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The efficacy and tolerability of MK-0633, a 5-lipoxygenase inhibitor, in chronic asthma.
Wasfi, YS, Villarán, C, de Tilleghem, Cle B, Smugar, SS, Hanley, WD, Reiss, TF, Knorr, BA
Respiratory medicine. 2012;(1):34-46
Abstract
Leukotriene B4 (LTB(4)) is a potent inflammatory mediator in asthma, and is increased in more severe asthma. Targeting LTB(4), in addition to cysteinyl leukotrienes, could be beneficial in asthma. This was a randomized, double-blind trial of once-daily MK-0633, a potent 5-lypoxygenase inhibitor, 10 mg, 50 mg, and 100 mg, and placebo in patients 18-70 years with a history of chronic asthma, and FEV(1) ≥45 and ≤85% predicted. There was a 6-week main period and optional 18-week and 34-week periods (52 weeks total), the latter two comparing only MK-0633 100 mg and placebo. The primary endpoint was the change from baseline in FEV(1) over the last 4 weeks of the 6-week primary treatment period. Secondary endpoints included symptom scores, β-agonist use, peak expiratory flow (PEF), asthma quality of life questionnaire (AQLQ), asthma control questionnaire (ACQ), asthma attacks, exacerbations, days with asthma control, post-β-agonist FEV(1), and blood eosinophils. MK-0633 100 mg was significantly more effective than placebo for the change from baseline in FEV(1) (0.20 L vs. 0.13 L; p = 0.004). The other MK-0633 doses were not significantly more effective than placebo. MK-0633 (at various doses) was also more effective than placebo for β-agonist use, AQLQ, AM and PM PEFR, ACQ, and post-β-agonist FEV(1) (p < 0.05 for all). MK-0633 was associated with a dose-dependent increase in elevated aspartate aminotransferase and alanine aminotransferase. Because of the relative benefit-risk ratio, the optional study periods were terminated after unblinding for the main study period. Overall, the benefit-risk ratio did not support the clinical utility of MK-0633 in asthma.
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The role of nebivolol in the prevention of contrast-induced nephropathy in patients with renal dysfunction.
Avci, E, Yeşil, M, Bayata, S, Postaci, N, Arikan, E, Cirit, M
Anadolu kardiyoloji dergisi : AKD = the Anatolian journal of cardiology. 2011;(7):613-7
Abstract
OBJECTIVE This prospective study was designed to evaluate the potential protective effect of nebivolol compared with metoprolol on the development of contrast-induced nephropathy (CIN) following coronary angiography in patients with renal dysfunction. METHODS Ninety patients with stable coronary angina pectoris with renal insufficiency (creatinine value ≥1.2 mg/dl) were included for this prospective study. Patients were divided into two groups. Patients in group 1 (n=55) received oral administration of nebivolol 5 mg/daily for coronary artery disease and/or hypertension. Group 2 consisted of 35 patients who received metoprolol 50 mg/daily for the same indications. All patients were hydrated with 0.9% NaCl at a rate of 1 mL/kg/hr for 12 hours before and 24 hours after the procedure. Patients were also given N-acetylcysteine (NAC) 600 mg twice a day, beginning 24 hours before and continuing 48 hours after the procedure. All patients underwent routine coronary angiography. Serum creatinine was assessed just before, immediately after and 48 hours after the procedure. CIN was defined as an increase in serum creatinine concentration of ≥25% within 48 hours after the procedure compared to the patient's baseline value. Tests for significance between groups were conducted using the independent sample t-test for continuous variables and Chi-square test for categorical variables. RESULTS Baseline serum creatinine levels were statistically comparable in two groups. Following angiography, serum creatinine levels increased in both groups. Post-angiographic creatinine levels were not statistically different in the nebivolol and the metoprolol groups. Contrast induced nephropathy developed in 13 patients (24%) of the nebivolol group and in 12 patients (33%) of the metoprolol group. The incidence of CIN was statistically significantly lower in the nebivolol group comparing with the metoprolol group (p=0.03). CONCLUSION The use of oral nebivolol for one week at a dose of 5 mg per day may decrease the incidence of contrast-induced nephropathy in patients who underwent coronary angiography with renal dysfunction. The small numbers of this study do not allow to draw final conclusion on the use of nebivolol in the prevention of CIN. Therefore, larger studies may be necessary to address the definite role of nebivolol in this setting.
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Quality of life and efficacy of nebivolol in an open-label study in hypertensive patients. the QoLaN study.
Hermans, MP, De Coster, O, Seidel, L, Albert, A, Van de Borne, P
Blood pressure. Supplement. 2009;:5-14
Abstract
BACKGROUND Nebivolol is a highly selective beta-adrenoreceptor antagonist with vasodilating properties. This study investigated its effect on quality of life (QoL) and blood pressure (BP) in real life conditions. In total, 1468 patients were enrolled, 12% diabetics. Nebivolol was prescribed as monotherapy, add-on or switch medication. METHODS In this open-label, prospective study, the JNC-VII BP target values were used: < 140/90 and < 130/80 mmHg for diabetics. The responder rate and the QoL was determined at baseline and after 4 and 8 weeks. RESULTS After 4 weeks, 27% of subjects reached target BP, 45% after 8 weeks. The responder rates were 92, 90 and 83% for the monotherapy, add-on and switch groups. Compared with baseline, all showed statistical significance at 8 weeks. Similarly to results for the QoL after 8 weeks, the mean improvement in QoL for all three groups was 9-10 points (total range: 0-88). CONCLUSIONS The study demonstrates that nebivolol in mild to moderate hypertension is associated with overall improvements in QoL, with a marked BP-lowering effect, in monotherapy, add-on or switch, irrespective of the glucose tolerance status. It may be hypothesized that its dual mode of action explains its BP-lowering effect as well as the tolerability.
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Effect of treatment with nebivolol on parameters of oxidative stress in type 2 diabetics with mild to moderate hypertension.
Peter, P, Martin, U, Sharma, A, Dunne, F
Journal of clinical pharmacy and therapeutics. 2006;(2):153-9
Abstract
AIM: The aim of this study was to examine the effect of the cadioselective B(1)-adrenoceptor blocker nebivolol on glycaemic control, lipid profile and markers of oxidative stress in patients with type 2 diabetes over a 6-month period. METHODS Twenty-six patients with mild to moderate hypertension (140-160 mmHg systolic, 90-105 mmHg diastolic) confirmed on 24-h blood pressure monitoring, were treated with nebivolol 5 mg daily for 6 months. Total serum cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) subfractions, lipid hydroperoxides (LHPs) and total antioxidant capacity (TAC) were measured before and after 6 months of treatment. RESULTS Nebivolol, as expected, reduced mean daytime systolic and diastolic pressures on ambulatory monitoring (149 +/- 9 to 140 +/- 13 mmHg, P = 0.02 and 84 +/- 7 to 77 +/- 9 mmHg, P < 0.001). There were no significant changes in serum cholesterol or triglycerides following treatment but a significant increase in HDL cholesterol was noted (1.12 +/- 0.19 to 1.25 +/- 0.36 mmol/L, P = 0.008). Patients showed a highly significant reduction in TAC from 501 +/- 57 to 422 +/- 29 trolox equivalent (P < 0.001). Baseline LHPs were very high and showed no significant change over the 6-month period (18.7 +/- 7.4 and 18.7 +/- 10.9 micromol/L). The LDL score increased significantly from 1.7 +/- 0.7 to 2.3 +/- 0.7 (P = 0.0002) at 6 months suggesting a change to a more atherogenic lipid profile. Neither weight nor glycaemic control changed during treatment. CONCLUSION Nebivolol appears to be lipid neutral and may even have a positive effect on HDL cholesterol. Despite this it may promote the formation of potentially atherogenic LDL subfractions possibly as a result of reduced antioxidant defences. Further studies are needed to clarify the changes observed in parameters of oxidative stress.
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Nebivolol decreases oxidative stress in essential hypertensive patients and increases nitric oxide by reducing its oxidative inactivation.
Fratta Pasini, A, Garbin, U, Nava, MC, Stranieri, C, Davoli, A, Sawamura, T, Lo Cascio, V, Cominacini, L
Journal of hypertension. 2005;(3):589-96
Abstract
OBJECTIVE To obtain further insight into the mechanism underlying the vasodilator effect of nebivolol. Since oxidative inactivation of nitric oxide (NO) is regarded as an important cause of its decreased biological activity, we studied (1) the effect of nebivolol on some oxidative parameters in essential hypertensive patients; (2) the effect of plasma of nebivolol-treated patients on reactive oxygen species production and NO availability in endothelial cells. METHODS A total of 20 healthy subjects and 20 matched essential hypertensive patients treated with atenolol or nebivolol according to a double-blind, randomized design participated in the study. We measured low-density lipoprotein (LDL) and plasma hydroperoxides, 8-isoprostanes, oxidized LDL, susceptibility of LDL to oxidation (lag phase) and LDL vitamin E and the effect of plasma of nebivolol- and atenolol-treated patients on reactive oxygen species production and NO availability in endothelial cells exposed to oxidative stress. RESULTS In hypertensive patients, nebivolol and atenolol significantly reduced blood pressure values after 4 weeks of treatment. Plasma and LDL hydroperoxides, plasma 8-isoprostanes, plasma ox-LDL and LDL lag phase were significantly improved only in the patients receiving nebivolol compared with the atenolol group. Similarly there was a reduction of reactive oxygen species (ROS) and O2*- concentration in endothelial cells exposed to oxidative stress after incubation of the cells with plasma of the patients enrolled in the trial only in the patients receiving nebivolol compared to atenolol group. Furthermore, the reduction of basal and stimulated NO induced by oxidative stress in endothelial cells was significantly lower in the patients receiving nebivolol compared to atenolol group. CONCLUSIONS The findings of the present study indicate that nebivolol, through its antioxidant properties, increases NO also by decreasing its oxidative inactivation.
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A comparison of the beta1-selectivity of three beta1-selective beta-blockers.
Nuttall, SL, Routledge, HC, Kendall, MJ
Journal of clinical pharmacy and therapeutics. 2003;(3):179-86
Abstract
OBJECTIVE To determine the relative beta1-selectivity of three beta-blockers (nebivolol, bisoprolol and atenolol), administered orally at normal therapeutic doses, by assessing their impact on the beta2-mediated, haemodynamic and biochemical responses to a terbutaline infusion, which decreases serum potassium and increases serum glucose and insulin. METHODS Twenty-four healthy volunteers (14 men, 10 women), with no history of respiratory disease, attended on five separate occasions; beta-blockers (nebivolol 5 mg, bisoprolol 10 mg, atenolol 50 and 100 mg) or placebo were supplied in random order. Three baseline blood samples were collected at 65-85 min post-beta-blocker. A 60-min terbutaline infusion was started 90 min after taking the beta-blocker. Blood samples were taken and blood pressure and heart rate recorded at 15 min intervals up to 30-min post-infusion. Blood samples were analysed for serum potassium, glucose and insulin concentrations. RESULTS Terbutaline increased heart rate. Pretreatment with nebivolol caused a modest and non-significant reduction in terbutaline-induced tachycardia whilst bisoprolol produced a more marked effect. Atenolol at both 50 and 100 mg doses caused a highly significant reduction in terbutaline-induced tachycardia. All active preparations had a comparable impact on the terbutaline-induced increase in systolic blood pressure, but the drugs had no impact on the changes produced in diastolic blood pressure. After pretreatment with placebo, the terbutaline infusion caused a significant decrease in serum potassium and increases in serum glucose and insulin. Pretreatment with nebivolol had no discernible effect on potassium compared with placebo. In contrast, when compared with either placebo or nebivolol, bisoprolol (P < 0.01) and both doses of atenolol (P < 0.001) significantly attenuated the hypokalaemic effect of terbutaline. Treatment with nebivolol and bisoprolol modestly but significantly reduced the terbutaline-induced increases in glucose (P < 0.05). The blocking effects of both doses of atenolol were highly significant (P < 0.001) when compared with placebo and also significant (P < 0.05 and P < 0.01, respectively) when compared with nebivolol and bisoprolol. A similar pattern of responses with the different beta-blocker treatments was observed for the effects on insulin concentrations during the terbutaline infusion. CONCLUSION The beta1-selectivity of three different beta1-blockers has been demonstrated in healthy volunteers using the blocking of biochemical and haemodynamic responses to a beta2 stimulus. Terbutaline alone caused an increase in heart rate, a rise in systolic blood pressure, a fall in serum potassium and a rise in both serum glucose and insulin. In this study, for both haemodynamic and biochemical responses, atenolol 100 mg had the greatest beta2-blocking effect, nebivolol 5 mg the least. Bisoprolol 10 mg and atenolol 50 mg had intermediate effects; bisoprolol was the more beta1-selective of these two.
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Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study.
Tzemos, N, Lim, PO, MacDonald, TM
Circulation. 2001;(5):511-4
Abstract
BACKGROUND Vascular endothelial dysfunction may predict future atherosclerosis. Hence, an antihypertensive agent that reverses endothelial dysfunction and lowers blood pressure might improve the prognosis of patients with hypertension. We hypothesized that nebivolol, a vasodilating beta-blocker, could improve endothelial dysfunction. We tested this hypothesis by comparing the effects of nebivolol and atenolol on endothelial function. METHODS AND RESULTS Twelve hypertensive patients with a mean ambulatory blood pressure of 154+/-7/97+/-10 mm Hg were randomized after a 2-week placebo run-in period (baseline) in a double-blind, crossover fashion to 8-week treatment periods with either 5 mg of nebivolol with 2.5 mg of bendrofluazide or 50 mg of atenolol with 2.5 mg of bendrofluazide. Forearm venous occlusion plethysmography and intra-arterial infusions of acetylcholine and N(G)-monomethyl-L-arginine (L-NMMA) were used to assess stimulated and basal endothelium-dependent nitric oxide release, respectively. Sodium nitroprusside was used as an endothelium-independent control. Nebivolol/bendrofluazide and atenolol/bendrofluazide each lowered the clinic blood pressure to the same extent (132+/-7/82+/-6 and 132+/-9/83+/-8 mm Hg, respectively; P<0.001 from baseline). The vasodilatory response to acetylcholine was significantly increased with nebivolol/bendrofluazide (maximum percentage change in forearm blood flow [mean+/-SEM], 435+/-27%, P<0.001) but not with atenolol/bendrofluazide. Similarly, the endothelium-dependent vasoconstrictive response to L-NMMA was significantly improved only with nebivolol treatment (percentage change in forearm blood flow, -54+/-5%; P<0.001). The response to sodium nitroprusside was not different between treatments, suggesting that the endothelium-independent pathway was unaffected. CONCLUSIONS Nebivolol/bendrofluazide increased both stimulated and basal endothelial nitric oxide release, whereas for the same degree of blood pressure control, atenolol/bendrofluazide had no effect on nitric oxide bioactivity. Thus, nebivolol may offer additional vascular protection in treating hypertension.