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22 pages, 3834 KiB  
Brief Report
Target the Heart: A New Axis of Alzheimer’s Disease Prevention
by Lawrence I. Heller, Allison S. Lowe, Thaís Del Rosario Hernández, Sayali V. Gore, Mallika Chatterjee and Robbert Creton
J. Dement. Alzheimer's Dis. 2025, 2(2), 10; https://doi.org/10.3390/jdad2020010 - 1 May 2025
Viewed by 1355
Abstract
Background/Objective: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer’s disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening [...] Read more.
Background/Objective: Cyclosporine A and other calcineurin inhibitors have been identified as prospective treatments for preventing Alzheimer’s disease. We previously found that calcineurin inhibitors elicit a unique behavioral profile in zebrafish larvae, characterized by increased activity, acoustic hyperexcitability, and reduced visually guided behaviors. Screening a large library of FDA-approved compounds using Z-LaP Tracker revealed that some heart medications produce a similar behavioral profile, suggesting these drugs may exert calcineurin-inhibitor-like effects relevant to prevent-ing or ameliorating Alzheimer’s disease. Methods: Screening a large library of FDA-approved drugs using Z-LaP Tracker, a neural network model, revealed a cluster of 65 drugs demonstrating a cyclosporine A-like behavioral profile. Fourteen of these drugs were heart medications, including angiotensin receptor blockers, beta blockers, al-pha-adrenergic receptor antagonists, and a statin. Results: Dual administration of the heart medications with cyclosporine A in Z-LaP Tracker revealed synergistic effects: lower doses of each heart medication could be delivered in conjunction with a lower dose of cyclosporine A to evoke a similar or larger behavioral effect than higher doses of each drug independently. Other studies have shown that many of these heart medica-tions drugs directly or indirectly inhibit the calcineurin–NFAT pathway, like cyclo-sporine A, providing a potential mechanism. Conclusions: Co-administering a low dose of cyclosporine A with select cardiac drugs could be a potentially effective treatment strategy for preventing Alzheimer’s disease occurrence and simultaneously treating cardiovascular dysfunction, while mitigating the side effects associated with higher doses of cyclosporine A. Given that heart disease precedes Alzheimer’s disease in many patients, physicians may be able to create a treatment regimen that addresses both con-ditions. Our results suggest that a calcineurin inhibitor combined with simvastatin, irbesartan, cilostazol, doxazosin, or nebivolol is the most promising candidate for future exploration. Full article
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1 pages, 127 KiB  
Retraction
RETRACTED: Elsherif et al. Investigation of the Potential of Nebivolol Hydrochloride-Loaded Chitosomal Systems for Tissue Regeneration: In Vitro Characterization and In Vivo Assessment. Pharmaceutics 2021, 13, 700
by Noha Ibrahim Elsherif, Abdulaziz Mohsen Al-Mahallawi, Abdelfattah Ahmed Abdelkhalek and Rehab Nabil Shamma
Pharmaceutics 2025, 17(1), 38; https://doi.org/10.3390/pharmaceutics17010038 - 30 Dec 2024
Viewed by 630
Abstract
The journal retracts the article “Investigation of the Potential of Nebivolol Hydrochloride-Loaded Chitosomal Systems for Tissue Regeneration: In Vitro Characterization and In Vivo Assessment” [...] Full article
16 pages, 4204 KiB  
Article
Nebivolol Exerts Hepatoprotective Activity During CLP-Induced Sepsis by Modulating Oxidative Stress, Liver Regeneration, and AKT/MAPK Pathways in Rats
by Rahma Tharwat Sabra, Amany Abdlrehim Bekhit, Nourhan Tharwat Sabra, Nadia Ahmed Abd El-Moeze and Moustafa Fathy
Stresses 2024, 4(4), 800-815; https://doi.org/10.3390/stresses4040053 - 2 Dec 2024
Viewed by 1255
Abstract
Sepsis is a potentially catastrophic organ dysfunction arising from an infection-induced immunologic reaction leading to severe inflammation, progression of septic shock, and damage to body organs. Sepsis is marked by noticeable hepatotoxicity caused by activating oxidative stress, inflammation, and apoptotic mechanisms. Through Cecal [...] Read more.
Sepsis is a potentially catastrophic organ dysfunction arising from an infection-induced immunologic reaction leading to severe inflammation, progression of septic shock, and damage to body organs. Sepsis is marked by noticeable hepatotoxicity caused by activating oxidative stress, inflammation, and apoptotic mechanisms. Through Cecal Ligation and Puncture (CLP) in rats, our study is the first to investigate the potential preventive effect of the antihypertensive medicine “Nebivolol” on sepsis-induced hepatotoxicity at a molecular level. Six groups of sixty albino Wistar rats (male) were randomly assigned. Biochemical and oxidative stress markers of liver function were measured. Additionally, apoptosis- and inflammatory-related gene and protein expressions were examined. Finally, the liver tissues were examined for histological assessments. The hepatic architecture was considerably altered by CLP, which also resulted in marked elevations of blood aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total and direct bilirubin levels, and hepatic malondialdehyde (MDA). In contrast, it decreased serum albumin level, hepatic superoxide dismutase (SOD) activity, and glutathione (GSH) level. It also significantly elevated all hepatic inflammatory mediators (Interlukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Interlukin-1 beta (IL-1β)) and alleviated Interlukin-10 (IL-10). It magnified the expression of p-AKT/t-AKT, p-JNK1/2/t-JNK1/2, and p-p38/t-p38 proteins, raised Matrix Metalloproteinase 2/9 (MMP 2/9) and nuclear factor-kappa B (NF-κB) gene transcriptions, and lessened Vascular Endothelial Growth Factor (VEGF) gene expression. In contrast, Nebivolol administration dramatically mitigated all biochemical and histological changes obtained by CLP. The present finding demonstrated that Nebivolol succeeded, for the first time, in improving the hepatic injury obtained from CLP-evoked sepsis through modulating oxidative stress, inflammatory mediators, and apoptotic pathways through targeting the crosstalk between protein kinase B (AKT), NF-κB, and mitogen-activated protein kinase (MAPK), making Nebivolol a hopeful treatment for hepatic injury. Full article
(This article belongs to the Collection Feature Papers in Human and Animal Stresses)
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8 pages, 5424 KiB  
Communication
Nebivolol, an FDA-Approved Drug, Has General Antibacterial and Antibiofilm Effects and Increases Pseudomonas aeruginosa Tolerance to Ciprofloxacin
by Yael Schlichter Kadosh, Noa Goorevitch, Kerem Teralı, Jacob Gopas and Ariel Kushmaro
Pharmaceuticals 2024, 17(11), 1472; https://doi.org/10.3390/ph17111472 - 1 Nov 2024
Viewed by 1691
Abstract
Background: The repurposing of approved drugs for new activities is gaining widespread attention, including drugs that have antibacterial properties. Nevertheless, besides the benefits of repurposing drugs, the discovery of new antibiotic activity in commonly used medicines raises concerns about inducing antibiotic tolerance and [...] Read more.
Background: The repurposing of approved drugs for new activities is gaining widespread attention, including drugs that have antibacterial properties. Nevertheless, besides the benefits of repurposing drugs, the discovery of new antibiotic activity in commonly used medicines raises concerns about inducing antibiotic tolerance and resistance due to the stress produced by the drugs. We found that nebivolol, which is used to treat hypertension, also has antibacterial activity. Methods: The antibacterial activity of nebivolol was tested by disc diffusion and kinetic O.D. measurements. Antibiofilm activity was determined by crystal violet staining. Results: Nebivolol has antibiotic and antibiofilm activity against several bacteria. However, its effect on Pseudomonas aeruginosa’s growth is limited, and it promotes biofilm formation. In addition, P. aeruginosa exposure to nebivolol induces resistance to ciprofloxacin but increases sensitivity to tobramycin. Conclusions: Nebivolol has antibiotic activity against several bacteria tested but is less effective and possibly detrimental in P. aeruginosa infections. The use of nebivolol, together with other antibiotics, should be further tested and carefully considered. Full article
(This article belongs to the Section Biopharmaceuticals)
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22 pages, 3364 KiB  
Review
Metabolite Measurement in Index Substrate Drug Interaction Studies: A Review of the Literature and Recent New Drug Application Reviews
by Jingjing Yu, Nathalie Rioux, Iain Gardner, Katie Owens and Isabelle Ragueneau-Majlessi
Metabolites 2024, 14(10), 522; https://doi.org/10.3390/metabo14100522 - 26 Sep 2024
Cited by 1 | Viewed by 2431
Abstract
Background/Objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug–drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 [...] Read more.
Background/Objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug–drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam). Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites. Results: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes. Discussion and Conclusions: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions. Full article
(This article belongs to the Special Issue The Role of Metabolites in Translational and Clinical Pharmacology)
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15 pages, 663 KiB  
Article
Beta-Blockers of Different Generations: Features of Influence on the Disturbances of Myocardial Energy Metabolism in Doxorubicin-Induced Chronic Heart Failure in Rats
by Igor Belenichev, Olexiy Goncharov, Nina Bukhtiyarova, Oleh Kuchkovskyi, Victor Ryzhenko, Lyudmyla Makyeyeva, Valentyn Oksenych and Oleksandr Kamyshnyi
Biomedicines 2024, 12(9), 1957; https://doi.org/10.3390/biomedicines12091957 - 28 Aug 2024
Cited by 3 | Viewed by 2135
Abstract
Beta-blockers are first-line drugs in the treatment of chronic heart failure (CHF). However, there is no consensus on the specific effects of the beta-blockers of the I-III generation on energy metabolism in CHF. The aim of this study is to conduct a study [...] Read more.
Beta-blockers are first-line drugs in the treatment of chronic heart failure (CHF). However, there is no consensus on the specific effects of the beta-blockers of the I-III generation on energy metabolism in CHF. The aim of this study is to conduct a study of beta-blockers of different generations on myocardial energy metabolism in experimental CHF. CHF was modeled in white outbred rats by administering doxorubicin. The study drugs were administered intragastrically—new drug Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide)-3.5 mg/kg, Metoprolol—15 mg/kg, Nebivolol −10 mg/kg, Carvedilol 50 mg/kg, and Bisoprolol, 10 mg/kg. In the myocardium, the main indices of energy metabolism were determined—ATP, ADP, AMP, malate, lactate, pyruvate, succinate dehydrogenase (SDH) activity, and NAD-dependent malate dehydrogenase (NAD-MDH) activity. Traditional second-generation beta-blockers (Metoprolol and Bisoprolol) did not affect the studied indices of energy metabolism, and third-generation beta-blockers with additional properties—Carvedilol and, especially, Nebivalol and Hypertril—improved myocardial energy metabolism. The obtained results will help to expand our understanding of the effect of beta-blockers of various generations used to treat cardiovascular diseases on energy metabolism, and are also an experimental justification for the practical choice of these drugs in the complex therapy of CHF. Full article
(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)
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18 pages, 2148 KiB  
Article
Nebivolol Polymeric Nanoparticles-Loaded In Situ Gel for Effective Treatment of Glaucoma: Optimization, Physicochemical Characterization, and Pharmacokinetic and Pharmacodynamic Evaluation
by Pradeep Singh Rawat, Punna Rao Ravi, Mohammed Shareef Khan, Radhika Rajiv Mahajan and Łukasz Szeleszczuk
Nanomaterials 2024, 14(16), 1347; https://doi.org/10.3390/nano14161347 - 14 Aug 2024
Cited by 2 | Viewed by 1735
Abstract
Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular [...] Read more.
Nebivolol hydrochloride (NEB), a 3rd-generation beta-blocker, was recently explored in managing open-angle glaucoma due to its mechanism of action involving nitric oxide release for the vasodilation. To overcome the issue of low ocular bioavailability and the systemic side effects associated with conventional ocular formulation (aqueous suspension), we designed and optimized polycaprolactone polymeric nanoparticles (NEB-PNPs) by applying design of experiments (DoE). The particle size and drug loading of the optimized NEB-PNPs were 270.9 ± 6.3 nm and 28.8 ± 2.4%, respectively. The optimized NEB-PNPs were suspended in a dual-sensitive in situ gel prepared using a mixture of P407 + P188 (as a thermo-sensitive polymer) and κCRG (as an ion-sensitive polymer), reported previously by our group. The NEB-PNPs-loaded in situ gel (NEB-PNPs-ISG) formulation was characterized for its rheological behavior, physical and chemical stability, in vitro drug release, and in vivo efficacy. The NEB-PNPs-loaded in situ gel, in ocular pharmacokinetic studies, achieved higher aqueous humor exposure (AUC0–t = 329.2 ng × h/mL) and for longer duration (mean residence time = 9.7 h) than compared to the aqueous suspension of plain NEB (AUC0–t = 189 ng × h/mL and mean residence time = 6.1 h) reported from our previous work. The pharmacokinetic performance of NEB-PNPs-loaded in situ gel translated into a pharmacodynamic response with 5-fold increase in the overall percent reduction in intraocular pressure by the formulation compared to the aqueous suspension of plain NEB reported from our previous work. Further, the mean response time of NEB-PNPs-loaded in situ gel (12.4 ± 0.6 h) was three times higher than aqueous suspension of plain NEB (4.06 ± 0.3 h). Full article
(This article belongs to the Topic Advances in Controlled Release and Targeting of Drugs)
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13 pages, 2720 KiB  
Article
The Repurposing of FDA-Approved Drugs as FtsZ Inhibitors against Mycobacterium tuberculosis: An In Silico and In Vitro Study
by Andrea Michel Tovar-Nieto, Luis Enrique Flores-Padilla, Bruno Rivas-Santiago, Juan Valentin Trujillo-Paez, Edgar Eduardo Lara-Ramirez, Yolanda M. Jacobo-Delgado, Juan Ernesto López-Ramos and Adrián Rodríguez-Carlos
Microorganisms 2024, 12(8), 1505; https://doi.org/10.3390/microorganisms12081505 - 23 Jul 2024
Cited by 3 | Viewed by 2096
Abstract
Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis, remains one of the leading causes of death from a single infectious agent. Furthermore, the growing evolution to multi-drug-resistant (MDR) strains requires de novo identification of drug targets for evaluating candidates or repurposing drugs. Hence, [...] Read more.
Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis, remains one of the leading causes of death from a single infectious agent. Furthermore, the growing evolution to multi-drug-resistant (MDR) strains requires de novo identification of drug targets for evaluating candidates or repurposing drugs. Hence, targeting FtsZ, an essential cell division protein, is a promising target. Methods: Using an in silico pharmacological repositioning strategy, four FDA-based drugs that bind to the catalytic site FtsZ were selected. The Alamar Blue colorimetric assay was used to assess antimicrobial activity and the effect of drugs on Mtb growth through growth curves. Bacterial load was determined with an in vitro infection model using colony-forming units (CFU)/mL, and cytotoxicity on human monocyte-derived macrophages (MDMhs) was assessed by flow cytometry. Results: Paroxetine and nebivolol exhibited antimycobacterial activity against both reference TB and MDR strains at a concentration of 25 µg/mL. Furthermore, both paroxetine and nebivolol demonstrated a significant reduction (p < 0.05) in viable bacteria compared to the untreated group in the in vitro infection model. Conclusions: Collectively, our findings demonstrate that the use of paroxetine and nebivolol is a promising strategy to help in the control of tuberculosis infection. Full article
(This article belongs to the Special Issue Prevention, Treatment and Diagnosis of Tuberculosis, 2nd Edition)
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14 pages, 2641 KiB  
Article
Development of Oral Tablets of Nebivolol with Improved Dissolution Properties, Based on Its Combinations with Cyclodextrins
by Francesca Maestrelli, Marzia Cirri, Natascia Mennini, Silvia Fiani, Beatrice Stoppacciaro and Paola Mura
Pharmaceutics 2024, 16(5), 633; https://doi.org/10.3390/pharmaceutics16050633 - 9 May 2024
Cited by 2 | Viewed by 1805
Abstract
New oral tablets of nebivolol have been developed aiming to improve, by cyclodextrin (CD) complexation, its low solubility/dissolution properties—the main reason behind its poor/variable oral bioavailability. Phase-solubility studies, performed using βCD and highly-soluble βCD-derivatives, indicated sulfobutylether-βCD (SBEβCD) as the best solubilizing/complexing agent. Solid [...] Read more.
New oral tablets of nebivolol have been developed aiming to improve, by cyclodextrin (CD) complexation, its low solubility/dissolution properties—the main reason behind its poor/variable oral bioavailability. Phase-solubility studies, performed using βCD and highly-soluble βCD-derivatives, indicated sulfobutylether-βCD (SBEβCD) as the best solubilizing/complexing agent. Solid drug-SBEβCD systems were prepared by different methods and characterized for solid-state and dissolution properties. The coevaporated product was chosen for tablet development since it provided the highest dissolution rate (100% increase in dissolved drug at 10 min) and almost complete drug amorphization/complexation. The developed tablets reached the goal, allowing us to achieve 100% dissolved drug at 60 min, compared to 66% and 64% obtained, respectively, with a reference tablet without CD and a commercial tablet. However, the percentage dissolved after 10 min from such tablets was only 10% higher than the reference. This was ascribed to the potential binding/compacting abilities of SBEβCD, reflected in the greater hardness and longer disintegration times of the new tablets than the reference (7.64 vs. 1.06 min). A capsule formulation with the same composition of nebivolol-SBEβCD tablets showed about a 90% increase in dissolved drug after 5 min compared to the reference tablet, and reached 100% dissolved drug after only 20 min. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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12 pages, 1957 KiB  
Article
Comparison of the Protective Effects of Nebivolol and Metoprolol against LPS-Induced Injury in H9c2 Cardiomyoblasts
by Rukhsana Gul, Meshail Okla, Amer Mahmood, Shahid Nawaz, Amina Fallata, Arwa Bazighifan, Musaad Alfayez and Assim A. Alfadda
Curr. Issues Mol. Biol. 2023, 45(11), 9316-9327; https://doi.org/10.3390/cimb45110583 - 20 Nov 2023
Cited by 2 | Viewed by 1940
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Mitochondrial Function and Dysfunction)
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17 pages, 2786 KiB  
Article
Blockade of ß-Adrenergic Receptors by Nebivolol Enables Tumor Control Potential for Uveal Melanoma in 3D Tumor Spheroids and 2D Cultures
by Lina S. Farhoumand, Hongtao Liu, Theodora Tsimpaki, Ulrike B. Hendgen-Cotta, Tienush Rassaf, Nikolaos E. Bechrakis, Miltiadis Fiorentzis and Utta Berchner-Pfannschmidt
Int. J. Mol. Sci. 2023, 24(6), 5894; https://doi.org/10.3390/ijms24065894 - 20 Mar 2023
Cited by 12 | Viewed by 3179
Abstract
Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As β-blockers are known to have anti-tumor effects on various cancer entities, this study focuses [...] Read more.
Uveal melanoma (UM) is the most common primary cancer of the eye in adults. A new systemic therapy is needed to reduce the high metastasis and mortality rate. As β-blockers are known to have anti-tumor effects on various cancer entities, this study focuses on investigating the effect of β1-selective blockers atenolol, celiprolol, bisoprolol, metoprolol, esmolol, betaxolol, and in particular, nebivolol on UM. The study was performed on 3D tumor spheroids as well as 2D cell cultures, testing tumor viability, morphological changes, long-term survival, and apoptosis. Flow cytometry revealed the presence of all three β-adrenoceptors with a dominance of β2-receptors on cell surfaces. Among the blockers tested, solely nebivolol concentration-dependently decreased viability and altered 3D tumor spheroid structure. Nebivolol blocked the repopulation of cells spreading from 3D tumor spheroids, indicating a tumor control potential at a concentration of ≥20 µM. Mechanistically, nebivolol induced ATP depletion and caspase-3/7 activity, indicating that mitochondria-dependent signaling is involved. D-nebivolol or nebivolol combined with the β2-antagonist ICI 118.551 displayed the highest anti-tumor effects, suggesting a contribution of both β1- and β2-receptors. Thus, the present study reveals the tumor control potential of nebivolol in UM, which may offer a perspective for co-adjuvant therapy to reduce recurrence or metastasis. Full article
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12 pages, 2583 KiB  
Article
The β1 Adrenergic Blocker Nebivolol Ameliorates Development of Endotoxic Acute Lung Injury
by Esra Nurlu Temel, Mehtap Savran, Yalcın Erzurumlu, Nursel Hasseyid, Halil Ibrahim Buyukbayram, Gozde Okuyucu, Mehmet Abdulkadir Sevuk, Ozlem Ozmen and Ayse Coskun Beyan
J. Clin. Med. 2023, 12(5), 1721; https://doi.org/10.3390/jcm12051721 - 21 Feb 2023
Cited by 3 | Viewed by 2328
Abstract
Acute lung injury (ALI) is a disease, with no effective treatment, which might result in death. Formations of excessive inflammation and oxidative stress are responsible for the pathophysiology of ALI. Nebivolol (NBL), a third-generation selective β1 adrenoceptor antagonist, has protective pharmacological properties, such [...] Read more.
Acute lung injury (ALI) is a disease, with no effective treatment, which might result in death. Formations of excessive inflammation and oxidative stress are responsible for the pathophysiology of ALI. Nebivolol (NBL), a third-generation selective β1 adrenoceptor antagonist, has protective pharmacological properties, such as anti-inflammatory, anti-apoptotic, and antioxidant functions. Consequently, we sought to assess the efficacy of NBL on a lipopolysaccharide (LPS)-induced ALI model via intercellular adhesion molecule-1 (ICAM-1) expression and the tissue inhibitor of metalloproteinases-1 (TIMP-1)/matrix metalloproteinases-2 (MMP-2) signaling. Thirty-two rats were split into four categories: control, LPS (5 mg/kg, intraperitoneally [IP], single dose), LPS (5 mg/kg, IP, one dosage 30 min after last NBL treatment), + NBL (10 mg/kg oral gavage for three days), and NBL (10 mg/kg oral gavage for three days). Six hours after the administration of LPS, the lung tissues of the rats were removed for histopathological, biochemical, gene expression, and immunohistochemical analyses. Oxidative stress markers such as total oxidant status and oxidative stress index levels, leukocyte transendothelial migration markers such as MMP-2, TIMP-1, and ICAM-1 expressions in the case of inflammation, and caspase-3 as an apoptotic marker, significantly increased in the LPS group. NBL therapy reversed all these changes. The results of this study suggest that NBL has utility as a potential therapeutic agent to dampen inflammation in other lung and tissue injury models Full article
(This article belongs to the Section Infectious Diseases)
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22 pages, 4589 KiB  
Article
Design, Characterization and Pharmacokinetic–Pharmacodynamic Evaluation of Poloxamer and Kappa-Carrageenan-Based Dual-Responsive In Situ Gel of Nebivolol for Treatment of Open-Angle Glaucoma
by Pradeep Singh Rawat, Punna Rao Ravi, Shahid Iqbal Mir, Mohammed Shareef Khan, Himanshu Kathuria, Prasanna Katnapally and Upendra Bhatnagar
Pharmaceutics 2023, 15(2), 405; https://doi.org/10.3390/pharmaceutics15020405 - 25 Jan 2023
Cited by 18 | Viewed by 3126
Abstract
This study developed a dual-responsive in situ gel of nebivolol (NEB), a selective β-adrenergic antagonist. The gel could achieve sustained concentrations in the aqueous humor to effectively treat glaucoma. The gel was prepared using a combination of poloxamers (Poloxamer-407 (P407) and Poloxamer-188 (P188)) [...] Read more.
This study developed a dual-responsive in situ gel of nebivolol (NEB), a selective β-adrenergic antagonist. The gel could achieve sustained concentrations in the aqueous humor to effectively treat glaucoma. The gel was prepared using a combination of poloxamers (Poloxamer-407 (P407) and Poloxamer-188 (P188)) and kappa-carrageenan (κCRG) as thermo-responsive and ion-sensitive polymers, respectively. Box–Behnken design (BBD) was used to optimize the effect of three critical formulation factors (concentration of P407, P188 and κCRG) on two critical response variables (sol-to-gel transition temperature of 33–35 °C and minimum solution state viscosity) of the in situ gel. A desirability function was employed to find the optimal concentrations of P407, P188 and κCRG that yielded a gel with the desired sol-to-gel transition temperature and solution state viscosity. An NEB-loaded gel was prepared using the optimized conditions and evaluated for in vitro drug release properties and ex vivo ocular irritation studies. Furthermore, ocular pharmacokinetic and pharmacodynamics studies were conducted in rabbits for the optimized formulation. The optimized NEB-loaded gel containing P407, P188 and κCRG had a sol-to-gel transition temperature of 34 °C and exhibited minimum viscosity (212 ± 2 cP at 25 °C). The optimized NEB-loaded gel sustained drug release with 86% drug release at the end of 24 h. The optimized formulation was well tolerated in the eye. Ocular pharmacokinetic studies revealed that the optimized in situ gel resulted in higher concentrations of NEB in aqueous humor compared to the NEB suspension. The aqueous humor Cmax of the optimized in situ gel (35.14 ± 2.25 ng/mL) was 1.2 fold higher than that of the NEB suspension (28.2 ± 3.1 ng/mL), while the AUC0–∞ of the optimized in situ gel (381.8 ± 18.32 ng/mL*h) was 2 fold higher than that of the NEB suspension (194.9 ± 12.17 ng/mL*h). The systemic exposure of NEB was significantly reduced for the optimized in situ gel, with a 2.7-fold reduction in the plasma Cmax and a 4.1-fold reduction in the plasma AUC0–∞ compared with the NEB suspension. The optimized gel produced a higher and sustained reduction in the intra-ocular pressure compared with the NEB suspension. The optimized gel was more effective in treating glaucoma than the NEB suspension due to its mucoadhesive properties, sustained drug release and reduced drug loss. Lower systemic exposure of the optimized gel indicates that the systemic side effects can be significantly reduced compared to the NEB suspension, particularly in the long-term management of glaucoma. Full article
(This article belongs to the Special Issue Nanoparticles in Ocular Drug Delivery Systems)
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13 pages, 2437 KiB  
Article
Nebivolol as a Potent TRPM8 Channel Blocker: A Drug-Screening Approach through Automated Patch Clamping and Ligand-Based Virtual Screening
by Farhad Jahanfar, Laura Sadofsky, Alyn Morice and Massimo D’Amico
Membranes 2022, 12(10), 954; https://doi.org/10.3390/membranes12100954 - 28 Sep 2022
Cited by 6 | Viewed by 3348
Abstract
Transient Receptor Potential Melastatin 8 (TRPM8) from the melastatin TRP channel subfamily is a non-selective Ca2+-permeable ion channel with multimodal gating which can be activated by low temperatures and cooling compounds, such as menthol and icilin. Different conditions such as neuropathic [...] Read more.
Transient Receptor Potential Melastatin 8 (TRPM8) from the melastatin TRP channel subfamily is a non-selective Ca2+-permeable ion channel with multimodal gating which can be activated by low temperatures and cooling compounds, such as menthol and icilin. Different conditions such as neuropathic pain, cancer, overactive bladder syndrome, migraine, and chronic cough have been linked to the TRPM8 mode of action. Despite the several potent natural and synthetic inhibitors of TRPM8 that have been identified, none of them have been approved for clinical use. The aim of this study was to discover novel blocking TRPM8 agents using automated patch clamp electrophysiology combined with a ligand-based virtual screening based on the SwissSimilarity platform. Among the compounds we have tested, nebivolol and carvedilol exhibited the greatest inhibitory effect, with an IC50 of 0.97 ± 0.15 µM and 9.1 ± 0.6 µM, respectively. This study therefore provides possible candidates for future drug repurposing and suggests promising lead compounds for further optimization as inhibitors of the TRPM8 ion channel. Full article
(This article belongs to the Special Issue Ion Channels on (Bio)Membranes)
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14 pages, 4636 KiB  
Article
New Data for Nebivolol after In Silico PK Study: Focus on Young Patients and Dosage Regimen
by Lara Marques, Bárbara Costa and Nuno Vale
Pharmaceutics 2022, 14(9), 1911; https://doi.org/10.3390/pharmaceutics14091911 - 9 Sep 2022
Cited by 3 | Viewed by 3667
Abstract
Nebivolol (NEB) is a highly selective β1 receptor antagonist with a distinct pharmacological profile. This drug is approved for the treatment of hypertension in the US, and hypertension and heart failure in Europe. Here, we review observations based on age dependence and explore [...] Read more.
Nebivolol (NEB) is a highly selective β1 receptor antagonist with a distinct pharmacological profile. This drug is approved for the treatment of hypertension in the US, and hypertension and heart failure in Europe. Here, we review observations based on age dependence and explore new drug regimens with in-silico studies, to achieve better efficacy and safety. The clinical data were obtained from six published literature reports. Then the data were used for model building, evaluation, and simulation. A two-compartment model with first-order absorption, lag time, linear elimination, and the following covariates: age and genotype were the ones best describing our population. Simulation of different dose regimens resulted in an increase chance of efficacy and safety when the dose regimen was altered to 6 mg every 36 h. It is worth noting that our population in this study constituted of young and healthy individuals. Studies regarding the effects of NEB according to age are scarce; however, they are needed to further improve efficacy and safety, and reduce adverse effects. Full article
(This article belongs to the Special Issue In Silico Pharmacology for Evidence-Based and Precision Medicine)
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