser, Alexis Ruiz, Mary Sobieski, Nghi Nguyen, Camille Johnson, Michael Johnson, Clifford Stephan, Meghana Trivedi. Screening of GPCR-targeting drugs for repositioning in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-10-19.

Nebivolol and Atenolol Roles in Doxorubicin-Induced Cardiotoxicity

Background: This study investigated the potential role of ivabradine (Nebivolol and Atenolol) in the attenuation of doxorubicin induced cardiotoxicity in mice. So we will seek the role of nebivolol and atenolol in reducing cardiotoxicity induced by doxorubicin in this experimental study. Aims: To investigate the potential roles of nebivolol and atenolol in the attenuation of doxorubicin (DXR)-induced cardiotoxicity in mice. Materials and Methods: A total of 42 Swiss-Albino male and female mice were used, which were divided into six equal groups: A negative control, a group 1 not received any agents, group 2 (DXR group) received a single dose of DXR 15 mg/kg, treated group 3 was pretreated with nebivolol 15 mg/kg plus DXR. Treated group 4 was pretreated with nebivolol 30 mg/kg plus DXR. Treated group 5 was pretreated with Atenolol 45 mg/kg plus DXR, and treated group 6 was pretreated with atenolol 90 mg/kg plus DXR. The duration of the study was 10 days. Inflammatory biomarkers including tumor necrosis factor-alpha (TNF-α), lactate dehydrogenase (LDH), malondialdehyde (MDA), and cardiac troponin (cTn-I) serum levels were measured. SPSS version 28.00 was used for data analysis. Results: TNF-α, LDH, MDA, and cTn-I serum levels were higher in the DXR-treated mice as compared to the control (P &lt; 0.05). Nebivolol and atenolol produced a dose-dependent effect in the reduction of TNF-α, LDH, MDA, and cTn-I serum levels as compared to the DXR-treated mice (P &lt; 0.05). Conclusion: Atenolol and nebivolol were effective agents in the mitigation of DXR-induced cardiotoxicity by their anti-inflammatory effects of both atenolol and nebivolol and antioxidant effects of nebivolol. Atenolol and nebivolol illustrated a dose-dependent effect in the attenuation of DXR-induced cardiotoxicity through inhibition of lipid peroxidation and cardiomyocyte injury.

Antihypertensive Efficacy Of Nebivolol And Low Dose Spironolactone In Patients With Resistant Hypertension.

Resistant hypertension is associated with increased mortality and morbidity. The optimal medical therapy is not fully elucidated in resistant hypertension. There are relatively few studies in the literature on the treatment of resistant hypertension. In this study, we compared the effectiveness of nebivolol 5 mg, a third generation beta-blocker, with spironolactone 25 mg in patients with resistant hypertension. A total of 81 patients with resistant hypertension were included in the study. The spironolactone group was composed of 38 patients while the nebivolol group was composed of 43 patients. Resistant hypertension was defined as having office blood pressure ≥ 140/90 mmHg while the patients were under 3 or more antihypertensive agents treatment which included diuretic agents. Office and ambulatory blood pressure at basal and after 8 weeks of treatment were recorded. Office systolic blood pressure and diastolic blood pressure in 24-hour ambulatory blood pressure monitoring were significantly lower when compared to basal values in both nebivolol and spironolactone groups. The decrease in 24-hour mean systolic and diastolic bloodpressure in nebivolol group was 14.9 ± 19.8 mmHg and 9.3 ± 12.7 mmHg compared to 19.5 ± 16.4 mmHg and 13.7 ± 10.8 mmHg in the spironolactone group, respectively. The decrease in 24-hour mean systolic and diastolic blood pressure was not significantly different between the nebivolol and spironolactone groups (P = 0.338 and P = 0.153). Nebivolol is an effective treatment option for resistant hypertension and the antihypertensive effect of nebivolol is similar to low-dose spironolactone.

Evaluation of Anticonvulsant Action of Nebivolol in Albino Mice

Background: Epilepsy is a disorder of brain function indicating periodic and unpredictable occurrence of seizures. Hypertension is the main cause of intracerebral hemorrhage which is a triggering factor for development of epilepsy. Nebivolol, a β-blocker is an anti-hypertensive drug, could decrease the glutaminergic transmission with addition of antioxidant property as a contributing factor may possibly provide anticonvulsant effect. Aim and Objective: The aim of the study was to study the anticonvulsant effect of Nebivolol in Albino mice. Materials and Methods: An either sex of Albino mice weighing between 18 and 22 g were used. Forty-eight animals (n = 48) were divided into eight groups with six in each group; four groups each for maximal electroshock (MES) and pentylenetetrazole (PTZ) models, respectively. Hind Limb Flexion, Hind Limb Extension, Clonus, and Postictal Depression were observed using MES model, Seizure latency and Duration of seizures were observed using PTZ model. Results: Nebivolol showed anticonvulsant effect with MES convulsions at both 0.25 mg/kg and 0.5 mg/kg but this effect is not equivalent to that of phenytoin in the present study. In terms of duration of tonic hind limb flexion and post-ictal depression, Nebivolol 0.5 mg/kg dose has comparable results to that of phenytoin. In PTZ model, Nebivolol decreased the seizure duration but did not delay the seizure onset, which were comparable to the standard Diazepam. Conclusion: Nebivolol may possibly be beneficial in treating generalized tonic clonic seizures and absence seizures. However, more extended studies are needed to prove the anticonvulsant effect of Nebivolol and enable its use in clinical practice.

Protective effect of nebivolol on rat ovary exposed to deltamethrin toxicity.

We aimed to investigate the antioxidant activity of nebivolol against possible damage to the ovarian tissue due to the application of deltamethrin as a toxic agent, by evaluating histopathological proliferating cell nuclear antigen (PCNA) and tumor necrosis factor-alpha (TNF-α) signal molecules immunohistochemically. The animals were divided into three groups as control, deltamethrin and deltamethrin + nebivolol groups. Vaginal smears were taken after the animals were mated and detected on the first day of pregnancy. After the sixth day, deltamethrin (0.5 mL of 30 mg/kg BW undiluted ULV), and 2 mL of sterile nebivolol solution were administered intraperitoneally every day for 6-21 periods. After routine histopathological follow-up, the ovarian tissue was stained with hematoxylin and eosin stain. Control group showed normal histology of ovarium. In deltamethrin group, hyperplasic cells, degenerative follicles, pyknotic nuclei, inflammation and hemorrhagic areas were observed. Nebivolol treatment restored these pathologies. Deltamethrin treatment increased TNF-α and PCNA reaction. However, nebivolol decreased the expression. It was thought that deltamethrin toxicity adversely affected follicle development by inducing degeneration and apoptotic process in preantral and antra follicle cells, and nebivolol administration might reduce inflammation and slow down the apoptotic signal in the nuclear phase and regulate reorganization.