Nebivolol prevents redox imbalance and attenuates bladder dysfunction induced by cyclophosphamide in mice.

Cyclophosphamide (CYP) is combined with cytoprotective agents to minimize its toxicity in the bladder, which is mediated by reactive oxygen species (ROS). Using multiple antioxidant mechanisms, nebivolol protects from oxidative stress in distinctive conditions. We hypothesized that nebivolol would attenuate both molecular and functional alterations induced by CYP in the bladder. Male C57BL/6 were pretreated or not with nebivolol (10 mg/kg/day, gavage), which was given 5 days before a single injection of CYP (300 mg/kg; i.p.). Molecular and functional parameters were assessed at 24 h in the bladder. Nebivolol prevented increases in ROS generation and lipoperoxidation as well as reduction of superoxide dismutase activity induced by CYP. Increased voiding frequency, decreased voiding interval, and reduced bladder capacity were found in CYP-treated mice. These responses were prevented by nebivolol. An augmented number of urinary spots and smaller urinary volumes were detected in CYP-injected mice, and nebivolol partially prevented these responses. The reduction of ROS levels is the primary mechanism by which nebivolol attenuates the deleterious effects of CYP in the bladder. The association of nebivolol with other cytoprotective agents could be an option to prevent CYP-associated oxidative damage to the bladder during chemotherapy.

Nebivolol hydrochloride and its impurities induce pseudo-allergic reactions via mast cell activation.

Nebivolol hydrochloride is a third-generation ß-blocker commonly used to treat cardiovascular diseases. However, it has been reported to induce allergic reactions in clinical use which deserves much attention. Therefore, this study focused on the ability of two isomers of nebivolol and chiral isomer impurities to induce allergic reactions. Our findings demonstrate that both nebivolol and two isomeric impurities can activate mast cell degranulation in vitro and show significant retention on Mas-related G-protein-coupled receptor X2 (MRGPRX2)-HEK293 cell membrane chromatography. These effects were further validated in vivo, where nebivolol and impurity IP-3 were observed to cause toe swelling and mast cell degranulation in mice. Molecular docking studies revealed interactions between these compounds and key amino acids of MRGPRX2, suggesting a mechanism for the induced allergic reactions. This work lays the foundation for improving the clinical safety of nebivolol.

Assessment of nebivolol efficacy in experimental models of toxoplasmosis: insights into parasite burden reduction and neuronal protection.

This study investigates the efficacy of nebivolol (NBV) in experimental models of toxoplasmosis, focusing on parasite burden reduction and neuronal protection. In the acute model of experimental toxoplasmosis, Swiss mice infected with RH strain tachyzoites received oral NBV chlorhydrate doses of 2 mg/kg/day and 4 mg/kg/day for 8 days. Treatment with NBV significantly reduced parasite burden compared to vehicle and standard drug (PYR) groups. In the chronic model of experimental toxoplasmosis, C57/BL6 mice infected with the ME49 strain received NBV chlorhydrate 41 days post-infection and were evaluated after 10 days of treatment. NBV chlorhydrate effectively reduced cyst number and area, as well as bradyzoite burden compared to controls. Histological analysis demonstrated that NBV chlorhydrate preserved neuronal count, with the 4 mg/kg/day dose yielding counts similar to non-infected mice. Statistical analysis confirmed significant differences compared to control groups. Furthermore, immunohistochemical analysis revealed a significant reduction in iNOS labeling in the brains of mice treated with NBV chlorhydrate, indicating a decrease in nitric oxide production compared to control groups. These findings suggest NBV's potential as a promising candidate for toxoplasmosis treatment, highlighting its ability to reduce parasite burden and protect neuronal integrity. Further research is warranted to elucidate NBV's mechanisms of action and its clinical application in managing toxoplasmosis.

Nanosized ethosomal dispersions for enhanced transdermal delivery of nebivolol using intradermal/transfollicular sustained reservoir: in vitro evaluation, confocal laser scanning microscopy, and in vivo pharmacokinetic studies.

Nebivolol (NBV), a BCS class II anti-hypertensive drug, suffers from limited solubility and oral bioavailability. Nanosized ethosomes were adopted as an approach to solubilize and deliver NBV transdermally, as a substitute to oral route. Ethosomal dispersions were prepared employing thin film hydration method. Formulation variables were adjusted to obtain entrapment efficiency; EE > 50%, particle size; PS < 100 nm, zeta potential; ZP > ±25 mV, and polydispersity index; PDI < 0.5. The optimized ethosomal dispersion (OED) showed accepted EE 86.46 ± 0.15%, PS 73.50 ± 0.08 nm, ZP 33.75 ± 1.20 mV, and PDI 0.31 ± 0.07. It also showed enhanced cumulative amount of NBV permeated at 8 h (Q8) 71.26 ± 1.46% and 24 h (Q24) 98.18 ± 1.02%. TEM images denoted spherical vesicles with light colored lipid bi-layer and dark core. Confocal laser scanning microscopy showed deeply localized intradermal and transfollicular permeation of the fluorolabelled OED (FL-OED). Nanosized FL-OED (<100 nm) can permeate through hair follicles creating a drug reservoir for enhanced systemic absorption. OED formulated into transdermal patch (OED-TP1) exhibited accepted physicochemical properties including; thickness 0.14 ± 0.01 mm, folding endurance 151 ± 0.07, surface pH 5.80 ± 0.15, drug content 98.64 ± 2.01%, mucoadhesion 8534 ± 0.03, Q8 87.61 ± 0.11%, and Q24 99.22 ± 0.24%. In vivo pharmacokinetic studies showed significantly enhanced bioavailability of OED-TP1 by 7.9 folds compared to oral Nevilob® tablets (p = 0.0002). It could be concluded that OED-TP1 can be a promising lipid nanocarrier TDDS for NBV and an efficacious alternative route of administration for hypertensive patients suffering from dysphagia.

Ethosomes loaded with lipophilic drugs, as NBV, can have two possible pathways of permeation through the skin; intradermal and transfollicular.Nanosized ethosomes (< 100 nm) can produce efficient intradermal and transfollicular reservoirs for sustained drug delivery.The formulated transdermal patch loaded with the optimized ethosomal dispersion (OED) showed enhanced bioavailability by 7.9 folds compared to Nevilob® oral tablets.

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.

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.

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.

Blockade of ß-Adrenergic Receptors by Nebivolol Enables Tumor Control Potential for Uveal Melanoma in 3D Tumor Spheroids and 2D Cultures.

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 ß-blockers are known to have anti-tumor effects on various cancer entities, this study focuses on investigating the effect of ß1-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 ß-adrenoceptors with a dominance of ß2-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 ß2-antagonist ICI 118.551 displayed the highest anti-tumor effects, suggesting a contribution of both ß1- and ß2-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.

Inhibition of eNOS Partially Blunts the Beneficial Effects of Nebivolol on Angiotensin II-Induced Signaling in H9c2 Cardiomyoblasts.

We have recently illustrated that nebivolol can inhibit angiotensin II (Ang II)-mediated signaling in cardiomyoblasts; however, to date, the detailed mechanism for the beneficial effects of nebivolol has not been studied. Here, we investigated whether the inhibition of NO bioavailability by blocking eNOS (endothelial nitric oxide synthase) using L-NG-nitroarginine methyl ester (L-NAME) would attenuate nebivolol-mediated favorable effects on Ang II-evoked signaling in H9c2 cardiomyoblasts. Our data reveal that the nebivolol-mediated antagonistic effects on Ang II-induced oxidative stress were retreated by concurrent pretreatment with L-NAME and nebivolol. Similarly, the expressions of pro-inflammatory markers TNF-α and iNOS stimulated by Ang II were not decreased with the combination of nebivolol plus L-NAME. In contrast, the nebivolol-induced reduction in the Ang II-triggered mTORC1 pathway and the mRNA levels of hypertrophic markers ANP, BNP, and ß-MHC were not reversed with the addition of L-NAME to nebivolol. In compliance with these data, the inhibition of eNOS by L-N5-(1-Iminoethyl) ornithine (LNIO) and its upstream regulator AMP-activated kinase (AMPK) with compound C in the presence of nebivolol showed effects similar to those of the L-NAME plus nebivolol combination on Ang II-mediated signaling. Pretreatment with either compound C plus nebivolol or LNIO plus nebivolol showed similar effects to those of the L-NAME plus nebivolol combination on Ang II-mediated signaling. In conclusion, our data indicate that the rise in NO bioavailability caused by nebivolol via the stimulation of AMPK/eNOS signaling is key for its anti-inflammatory and antioxidant properties but not for its antihypertrophic response upon Ang II stimulation.

Therapeutic Properties of Highly Selective ß-blockers With or Without Additional Vasodilator Properties: Focus on Bisoprolol and Nebivolol in Patients With Cardiovascular Disease.

Bisoprolol and nebivolol are highly selective ß1-adrenoceptor antagonists, with clinical indications in many countries within the management of heart failure with reduced left ventricular ejection fraction (HFrEF), ischaemic heart disease (IHD), and hypertension. Nebivolol has additional vasodilator actions, related to enhanced release of NO in the vascular wall. In principle, this additional mechanism compared with bisoprolol might lead to more potent vasodilatation, which in turn might influence the effectiveness of nebivolol in the management of HFrEF, IHD and hypertension. In this article, we review the therapeutic properties of bisoprolol and nebivolol, as representatives of "second generation" and "third generation" ß-blockers, respectively. Although head-to-head trials are largely lacking, there is no clear indication from published studies of an additional effect of nebivolol on clinical outcomes in patients with HFrEF or the magnitude of reductions of BP in patients with hypertension.

Nebivolol alleviates liver damage caused by methotrexate via AKT1/Hif1α/eNOS signaling.

Despite the wide clinical indications, methotrexate (MTX) use is limited because of serious side effects including liver toxicity. MTX was shown to cause tissue damage by mainly oxidative stress and also inflammation and apoptosis. Thus, Nebivolol (NEB) which has antioxidant and antiapoptotic properties were thought to be effective against MTX-induced injury. This study aimed to evaluate the effects of NEB on MTX-induced liver toxicity via AKT/Hypoxia-Inducible Factor 1 Alpha (HIF1α)/Endothelial Nitric Oxide Synthase (eNOS) signaling pathways. Rats were divided into three groups as control, MTX, and NEB. A single dose of MTX (20 mg/kg intraperitoneally) was given to the rats on the first day of the experiment and NEB (10 mg/kg, daily by oral gavage) was given to the treatment group for a week. At the end of the experiment, bloods were taken for aspartate transaminase (AST), alanine aminotransferase (ALT), and total bilirubin (T-BIL) analyses. Liver tissues were harvested for biochemical (total oxidant status (TOS) and total antioxidant status (TAS), genetic (PCR analyses for AKT1, eNOS, and HIF1a), and histological (Hemotoxylin-Eosin, Masson Trichome, Periodic Acid Schiff-Asien Blue, reticulin for histological, and CD3 for immunohistochemical staining) analyses. MTX increased the levels of TOS values, AST, ALT, T-BIL levels and decreased the expressions of AKT/HIF1α/eNOS. NEB treatment reversed all these changes markedly via decreasing inflammation by nitric oxid (NO) production. In conclusion, NEB treatment significantly preserves the liver by decreasing oxidant levels and inflammatory parameters through HIF1α/eNOS signaling. Due to the antioxidant properties of NEB, it can be used in other liver injury models sharing the same pathway.

Nebivolol elicits a neuroprotective effect in the cuprizone model of multiple sclerosis in mice: emphasis on M1/M2 polarization and inhibition of NLRP3 inflammasome activation.

BACKGROUND AND AIM: Multiple sclerosis (MS) is a demyelinating neurodegenerative inflammatory disease affecting mainly young adults. Microgliosis-derived neuroinflammation represents a key hallmark in MS pathology and progression. Nebivolol (Neb) demonstrated antioxidant, anti-inflammatory and neuroprotective properties in several brain pathologies. This study was conducted to investigate the potential neuroprotective effect of Neb in the cuprizone (Cup) model of MS. METHODS: C57Bl/6 mice were fed 0.2% Cup mixed into rodent chow for 5 weeks. Neb (5 and 10 mg/kg/day) was administered by oral gavage during the last 2 weeks. RESULTS: Neb prevented Cup-induced weight loss and motor deficits as evidenced by increased latency to fall in the rotarod test and enhanced locomotor activity as compared to Cup-intoxicated mice. Neb reversed Cup-induced demyelination as confirmed by Luxol fast blue staining and myelin basic protein western blotting. Administration of Neb modulated microglial activation status by suppressing M1 markers (Iba-1, CD86, iNOS, NO and TNF-α) and increasing M2 markers (Arg-1 and IL-10) as compared to Cup-fed mice. Furthermore, Neb hindered NLRP3/caspase-1/IL-18 inflammatory cascade and alleviated oxidative stress by reducing lipid peroxidation, as well as increasing catalase and superoxide dismutase activities. CONCLUSION: These findings suggest the potential neuroprotective effect of Neb in the Cup-induced model of MS in mice, at least partially by virtue of shifting microglia towards M2 phenotype, mitigation of NLRP3 inflammasome activation and alleviation of oxidative stress.

Nebivolol protects against cyclophosphamide-induced nephrotoxicity through modulation of oxidative stress, inflammation, and apoptosis.

The usefulness of cyclophosphamide (CP) in the treatment of multiple human malignancies and immunological diseases is hindered by the danger of developing nephrotoxicity. The toxic metabolites of CP are suggested to be responsible for oxidative stress resulted from the production of reactive oxygen species (ROS) and stimulation of lipid peroxidation. Nebivolol (NEB) is a third-generation selective B1 adrenoceptor antagonist, but it has also various pharmacological properties such as anti-inflammation, anti-apoptotic, and antioxidant activities. Thus, the present study aims to explore the potential protective effect of NEB against CP-induced nephrotoxicity. A cumulative dose of CP (75 mg/kg) was administered to albino rats by intraperitoneal injection. The protective effect of NEB was investigated by co-administration of NEB (10 mg/kg orally daily). Administration of NEB with CP significantly improved renal functions and reduced the oxidative renal changes induced by CP injection. Co-administration of NEB ameliorated apoptosis and inflammatory markers that were markedly exaggerated by CP. Our results indicated that NEB could be used as a protective agent against CP-induced nephrotoxicity.

Early nebivolol treatment is beneficial in myocardial infarction in rats partly through ß3-adrenoceptor remodelling.

It remains unknown whether ß-blockers are useful and safe in acute myocardial infarction (MI). Owing to its pharmacological profile and vasodilating action, nebivolol (N) is useful in MI. The aim of the present study was to assess in rat whether early nebivolol treatment could be beneficial in MI. It remains unknown whether ß-blockers are useful and safe in acute MI. On day (D) 0, male Sprague-Dawley rats underwent left coronary artery ligation (MI) or simple thoracotomy (SHAM). On D1 and D2, the rats were treated with either nebivolol (5 mg.kg-1 .day-1 , MI-N and Sham-N) or vehicle (V, MI-V and Sham-V). On D3, heart rate, left ventricle (LV) intrinsic contractility (PESmid) and arterial elastance were measured. Cardiac and aortic ß-Adrenoceptor (AR) subtype mRNA were quantified using real time quantitative RT-qPCR. Catecholamine response was assessed on isolated heart and aortic rings with isoproterenol. PESmid was decreased in MI without worsening the decrease nebivolol. In LV, ß1 - and ß3 -AR mRNA were respectively decreased and increased in all MI. ß3 -AR mRNA increase was partly limited by nebivolol. Ex vivo, basal contractility was less decreased in MI-N than in MI-V. Isoproterenol response was only altered in MI-V. In MI aorta, Nebi prevented ß2 - and ß3 -AR mRNA increases. In addition, Acetylcholine-induced relaxation was lowered in MI-V but preserved with nebivolol. We demonstrated an early modulation of cardiovascular ß3 -AR transcription early MI. Despite its putative negative inotropic properties, nebivolol did not worsen cardiac function in basal conditions and preserved LV catecholamine response.

The Effects of Nebivolol and Irbesartan on Ambulatory Aortic Blood Pressure and Arterial Stiffness in Hemodialysis Patients with Intradialytic Hypertension.

BACKGROUND: Intradialytic hypertension occurs in 5-15% of hemodialysis patients and is associated with increased cardiovascular risk, but the responsible mechanisms remain unknown. This study examined the effects of nebivolol and irbesartan on ambulatory central blood pressure (BP), arterial stiffness, and wave-reflection parameters in patients with intradialytic hypertension. METHODS: This is a prespecified analysis of a single-blind, randomized, cross-over study in 38 hemodialysis patients with intradialytic hypertension. Patients were randomized to nebivolol 5 mg followed byirbesartan 150 mg, or vice versa. In a non-randomized manner, the first half of the patients (n = 19) received a single drug dose 1 h prior to dialysis session and the remaining received the drugs for a whole week before the evaluation. Ambulatory central BP, arterial stiffness, and wave-reflection parameters were estimated with Mobil-O-Graph NG device, during a midweek dialysis day. RESULTS: Intake of a single dose of nebivolol or irbesartan resulted in lower postdialysis central systolic BP (c-SBP) (baseline: 140.9 ± 15.4; nebivolol: 130.3 ± 19.5, p = 0.009; irbesartan: 127.3 ± 24.4 mm Hg, p = 0.007). Single-dose nebivolol also produced marginally lower 24-h c-SBP (p = 0.064) and lower 24-h central diastolic BP (c-DBP) (p = 0.029). Weekly administration of both drugs reduced postdialysis c-SBP (baseline: 144.1 ± 15.3; nebivolol: 131.8 ± 14.1, p = 0.014; irbesartan: 126.4 ± 17.8, p = 0.001) and 24-h c-SBP and c-DBP (baseline: 135.5 ± 10.3/91.9 ± 9.2; nebivolol: 126.4 ± 8.4/86.6 ± 7.2, p < 0.001/p = 0.002; irbesartan: 128.7 ± 11.6/87.0 ± 9.4, p = 0.061/p = 0.051 mm Hg). Single-dose intake of both drugs did not affect heart rate-adjusted augmentation index [AIx(75)], but decreased postdialysis pulse wave velocity (PWV). Importantly, weekly administration of both drugs reduced 24-h PWV (baseline: 10.0 ± 2.5; nebivolol: 9.7 ± 2.5, p = 0.012; irbesartan: 9.7 ± 2.7, p = 0.041). In between drug-group comparisons, no significant differences were noted. CONCLUSIONS: This is the first randomized evaluation on the effects of pharmacological interventions on central BP and PWV in patients with intradialytic hypertension. Weekly administration of both nebivolol and irbesartan reduced 24-h central BP and PWV, but not AIx(75).

Synchronized determination of sacubitril and valsartan with some co-administered drugs in human plasma via UPLC-MS/MS method using solid-phase extraction.

An accurate and sensitive UPLC-MS/MS method was developed and validated for the simultaneous estimation of the newly developed combination of sacubitril and valsartan and the co-administered drugs nebivolol, chlorthalidone and esomeprazole in human plasma. Solid-phase extraction was conducted for the purification and extraction of the drugs from human plasma. Chromatographic separation was carried out on an Agilent SB-C18 (1.8 µm, 2.1 × 50 mm) column using losartan as internal standard. Isocratic elution was applied using acetonitrile-0.1% formic acid in water (85: 15, v/v) as mobile phase. Detection was carried out using a triple-quadrupole tandem mass spectrometer using multiple reaction monitoring, at positive mode at m/z 412.23 → 266.19 for sacubitril, m/z 436.29 → 235.19 for valsartan, m/z 405.8 → 150.98 for nebivolol, m/z 346.09 → 198 for esomeprazole and a selected combination of two fragments m/z 423.19 → 207.14 and 423.19 → 192.2 for losartan (internal standard), and in negative ionization mode at m/z 337.02 → 190.12 for chlorthalidone. The method was linear over the concentration ranges 30-2,000 ng/ml for sacubitril, 70-2,000 ng/ml for valsartan, esomeprazole and chlorthalidone and 70-5,000 pg/ml for nebivolol. The developed method is sensitive and selective and could be applied for dose adjustment, bioavailability and drug-drug interaction studies.

Comparison of tablet splitting techniques for dosing accuracy of nebivolol tablets: Hand splitting versus tablet cutter and knife.

Tablet splitting is a common practice in clinical settings to lower doses, facilitate swallowing or save costs. Splitting devices can be used when hand splitting is difficult or painful. However, data on the accuracy of tablet splitting are limited and it presents a number of patient or formulation-related problems. Thirty nebivolol IR tablets on the Turkish market were split by hand, a tablet cutter (Rabir®) or a knife, and tested for weight variation, loss of mass, disintegration, and friability. The accuracy of split tablets was in the range of 75.4-121, 82.4-115, and 86.9-115% when split by hand, the cutter, and knife, respectively. No significant difference in accuracy was determined between the left and right sides split by the cutter (p = 0.222). The differences were significant for hand and knife splittings (p < 0.005). The precision was 9.02, 7.87, and 6.11% (CV%) for hand, tablet cutter, and knife, respectively. Only hand splitting failed to comply with the subdivision test of European Pharmacopoeia. The split portions met USP standards for friability (<1%). Splitting decreased the disintegration time (4.5 vs. 2.2 min). Overall, the accuracy of the tablet cutter was more favorable than hand splitting and knife. The study demonstrated that the splitting technique may result in inaccurate dosing and significant drug fluctuations for nebivolol tablets.

BIOCHEMICAL MARKERS OF ENDOTHELIAL DYSFUNCTION, THEIR CHANGES UNDER THE INFLUENCE OF TREATMENT WITH VARIOUS BETA-ADRENOBLOCKERS IN YOUNG MEN WITH MYOCARDIAL INFARCTION.

OBJECTIVE: The aim: Is to determine the levels of markers of endothelial dysfunction in young men with myocardial infarction and their changes during the treatment with beta-blockers with different pharmacological properties. PATIENTS AND METHODS: Materials and methods: 112 male patients of Caucasian race of the Ukrainian population under the age of 50 with MI. Group I received Nebivolol, group II - bisoprolol. RESULTS: Results: During the 6-month follow-up, positive dynamics of NOS-2 and ET-1 was observed. The level of NOS-2 in groups I - II was 4272.3±162.7, 4629.7±161.2 pg/mL, respectively (p<0.05). The dynamics of ET-1 showed significant decrease of its level in all groups. CONCLUSION: Conclusions: Significant changes in markers of endothelial dysfunction, namely NOS3/eNOS, NOS2/iNOS and ET-1, are observed in young male patients of the Ukrainian population with MI. During 6 months of treatment, positive changes were observed in the form of an increase in NOS-3 levels and a significant decrease in ET-1 and NOS-2 levels. The inclusion of Nebivolol in the basic therapy for this group of patients is associated with an additional positive effect on the normalization of levels NO synthase and the reduction of ET-1.

Choosing among ß-blockers in heart failure patients according to ß-receptors' location and functions in the cardiopulmonary system.

Several large clinical trials showed a favorable effect of ß-blocker treatment in patients with chronic heart failure (HF) as regards overall mortality, cardiovascular mortality, and hospitalizations. Indeed, the use of ß-blockers is strongly recommended by current international guidelines, and it remains a cornerstone in the pharmacological treatment of HF. Although different types of ß-blockers are currently approved for HF therapy, possible criteria to choose the best ß-blocking agent according to HF patients' characteristics and to ß-receptors' location and functions in the cardiopulmonary system are still lacking. In such a context, a growing body of literature shows remarkable differences between ß-blocker types (ß1-selective blockers versus ß1-ß2 blockers) with respect to alveolar-capillary gas diffusion and chemoreceptor response in HF patients, both factors able to impact on quality of life and, most likely, on prognosis. This review suggests an original algorithm for choosing among the currently available ß-blocking agents based on the knowledge of cardiopulmonary pathophysiology. Particularly, starting from lung physiology and from some experimental models, it focuses on the mechanisms underlying lung mechanics, chemoreceptors, and alveolar-capillary unit impairment in HF. This paper also remarks the significant benefit deriving from the correct use of the different ß-blockers in HF patients through a brief overview of the most important clinical trials.

Role of cardioprotective agents on chemotherapy-induced heart failure: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Although previous clinical randomized controlled trials (RCTs) have tested the effect of a variety of cardioprotective agents on cancer therapy-induced cardiotoxicity, the number of included patients was limited, and the results remained controversial. In this study, we aimed to evaluate the preventive or therapeutic effects of cardioprotective agents on heart failure (HF) caused by cardiotoxicity induced by cancer therapy. METHODS: We included trials of the following cardioprotective drugs: Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone antagonists and stains. We extracted the relevant information with predefined data extraction forms, and assessed the risk of bias in randomized controlled trials with the Cochrane risk of bias tool. The primary outcome was the left ventricular ejection fraction of patients after chemotherapy. We used the random-effects model to carry out pair-wise meta-analysis, and then carry out the random-effects network meta-analysis within the Bayesian framework. RESULTS: Twenty-two relevant RCTs, including 1 916 patients (79.6 % women) with a mean age of 48.4 years, were included. Based on the evaluation of all drug species from 20 studies (26 comparisons), the analysis found that 4 therapies, aldosterone antagonists (MD, 12.78 [95 % CI, 2.87-22.69] and MD, 13.75 [95 % CI, 2.21-25.30]), ACEIs (MD, 6.79 [95 % CI, 2.11-11.48] and MD, 7.76 [95 % CI, 2.64-12.88]), statin (MD, 8.35 [95 % CI, 1.11-15.59]), and beta-blockers (MD, 4.00 [95 % CI, 0.87-7.14]), had a higher efficacy than placebo and/or control, suggesting an LVEF protective effect of cardioprotective therapy. In the analysis classified by single drug or drug combination, based on 22 studies (31 comparisons), spironolactone (MD, 12.77 [95 % CI, 1.76-23.79] and MD, 14.62 [95 % CI, 1.70-27.55]), a combination of candesartan and carvedilol (MD, 12.40 [95 % CI, 0.99-23.81]), enalapril (MD, 7.35 [95 % CI, 1.16-13.54] and MD, 9.20 [95 % CI, 2.61-15.79]), and statin (MD, 8.36 [95 % CI, 0.36-16.36]) showed significant benefits in protecting left ventricular (LV) systolic function compared with the placebo and/or control. CONCLUSION: When classified according to drug type, aldosterone antagonists, ACEIs, statins, and beta-blockers could substantially improve the LV systolic function. In the analysis classified by single drug or drug combination, spironolactone, enalapril, and statin have a significant cardioprotective effect. However, ARBs have no cardioprotective effect and fail to improve the LVEF.