Protective effect of nebivolol on rat ovary exposed to deltamethrin toxicity

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

Clinical advantages of nebivolol in the treatment of hypertension / 中国药房

β-blocker is one of the commonly used anti-hypertensive drugs， and there are obvious differences in the selection of this class of drugs. Nebivolol is a third-generation β-blocker with a unique mechanism of action. This article summarizes the clinical application of nebivolol in anti-hypertensive treatment in recent years， and it is found that compared with other β-blockers， nebivolol has certain clinical treatment advantages. In addition to having a significant antihypertensive effect， it also has little impact on sexual function and heart rate of patients， and does not affect the blood glucose and lipid metabolism， so the drug is more suitable for some special groups of patients， including sexually active male hypertensive patients， hypertensive patients with complications such as type 2 diabetes mellitus and metabolic syndrome.

Experimental design approach for development of novel microemulsion system and immediate release self microemulsifying tablet of nebivolol HCl

The objective of this study was to determine specific combination of pharmaceutical excipients that lead to formulation of efficient nebivolol hydrochloride SMEDDS and its subsequent formulation into IR-SET (Immediate release- Self emulsifying tablet) which will enhance its solubility and dissolution. Solubility and Pseudo-ternary phase studies were carried out to identify the excipients showing highest solubility and to identify the zone of microemulsion with selected ingredients. Liquid-SMEDDS (L-SMEDDS) were optimized for Concentration of oil(X1) and Smix(X2) and formulated using a combination of Kollisolv GTA as oil, Tween 80 as surfactant and propylene glycol as co-surfactant which gave smaller droplet size(Y1) 55.98nm , Emulsification time (Y2) 16±1.5 s,% transmittance (Y3) 99.94±0.47%. Neusilin US2 was used as solid carrier for solidification of L-SMEDDS in to Solid-SMEDDS (S-SMEDDS) by adsorption technique. IR-SET of nebivolol were formulated with S-SMEDDS and optimized for the concentration of binder (X1) (PVP K30) and superdisintegrant (X2) (KOLLIDON CL) which showed low Disintegration time (Y1) (92±0.5s) and low Friability(Y2)(0.424±0.03%). Also the DSC and XRD data revealed the molecular state of the drug in S-SMEDDS. The extent of in-vivo drug release and ex-vivo diffusion values from L-SMEDDS and IR-SET was much higher than pure drug and marketed tablet. In conclusion, the results showed potential of SMEDDS to improve solubility and thus the bioavailability.

Role of nebivolol in anthracycline-induced cardiotoxicity

Background: Anthracyclines are extensively used in the treatment of breast cancer. However, these therapeutic agents are responsible for chemotherapy-induced cardiotoxicity. Aim of this study was to assess the effect of use of prophylactic nebivolol for the prevention of anthracycline-induced cardiotoxicity in breast cancer patients.Methods: This was a prospective, randomized, single-blind, and placebo-controlled trial involving 80 participants with breast cancer, scheduled to undergo chemotherapy with doxorubicin. Patients were randomly divided into two groups: the nebivolol group (n=40) to receive nebivolol 5 mg daily and the placebo group (n=40) to receive placebo. All patients were evaluated with baseline Electrocardiogram (ECG) and echocardiography prior to treatment, and at the 6-month follow-up. Echocardiography included 2D echocardiography, colour doppler and tissue doppler imaging.Results: The study groups had comparable baseline echocardiographic variables. At the 6-month echocardiographic follow-up, there were no changes of statistical significance in any 2D echocardiographic variables in either group. However, there were minimal reductions of 0.4% in left ventricular ejection fraction in the nebivolol group (62.2±4.4% to 61.9±4.2%, p=0.75) and 1.6% in the placebo group (62.8±3.6% to 61.8±3.2%, p=0.18). Doppler examinations also did not reveal any statistically significant changes in variables such as peak A velocity, peak E velocity, E/A ratio, isovolumic relaxation time, and isovolemic contraction time in either group.Conclusions: Prophylactic use of nebivolol treatment may possess cardioprotective properties against anthracycline-induced cardiotoxicity in breast cancer patients although not statistically significant in this study.

Spectrophotometric Method Development And Validation For Simultaneous Estimation Of Nebivolol Hydrochloride And Valsartan In Bulk And Combined Pharmaceutical Dosage Form In Release Media

A simple, rapid, precise, accurate and sensitive spectrophotometric method has been developed for the simultaneous estimation and validation of Nebivolol Hydrochloride (NEB) and Valsartan (VAL) in pure and combined tablet dosage forms. Pure drug samples of NEB and VAL were dissolved in 67 mM Phosphate buffer pH 6.8 with 0.5 % sodium dodecyl sulphate (SDS) and found to have absorbance maxima at 280 nm for NEB and 250 nm for VAL, respectively. The linearity lies between 10-70 μg/ml for NEB and 10-60 μg/ml for VAL in this method. The correlation coefficient (r2) was found to be 0.9965 for NEB and 0.9960 for VAL. The % recoveries obtained were 95.65 % – 109.85 % for NEB and 97.42 % – 101.43 % for VAL. The % RSD found 0.271 %-1.490 % for intraday and 0.334 %-1.917 % for interday for NEB and 0.188 %-0.944 % for intraday and 0.392 %-1.197 % for interday for VAL. The limit of detection and limit of quantitation for NEB were found to be 4.608 μg/ml and 13.965 μg/ml respectively and the limit of detection and limit of quantitation for VAL were found to be 4.348 μg/ml and 13.178 μg/ml respectively. Simultaneous calibration of both drugs in 67 mM Phosphate buffer pH 6.8 with 0.5 % SDS shows that λmax of one drug does not interfere on the λmax of other drug. Recovery study was performed to confirm the accuracy of the method. The results of analysis have been validated statistically by recovery studies as per International Conference on Harmonization guidelines. The method showed good reproducibility and recovery with % RSD <2. Hence, this proposed method was found to be rapid, specific, precise, accurate and can be successfully applied for the routine analysis of NEB and VAL in pure and combined tablet dosage form.

A comparative study of effects of nebivolol and atenolol on blood pressure and lipid profile in patients of mild to moderate hypertension

Background: Beta blockers have been used in the treatment of hypertension, since last four decades and are widely accepted as the first-line treatment for hypertension. Nebivolol, a third generation ?-blocker has highest ?1 selectivity and is devoid of intrinsic sympathomimetic activity. Along with peripheral vasodilatation and nitric oxide (NO)-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, nebivolol promotes better protection from cardiovascular events. The objective of the study was to compare the effects of atenolol and nebivolol on both blood pressure and lipid profile in patients of mild to moderate hypertension.Methods: This was a prospective, randomized, parallel, open labelled study. Patients were recruited from the medicine out-patient department (OPD) and cardiology OPD. A total of 100 patients were enrolled in the study. 50 patients were allocated to atenolol group and 50 patients to nebivolol group. BP and baseline investigations such as lipid profile were performed. Tests to determine lipid profile were performed on the first visit (Week 0) and at 24 weeks. Continuous variables between the two treatment groups were analyzed by unpaired t-test. Efficacy endpoints within the group were analyzed by using paired t-test.Results: All the lipid levels except HDL-C were increased with atenolol therapy. At 24 weeks, atenolol therapy led to increase in LDL-C, VLDL-C, TC and TG which was highly significant (p<0.0001). HDL levels were decreased at 24 weeks which was also statistically highly significant (p<0.0001). The mean values of lipids in nebivolol group at baseline and at 24 weeks. At 24 weeks, nebivolol therapy led to changes in LDL-C, VLDL-C, HDL-C, TC and TG which was not statistically significant (p>0.05).Conclusions: From study it can be concluded that atenolol and nebivolol are equally effective in reducing BP but atenolol worsens lipid profile as compared to nebivolol.

Investigation of the antioxidant effects of pheniramine maleate and nebivolol on testicular damage in rats with experimentally induced testis torsion

Abstract Purpose: To investigate the biochemical, histopathologic, and spermatogenetic changes in the detorsionated testicle after experimental torsion and to study the antioxidant effects of pheniramine maleate and nebivolol. Methods: Twenty-four Sprague-Dawley male rats were divided into 4 groups: Group 1: Sham; Group 2: Torsion/Detorsion (T/D); Group 3: T/D + Pheniramine maleate (PM); Group 4: T/D + Nebivolol (NB) group. Paroxanase (PON), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stres index (OSI) were measured, and spermatogenetic and histopathologic evaluation was performed in tissue and blood samples. Results: The evaluation of tissue TAS indicated no statistically significant difference in Group 3 compared to Group 2. A statistically significant increase was detected in Group 4 compared to Group 2. Serum PON levels revealed a statistically significant increase in Groups 3 and 4 compared to Groups 1 and 2. The Johnsen testicular biopsy score decreased in Groups 3 and 4, but the decrease was not statistically significant. Conclusions: Pheniramine maleate and nebivolol have antioxidant effects against ischemia-reperfusion damage. They also support tissue recovery, which is more significantly observed by nebivolol.

Efecto de la administración de atenolol o nebivolol sobre la variabilidad de la presión arterial y su impacto sobre el daño de órgano blanco en ratas espontáneamente hipertensas / Effect of Atenolol or Nebivolol Administration on Blood Pressure Variability and its Impact on White Organ Damage in Spontaneously Hypertensive Rats

Introducción: Tradicionalmente se ha considerado que el riesgo cardiovascular asociado con la hipertensión es producto de la elevación sostenida de la presión arterial, que lleva al daño de órgano blanco. En los últimos años se ha descripto que otros factores, como la variabilidad de la presión arterial y la presión arterial central, también afectan directamente el daño de órgano blanco. Objetivo: Determinar los efectos de la administración crónica de atenolol o nebivolol sobre la variabilidad de la presión arterial a corto plazo y el daño de órgano blanco a nivel del ventrículo izquierdo y de la aorta. Material y métodos: Se incluyeron ratas espontáneamente hipertensas (REH) que fueron tratadas durante 8 semanas con una única administración diaria de atenolol, nebivolol o vehículo. Se determinaron la presión arterial y su variabilidad a corto plazo y se realizó ecocardiografía. Se extrajeron el ventrículo izquierdo y la aorta torácica para cuantificar la expresión del factor de crecimiento transformante b y realizar estudios histológicos. Resultados: El tratamiento crónico con nebivolol redujo la presión arterial media (PAM) y su variabilidad en mayor medida que el atenolol (PAM WKY: 118,6 ± 8,0 mm Hg; REH: 174,6 ± 2,1ª mm Hg; REH-atenolol: 155,2 ± 2,1a, b mm Hg; REH-nebivolol: 122,3 ± 2,3b, c mm Hg; desviación estándar de la PAM WKY: 3,8 ± 0,2 mm Hg; REH: 6,2 ± 0,3ª mm Hg; REH-atenolol: 5,2 ± 0,3a, b mm Hg; REH-nebivolol: 4,2 ± 0,2b, c mm Hg; ªp < 0,05 vs. ratas WKY; b p < 0,05 vs. REH; c p < 0,05 vs. REH-atenolol). Conclusiones: El análisis del daño de órgano blanco establece que el nebivolol reduce el contenido de fibrosis ventricular, disminuye el espesor de la media aórtica e induce una mayor reducción de la sobreexpresión del factor de crecimiento transformante b en ambos órganos en comparación con REH tratadas con vehículo o atenolol. Estos hallazgos sugieren que la mayor reducción de la presión arterial central, junto con la disminución de la labilidad de la presión arterial, contribuiría en la superior protección del daño de órgano blanco por el nebivolol respecto del atenolol.

Determination of Equilibrium Solubility and Apparent Oil/Water Partition Coefficient of Nebivolol Hydrochloride / 中国药师

Objective:To determine the equilibrium solubility and the apparent oil/water partition coefficient of nebivolol hydrochloride to provide experimental basis for the development of new preparations.Methods:The concentration of nebivolol hydrochloride was determined by an HPLC method,and a saturated solution method and a shake-flask method were respectively applied to determine the equilibrium solubility and the apparent oil/water partition coefficient of nebivolol hydrochloride in water,0.1 mol·L-1 HCl solution and phosphate buffer solution with different pH values(pH2.0,pH6.8,pH7.4 and pH8.0).Results:At (37±0.5)℃,the equilibrium solubility of nebivolol hydrochloride in water and in 0.1 mol·L-1 HCl solution was 722.53 μg·ml-1and 56.07μg·ml-1,respectively.The apparent oil/water partition coefficient (Log P) of nebivolol hydrochloride was 1.17 and 1.32,respectively.Within the pH range of 2.0-7.4,with the increase of pH value, the equilibrium solubility and the Log P decreased and increased,respectively,while pH value increased from 7.4 to 8.0,the equilibrium solubility of nebivolol hydrochloride increased and Log P decreased.Conclusion:The method is accurate and reliable.Nebivolol hydrochloride has poor water solubility,and the equilibrium solubility and the Log P are both influenced by pH values.

Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction / Efeito do Nebivolol sobre Parâmetros do MIBG e Exercício na Insuficiência Cardíaca com Fração de Ejeção Normal

Abstract Background: More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. Objectives: To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. Methods: Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. Results: After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. Conclusion: Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

Resumo Fundamento: Mais de 50% dos pacientes com insuficiência cardíaca têm fração de ejeção preservada (ICFEN). A cintilografia marcada com iodo 123 com metaiodobenzilguanidina (123I-MIBG) e o teste cardiopulmonar do exercício (TCPE) são marcadores de prognóstico da ICFEN. O nebivolol é um betabloqueador com propriedade vasodilatadora. Objetivos: Avaliar o impacto da terapia com nebivolol sobre as variáveis da cintilografia com 123I-MIBG e do TCPE em pacientes com ICFEN. Métodos: Vinte e cinco pacientes realizaram cintilografia com 123I-MIBG para avaliar a taxa de washout e a relação coração/mediastino precoce e tardia. Durante o TCPE, foi analisado o comportamento da pressão arterial sistólica (PAS), frequência cardíaca (FC) durante o esforço e a recuperação (FCR) e o consumo de oxigênio (VO2). Após avaliação inicial, separamos nossa amostra em grupos controle versus intervenção, iniciamos o nebivolol e repetimos os exames após 3 meses. Resultados: Após o tratamento, o grupo intervenção apresentou melhora na PAS (149 mmHg [143,5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0,016]), FC em repouso (78 bpm [65,5-84 bpm] versus 64,5 bpm [57,5-75,5 bpm, p = 0,028]), PAS no pico do esforço (235 mmHg [216,5-249 mmHg] versus 198 mmHg [191-220,5 mmHg], p = 0,001), FC no pico do esforço (124,5 bpm [115-142 bpm] versus 115 bpm [103,7-124 bpm], p = 0,043) e FCR no 1º minuto (6,5 bpm [4,75-12,75 bpm] versus 14,5 bpm [6,7-22 bpm], p = 0,025) e no 2º minuto (15,5 bpm [13-21,75 bpm] versus 23,5 bpm [16-31,7 bpm], p = 0,005), porém não apresentou mudança no VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. Conclusão: Apesar de um melhor controle da PAS e na FC em repouso e durante o esforço e uma melhora na FCR, o nebivolol não ocasionou efeito positivo sobre o VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. A ausência de efeito sobre a atividade adrenérgica pode ser a causa da falta de efeito sobre a capacidade funcional.

Formulation, characterization and in vivo evaluation of novel edible dosage form containing nebivolol HCl

ABSTRACT The objective of this investigation was to develop a novel oral edible gel dosage form for nebivolol hydrochloride, with suitable rheological characteristics that can provide a means of administering the drug to dysphagic and geriatric patients. Edible gels were prepared using low acetylated gellan gum and sodium citrate in different concentrations. The effect of concentration of the solution on gelation time, viscosity, and drug release was studied. Optimized formulation had "spoon thick" consistency that is considered suitable for dysphagic patients as suggested by National Dysphagia Diet Task Force. The optimized formulation containing gellan gum (0.4 % w/v) and sodium citrate (0.3 % w/v) showed more than 95% drug release in 20 minutes. This formulation also showed significantly better pharmacokinetic profile when compared to marketed conventional tablets in New Zealand white rabbits (n = 3). Optimized formulation was found stable for 6 months when stored at 25 °C ± 0.2 °C/60 ± 5% RH. From this study, it can be concluded that the novel edible gel dosage form containing nebivolol hydrochloride may prove to be more efficacious in the treatment of hypertension in dysphagic patients.

RESUMO O objetivo deste trabalho foi desenvolver um gel comestível para veiculação de cloridrato de nebivolol, com características reológicas adequadas, que podem fornecer meio de administrar o fármaco em casos de disfagia orofaríngea e pacientes geriátricos. Géis comestíveis foram preparados utilizando goma gelana de baixa acetilação e citrato de sódio, em diferentes concentrações. Estudou-se o efeito da concentração da solução no tempo de gelificação, a viscosidade e a liberação do fármaco. A formulação otimizada apresentava consistência de pudim, o que é considerado adequado para pacientes disfágicos como sugerido pela National Dysphagia Diet Task Force. A formulação otimizada contendo 0,4% (m/v) de goma gelana e 0,3% (m/v) de citrato de sódio mostrou que mais de 95% de fármaco foi liberado em 20 minutos. Esta formulação também mostrou, significativamente, melhor perfil farmacocinético, quando comparado com os comprimidos convencionais comercializados administrados a coelhos brancos neozelandeses (n = 3). A formulação otimizada manteve-se estável durante 6 meses, armazenada a 25 oC ± 0,2 °C/60 ± 5% de UR. A partir deste estudo, conclui-se que a nova forma de gel comestível contendo cloridrato de nebivolol pode ser mais eficaz no tratamento de hipertensão em pacientes portadores de disfagia.

Rhabdomyolysis in a patient taking nebivolol

β Blockers such as propranolol and labetalol are known to induce toxic myopathy because of their partial β₂ adrenoceptor agonistic effect. Nebivolol has the highest β1 receptor affinity among β blockers, and it has never been reported to induce rhabdomyolysis until now. We report a patient who developed rhabdomyolysis after changing medication to nebivolol. A 75-year-old woman was admitted to our hospital because of generalized weakness originating 2 weeks before visiting. Approximately 1 month before her admission, her medication was changed from carvedilol 12.5 mg to nebivolol 5 mg. Over this time span, she had no other lifestyle changes causing rhabdomyolysis. Her blood chemistry and whole body bone scan indicated rhabdomyolysis. We considered newly prescribed nebivolol as a causal agent. She was prescribed carvedilol 12.5 mg, which she was previously taking, instead of nebivolol. She was treated by hydration and urine alkalization. She had fully recovered and was discharged.

To study the comparative effects of nebivolol and metoprolol on lipid profile in patients of essential hypertension.

Background: Hypertension and certain alteration in serum lipoproteins are complementary coronary risk factors. The effect of antihypertensive agents on lipid metabolism exhibits a wide range. Numerous studies have established that vasodilating beta-blockers are associated with more favorable effects on glucose and lipid profiles than non-vasodilating beta-blockers. The study was conducted to study the comparative effects of nebivolol and metoprolol on lipid profile in patients of essential hypertension. Methods: A prospective, randomized open label single center study was conducted in the Department of Pharmacology in collaboration with Department of Medicine, MGM’s Medical College and Hospital, Aurangabad in newly diagnosed patients of essential hypertension. Sixty patients of either sex in the age group of 30-65 years with blood pressure (BP) of ≥140/90 mmHg with deranged lipid parameters according to National Cholesterol Education Program were randomized into two groups. Group I received metoprolol (50 mg) and Group II received nebivolol (5 mg), both given once daily for 12 weeks. BP and lipid parameters were evaluated at baseline as well as at the end of 12 weeks. Results: There was significant reduction in BP values (p<0.0001) as compared to baseline in both the groups, however no significant difference was observed between two drugs revealing that their efficacy in reducing systolic BP/diastolic BP is comparable. Furthermore, both the drugs had a favorable effect on lipid profile, but more significant results on lipid profile were observed in the nebivolol group as compared to metoprolol group (p<0.0001). Conclusions: In our comparison study, it is seen that the favorable effect of nebivolol on serum lipids and its good tolerability profile make it a good choice for control of hypertension as well as preventing the long-term cardiovascular morbidities and mortalities.

Perfil farmacocinético y farmacodinámico del nebivolol en un modelo experimental de síndrome metabólico / Pharmacokinetic and Pharmacodynamic Profile of Nebivolol in an Animal Model of Metabolic Syndrome

Con el objetivo en este estudio de evaluar los efectos cardiovasculares y la farmacocinética del nebivolol en ratas hipertensas por sobrecarga de fructosa y en ratas control, se registraron los efectos de la administración intravenosa de nebivolol, 3 mg/kg o 10 mg/kg, sobre la presión arterial, la frecuencia cardíaca y la variabilidad de la presión arterial a corto plazo y latido-a-latido, y se evaluó la farmacocinética enantioselectiva a partir del análisis de la concentración plasmática de los enantiómeros d-nebivolol y l-nebivolol. La variabilidad de la presión arterial a corto plazo y latido-a-latido se evaluó mediante la desviación estándar y el análisis espectral del registro de la presión arterial, respectivamente. El estado hipertensivo alteró la farmacocinética del nebivolol, evidenciado por una reducción en el aclaramiento del nebivolol en el grupo fructosa respecto del grupo control luego de la administración de la dosis más alta. El efecto antihipertensivo del nebivolol fue similar en ambos grupos, en tanto que el efecto bradicardizante fue mayor en las ratas del grupo control. Aunque no se observaron diferencias significativas en la variabilidad de la presión arterial latido-a-latido, la reducción de la variabilidad de la presión arterial a corto plazo inducida por el nebivolol fue significativamente superior en las ratas del grupo fructosa en comparación con los animales normotensos (-57,9% ± 11,8% vs. -19,6% ± 9,2%; p < 0,05). En conclusión, si bien el nebivolol reduce la presión arterial y la variabilidad de la presión arterial en ambos grupos, no se encontraron diferencias significativas en las ratas con sobrecarga de fructosa en cuanto a la farmacocinética y los efectos cardiovasculares, a excepción de una eficacia bradicardizante menor y una reducción mayor de la variabilidad de la presión arterial a corto plazo.

The cardiovascular and pharmacokinetic effects of nebivolol were evaluated in hypertensive fructose-fed and control rats, analyzing the effect of intravenously administered nebivolol 3 or 10 mg/kg on blood pressure, heart rate, and short-term and beat-to-beat blood pressure variability. The enantioselective pharmacokinetic profile of d- and l-nebivolol enantiomers was evaluated. Short-term and beat-to-beat blood pressure variability was assessed using standard deviation and blood pressure spectral analysis, respectively. The hypertensive state altered the pharmacokinetics of nebivolol, evidenced by reduction of nebivolol clearance in the fructose group compared to the control group after administration of the highest dose. The antihypertensive effect of nebivolol was similar in both groups, while the bradycardic effect was greater in control rats. Although no significant differences were found in beat-to-beat blood pressure variability, short-term blood pressure variability showed greater reduction after nebivolol administration in fructose-fed rats compared to control normotensive animals (-57.9%±11.8% vs.-19.6%±9.2%; p<0.05). In conclusion, although nebivolol reduces blood pressure and blood pressure variability in both groups, no significant differences were found in the pharmacokinetics and cardiovascular effects of fructose-fed rats, except for lower bradycardic efficacy and greater reduction in short-term blood pressure variability.

An open-label study to assess the effect of a single dose of Nebivolol and Ivabradine on heart rate and pulse wave velocity in hypertensive patients receiving amlodipine.

Background: Increased resting heart rate (HR) has emerged as an independent risk factor in the general population and in patients with hypertension, coronary artery disease, and myocardial infarction. HR is strongly and directly associated with arterial rigidity in hypertensive patients. Nebivolol (N) and Ivabradine (I) were established HR lowering agents. In this study, we have evaluated Nebivolol and Ivabradine on HR and pulse wave velocity in hypertensive patients who were receiving Amlodipine. Methods: A total of 18 hypertensive patients on Amlodipine participated in our study. Nine received Nebivolol and others received Ivabradine. We measured HR, blood pressures (BPs) and carotid-femoral pulse wave velocity (cf PWV - an index of large artery stiffness) non-invasively at baseline and 2 hrs after administration of single oral dose of 5 mg N and 5 mg of I. Results: The mean change in HR (−21.7±7.1 vs. −13.89±7.4 beats/min p=0.03) and cf PWV (−0.27±0.58 vs. −2.31±2.1 m/s p=0.01) was statistically signifi cant after treatment in N and I groups respectively. However, there was no signifi cant change in systolic BP (−17.3±9.1 vs. −15.1±11.1 mmHg p=0.65) and diastolic BP (−3.5±5.0 vs. −8.0±6.4 mmHg p=0.11) after treatment in N and I groups, respectively. Conclusions: Nebivolol is an effective HR lowering agent compared to Ivabradine. However, signifi cant decrease in arterial stiffness was observed with Ivabradine.

A study of atenolol and nebivolol in prehypertension.

Background: Patients with prehypertension have an increased risk of cardiovascular disease. The coexistence of prehypertension with risk factors increases cardiovascular morbidity and mortality. That’s why it is important to treat pre-hypertensive patients having risk factors. The objective was to evaluate the effect of atenolol and nebivolol in pre-hypertensive patients. Methods: Pre-hypertensive patients having risk factors were selected, and non-pharmacological therapy was advised to all patients. Those patients who were not able to follow strictly non-pharmacological guidelines and remained pre-hypertensive were included in this study. Pre-hypertensive patients were divided into three groups. One group received atenolol 50 mg orally, once daily. Second group received nebivolol 5 mg orally, once daily. Third group received placebo orally, once daily. All groups received treatment for 1 month. Results: In the nebivolol group after 1 month of study, the mean reduction in systolic blood pressure (SBP) was 134.2±3.07-118.26±4.66 and mean reduction in diastolic BP (DBP) was 87.13±1.87-80.73±1.99. Reduction in SBP and DBP in the nebivolol group was significant (p≤0.0001). In the placebo, and atenolol group results were not significant. Conclusion: Nebivolol produces a significant reduction in SBP and DBP in pre-hypertensive patients. Atenolol and placebo did not show beneficial results.

The efficacy of Nebivolol on patient with mild or moderate mssential hypertension by different smbulatory blood pressure monitoring methods / 中国综合临床

Objective To evaluate the efficacy of Nebivolol on patients with mild or moderate essential hypertension(EH) using different methods of ambulatory blood pressure monitoring.Methods Forty-seven patients with mild or moderate EH were enrolled as our subjects after a 2-week administration of placebo.They were administrated Nebivolol (5 mg) once daily for 12 weeks.All the patients completed ambulatory blood pressure monitoring before and after taking Nebivolol for 12 weeks.The overall and individual methods were used to calculate the trough-to-peak ratio (T/P ratio) and smooth index (SI).Results (1) For all of 42 patients treated with Nebivolol (5 mg) for 12 weeks,the systolic blood pressure(SBP),diastolic blood pressure(DBP) of the whole-day,daytime and nighttime after treatment were decreased compared to before treatment (the whole day:(144.1 ± 9.8),(124.4 ± 10.4) mmHg vs.(93.2 ± 6.3),(79.2 ± 7.2) mmHg;daytime:(148.9 ± 9.7),(128.3 ± 10.5) mmHg vs.(96.8 ±6.1),(82.2 ±7.5) mmHg;nighttime:(133.9 ± 11.9),(115.9 ± 12.0) mmHg vs.(85.7 ± 8.0),(72.5 ± 7.5) mmHg),and there was significant difference (t =8.06,8.74,8.00,8.82,5.75,and 6.57 respectively; P ＜ 0.01).T/P ratios of SBP/DBP calculated by overall method were 78.4％ (17.4/22.2) and 61.2％ (9.0/14.7),but it were (79.3 ±0.4) ％ and (58.5 ±0.5) ％ by individual calculation method.(2) Among 30 patients with better effect,the SBP,DBP of the whole-day,daytime and nighttime after treatment were decreased compared to before treatment (the whole day:(143.4 ± 9.1),(127.5 ±10.7) mmHgvs.(92.6 ±6.2),(81.6±7.6) mmHg;daytime:(147.8 ±9.1),(131.0 ±10.5)mmHg vs.(95.8 ± 6.4),(84.1 ± 7.5) mmHg; nighttime:(134.7 ± 11.6),(119.6 ± 13.2) mmHg vs.(86.2 ± 7.4),(75.2 ± 8.5) mmHg),and there was significant difference(t =11.18,12.77,11.14,12.85,7.37,and 8.74 respectively,P ＜0.01).T/P ratios of SBP/DBP were 78.9％ (18.3/23.2),75.3％ (11.6/15.4) and SIof SBP/DBP were 7.4(19.5/2.6),7.1 (14.2/2.0) calculated by overall method,but T/P ratios of SBP/DBPwere (78.4 ± 0.4) ％,(74.6 ± 0.4) ％ and SI were (1.35 ± 0.73),(1.34 ± 0.54) calculated by individualmethod.Conclusion Nebivolol (5 mg once daily) can significantly reduce ambulatory blood pressure.Overall calculation method is better than individual method in terms of assessing the time of durative action and smooth effect by trough peak ratio and smooth index.

Development of fast dispersing tablets of nebivolol: experimental and computational approaches to study formulation characteristics

Formulation of FDT (fast dispersing tablets) of nebivolol was optimized and evaluated using simplex lattice design (SLD). The influence of type and concentration of three disintegrants viz., Ac-Di-Sol, Primojel and Polyplasdone XL on hardness, friability and disintegration time of tablet was studied. Response surface plot and the polynomial equations were used to evaluate influence of polymer on the tablet properties. Results were statistically analyzed using ANOVA, and a p < 0.05 was considered statistically significant. Results reveal that fibrous integrity and optimal degree of substitution in Primojel and Ac-Di-Sol are mainly responsible for the hardness of the tablet. Use of Polyplasdone in higher percentage in tablet formulation may result in high friability. Increase in concentration of Ac-Di-Sol increases the disintegration time but increased concentration of Primojel in the tablet formulation decreases the disintegration time. This is also evident from model terms for disintegration time with a high 'F' value of 14.69 and 'p' value of 0.0031 (<0.05). The reason could be that Primojel has higher swelling properties and an optimum hydration capacity, which favors fast disintegration of a tablet. In conclusion, careful selection of disintegrant for FDT could improve their properties. Use of Simplex Lattice Design for formulation development could simplify the formulation process and reduce the production cost.

Otimizou-se e avaliou-se formulação de comprimidos de dispersão rápida (CDR) de nebivolol, usando planejamento de grade simplex (PGS). Estudou-se a influência do tipo e da concentração de três desintegrantes viz, Ac-Di-Sol, Primojel e Poliplasdona XL, na dureza, friabilidade e tempo de desintegração do comprimido. O gráfico de superfície de resposta e as equações polinomiais foram utilizados para avaliar a influência do polímero nas propriedades do comprimido. Os resultados foram analisados estatisticamente por ANOVA, considerando-se p < 0,05 como estatisticamente significativo. Os resultados revelam que a integridade das fibras e o grau de substituição ótimo no Primojel e Ac-Di-Sol são os principais responsáveis pela dureza do comprimido. O uso de Poliplasdona em maior porcentagem na formulação pode produzir friabilidade elevada. O aumento de Ac-Di-Sol aumenta o tempo de desintegração, mas o aumento da concentração de Primojel na formulação diminui o tempo de desintegração. Isto é, também, evidente no modelo de tempo de desintegração com alto valor de "F" de 14,69 e "p" de 0,0031 (< 0,05). A razão poderia ser que o Primojel tem maiores propriedades de intumescimento e ótima capacidade de hidratação, favorecendo a desintegração rápida do comprimido. Em conclusão, a cuidadosa seleção de um desintegrante para CDR poderia aprimorar suas propriedades. O uso do PGS para o desenvolvimento da formulação poderia simplificar o processo de formulação e reduzir o custo de produção.

Effects of Cardioselective Beta Blocker Nebivolol on Different Biochemical Parameters in Essential Hypertensive Patients.

Background : Nebivolol is a third-generation highly selective b1-blocker with additional endothelial nitric oxide (NO) mediated vasodilating activity. This property may potentiate the blood pressure-lowering effect of Nebivolol. Nebivolol is also claimed to have neutral or favourable effect on carbohydrate metabolism and lipid profile. Therefore this study was conducted to evaluate effects of Nebivolol on different biochemical parameters in essential hypertensive patients. Materials and Methods : 21 newly diagnosed patients of either sex with essential hypertension were included in the study. Patients having co-morbidities e.g. Diabetes mellitus, hyperlipidemia, gout, pregnant females were excluded from the study. Baseline readings of lipid profile, serum electrolytes, fasting blood sugar and uric acid were recorded before starting Nebivolol drug therapy. Same biochemical tests were repeated after six months drug treatment. Results and Observation : After comparing the means there is increase in total cholesterol, LDL, Serum electrolytes, blood sugar levels but this increase is within normal limits and is not statistically significant. While there is decrease in TG level but statistically not significant. No significant change in HDL, uric acid levels. Conclusion : Nebivolol is a unique, highly selective b1-blocker due to its neutral metabolic properties and is potentially safe over conventional b-blockers.

Nebivolol na insuficiência cardíaca de pacientes não idosos / Nebivolol in heart failure in elderly patients

A insuficiência cardíaca é uma síndrome muito prevalente, complexa, progressiva e com alta morbimortalidade. O esquema medicamentoso empregando beta-bloqueadores, inibidores da enzima conversora e espironolactona constitui hoje a espinha dorsal do tratamento da IC. Os beta-bloqueadores por reverterem a dilatação cardíaca e reduzirem importantemente a mortalidade e a morbidade se transformaram no principal medicamento no controle da IC. O nebivolol é o mais novo dos beta-bloqueadores de comprovada eficiência na IC e teve sua eficácia comprovada segundo a Medicina Baseada em Evidências no estudo SENIORS, que estudou pacientes idosos. Baseado no estudo SENIORS o nebivolol deveria ser a medicação de escolha para tratar idosos com IC. Neste artigo apresentamos estudo que documenta que o nebivolol é também eficaz em pacientes não idosos. Os dados do nebivolol foram comparados aos do carvedilol, não havendo diferenças na eficácia.