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Singular and combined effects of nebivolol and lifestyle modification on large artery stiffness in hypertensive adults.
Werner, TJ, Boutagy, NE, Osterberg, KL, Rivero, JM, Davy, KP
Therapeutic advances in cardiovascular disease. 2013;(6):285-92
Abstract
BACKGROUND We hypothesized that the combination of nebivolol and lifestyle modification would reduce large artery stiffness in middle-aged and older hypertensive adults more than either intervention alone. METHODS To address this, 45 men and women (age 40-75 years) with stage I hypertension were randomized to receive either nebivolol (NB; forced titration to 10 mg OD; n = 15; age 57.2 ± 11.4 years; body mass index [BMI] 30.8 ± 5.8 kg/m(2)), lifestyle modification (LM; 5-10% weight loss via calorie restriction and physical activity; n = 15; age 52.7 ± 8.5 years; BMI 33.9 ± 7.2 kg/m(2)) or nebivolol plus lifestyle modification (NBLM; n = 15; age 58.9 ± 9.4 years; BMI 32.5 ± 4.9 kg/m(2)) for 12 weeks. β-stiffness index, a blood-pressure-independent measure of arterial stiffness, and arterial compliance were measured via high-resolution ultrasound and tonometry at baseline and after the 12-week intervention. There was no difference between groups in age, body weight or composition, blood pressure, or in β-stiffness index or arterial compliance at baseline (all p > 0.05). RESULTS Following the 12-week intervention, body weight decreased ~5% (p < 0.05) in the LM and NBLM groups but did not change from baseline in the NB group (p > 0.05). Supine brachial and carotid systolic and diastolic blood pressure declined following treatment in each of the groups (p < 0.05). However, the magnitude of reduction was not different (p < 0.05) between groups. β-stiffness index declined (-2.03 ± 0.60, -1.87 ± 0.83 and -2.51 ± 0.90 U) and arterial compliance increased similarly (both p > 0.05) in the NB, LM and NBLM groups, respectively. CONCLUSION In summary, our findings indicate that the combination of nebivolol and lifestyle modification reduced large artery stiffness to a similar degree as either intervention alone in middle-aged and older hypertensive adults.
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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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Does nebivolol prevent contrast-induced nephropathy in humans?
Günebakmaz, O, Kaya, MG, Koc, F, Akpek, M, Kasapkara, A, Inanc, MT, Yarlioglues, M, Calapkorur, B, Karadag, Z, Oguzhan, A
Clinical cardiology. 2012;(4):250-4
Abstract
BACKGROUND An experimental study showed that nebivolol is an effective agent in contrast-induced nephropathy (CIN) prophylaxis. HYPOTHESIS We hypothesized that prophylactic nebivolol use had protective effects on renal function in human beings subjected to iodinated contrast agent since it has vasodilatory effect and antioxidant properties. METHODS The present study enrolled 120 patients scheduled for coronary angiography and ventriculography. All patients were hydrated with intravenous isotonic saline. The patients in group I received 600 mg N-acetylcysteine every 12 hours for 4 days. The patients in group II received 5 mg nebivolol every 24 hours for 4 days. The patients in group III were only hydrated. The primary endpoint was the occurrence of CIN. The secondary endpoint was the change in serum creatinine (Cr) levels at 2 days and 5 days after the contrast exposure. RESULTS Nine (22.5%) patients in group I developed CIN, as did 8 patients (20.0%) in group II and 11 patients (27.5%) in group III (P = 0.72). Changes in mean Cr level from baseline to day 2 were not statistically significant in all groups. However, we detected a statistically significant increase in mean Cr levels at day 5 compared with baseline levels in group I and group III (from 1.42 ± 0.13 to 1.52 ± 0.26, p2 = 0.02; and from 1.43 ± 0.14 to 1.55 ± 0.30, p2 = 0.01, respectively). Although an increase was detected in mean Cr level from baseline to the 5-day Cr level in group II, this did not reach statistical significance (from 1.40 ± 0.12 to 1.48 ± 0.23, P = 0.06). CONCLUSIONS Pretreatment with nebivolol is protective against nephrotoxic effects of contrast media.
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Arterial stiffness, hypertension, and rational use of nebivolol.
Agabiti-Rosei, E, Porteri, E, Rizzoni, D
Vascular health and risk management. 2009;(1):353-60
Abstract
Arterial stiffness plays a key role in the pathophysiology of the cardiovascular system. Some indices of arterial stiffness (pulse wave velocity, augmentation index, characteristics of central blood pressure waveform) may be presently calculated and evaluated in the clinical setting. Age and blood pressure are the two major clinical determinants of increased arterial stiffness, while molecular determinants of arterial stiffness are related to fibrotic components of the extracellular matrix, mainly elastin, collagen and fibronectin. Increased arterial stiffness has been consistently observed in conditions such as hypertension, dyslipidemia and diabetes. Arterial stiffness evaluated by means of carotid-femoral pulse wave velocity yielded prognostic significance beyond and above traditional risk factors. A more favorable effect of calcium channel blockers, diuretics and ACE inhibitors compared with beta-blockers on indices of arterial stiffness was observed in several studies. It is conceivable that newer beta-blockers with additional vasodilating properties, such as nebivolol, which has favorable effects on carbohydrate and lipid metabolism, as well as on endothelial function and on oxidative stress, may have favorable effects on arterial stiffness, compared with atenolol. In fact, in recent studies, nebivolol was demonstrated to improve artery stiffness to a greater extent than older beta-blockers. Because endothelial dysfunction and increased arterial stiffness play an important role in the early atherosclerotic processes and are associated with poor outcomes and increased mortality, independently of blood pressure, the ability of nebivolol to enhance release of endothelium-derived nitric oxide, and consequently improve endothelial function and arterial stiffness, may have significant clinical implications for the use of this agent in the treatment of hypertension and cardiovascular diseases.
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KATP channel openers of the benzopyran type reach their binding site via the cytosol.
Stephan, D, Salamon, E, Weber, H, Russ, U, Lemoine, H, Quast, U
British journal of pharmacology. 2006;(2):199-205
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Abstract
BACKGROUND AND PURPOSE ATP-sensitive K+ (KATP) channels are composed of pore-forming subunits (Kir6.x) and of sulphonylurea receptors (SUR). Both sulphonylureas and K(ATP) channel openers act by binding to SUR. Sulphonylureas reach their binding site from the cytosol but it remains unknown whether this holds for openers too. EXPERIMENTAL APPROACH A poorly membrane-permeant sulphonic acid derivative of the benzopyran-type opener, bimakalim, was synthesized, descyano-bimakalim-6-sulphonic acid (BMSA). Binding of BMSA and bimakalim was compared in membranes and intact cells expressing the Kir6.2/SUR2B channel and channel opening was compared in inside-out patches and whole cells. KEY RESULTS In membranes, bimakalim and BMSA bound to Kir6.2/SUR2B with Ki values of 61 nM and 4.3 microM, showing that the negative charge decreased affinity 69-fold. In intact cells, however, binding of BMSA was much weaker than in membranes (75-fold) whereas that of bimakalim was unchanged. The Ki value of BMSA decreased with increasing incubation time. In inside-out patches, bimakalim (1 microM) and BMSA (100 microM) opened the Kir6.2/SUR2B channel closed by MgATP to a similar degree whereas in whole-cell experiments, only bimakalim was effective. CONCLUSIONS AND IMPLICATIONS Despite its negative charge, BMSA is an effective channel opener. The fact that BMSA binds and acts more effectively when applied to the inner side of the cell membrane shows that benzopyran openers reach their binding site at SUR from the cytosol. This suggests that the binding pocket of SUR is only open on the cytoplasmic side.