Additivity of nebivolol/valsartan single-pill combinations versus other single-pill combinations for hypertension.

The single-pill combination (SPC) comprising nebivolol (5 mg), a vasodilatory ß1 -selective antagonist/ß3 -agonist, and valsartan (80 mg), a renin-angiotensin-aldosterone system inhibitor, is the only Food and Drug Administration-approved ß-blocker/renin-angiotensin-aldosterone system inhibitor SPC for hypertension. Additive effects of four nebivolol/valsartan SPC doses (5 mg/80 mg, 5/160 mg, 10/160 mg, 10/320 mg nebivolol/valsartan) were compared with five Food and Drug Administration-approved non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs (aliskiren/hydrochlorothiazide, aliskiren/amlodipine, valsartan/amlodipine, aliskiren/valsartan, and telmisartan/amlodipine). Additivity is the ratio of placebo-adjusted SPC blood pressure (BP) reduction to the placebo-adjusted monotherapy component BP reduction sums. A weighted average of comparator scores was calculated and compared vs nebivolol/valsartan. Additivity ratio scores for nebivolol/valsartan SPCs (diastolic BP range: 0.735-0.866; systolic BP range: 0.717-0.822) were similar to the comparator weighted average (diastolic BP: 0.837; systolic BP: 0.825). Among the nebivolol/valsartan SPCs, 5/80 mg had the greatest additivity (diastolic BP: 0.866; systolic BP: 0.822). BP reduction contributions with monotherapy were similar for nebivolol/valsartan 5/80 mg SPC. Additivity scores for nebivolol/valsartan and select non-ß-blocker/renin-angiotensin-aldosterone system inhibitor SPCs were comparable.

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

Nebivolol/valsartan: Fixed-dose combination for treatment of hypertension.

Clinical trials demonstrated that a fixed-dose combination (FDC) of the beta-blocker nebivolol (5 mg) and the angiotensin II antagonist valsartan (80 mg) produced a significant reduction of both diastolic and systolic blood pressure in patients with hypertension. Both nebivolol and valsartan contributed to this effect, partial additivity of 86.6% and 82.2% being observed for diastolic and systolic blood pressure, respectively. These values are very similar to the additivity ratios of other recently approved FDCs for hypertension. Use of the FDC nebivolol 5 mg/valsartan 80 mg formulation was associated with a low incidence of treatment-related adverse effects and of serious adverse effects. There was no evidence of adverse effects due to beta2-adrenoceptor blockade. The FDC (Byvalson) was approved and launched in 2016 in the U.S. for the treatment of hypertension.

Olodaterol for the treatment of chronic obstructive pulmonary disease.

PURPOSE: Published data on the pharmacology, pharmacokinetics, efficacy, and safety of the once-daily, long-acting ß2-agonist (LABA) olodaterol are reviewed. SUMMARY: Olodaterol (Striverdi Respimat, Boehringer Ingelheim), a LABA with high selectivity for ß2-adrenergic receptors, is indicated for the treatment of chronic obstructive pulmonary disease (COPD); the recommended dose is 5 µg, to be delivered once daily via the Respimat inhaler. In 48- and 6-week Phase III clinical trials of olodaterol evaluating various lung function and symptomatic outcomes in patients with moderate to very severe COPD, olodaterol use was associated with significant improvements in spirometry outcomes, such as postbronchodilator forced expiratory volume in one second (FEV1), as well as dyspnea severity and quality-of-life measures. Other clinical trials demonstrated that olodaterol produced beneficial effects on FEV1 measures throughout the 24-hour dosing interval. A meta-analysis of data from 20 published research reports indicated that olodaterol's efficacy was comparable to that of the once-daily LABA indacaterol and that the combination of olodaterol and tiotropium provided improvements in lung function greater than those provided by tiotropium alone. Analysis of pooled data from four long-term trials showed that olodaterol's safety profile was comparable to that of formoterol; the most frequently reported adverse effects associated with olodaterol use were bronchitis, nasopharyngitis, and upper respiratory tract infection. CONCLUSION: Once-daily olodaterol 5 µg is an effective therapy in improving lung function and symptomatic outcomes in patients with moderate to very severe COPD receiving other maintenance therapy, with a satisfactory safety profile.

Pharmacokinetics and safety of olodaterol administered with the Respimat Soft Mist inhaler in subjects with impaired hepatic or renal function.

PURPOSE: In two trials, the influences of hepatic and renal impairment on the pharmacokinetics of olodaterol, a novel long-acting inhaled ß2-agonist for treatment of COPD, were investigated. SUBJECTS AND METHODS: The first trial included eight subjects with mild hepatic function impairment (Child-Pugh A), eight subjects with moderate impairment (Child-Pugh B), and 16 matched healthy subjects with normal hepatic function. The second trial included eight subjects with severe renal impairment (creatinine clearance <30 mL·min(-1)) and 14 matched healthy subjects with normal renal function. Subjects received single doses of 20 or 30 µg olodaterol administered with the Respimat Soft Mist inhaler. RESULTS: Olodaterol was well tolerated in all subjects. The geometric mean ratios and 90% confidence intervals of dose-normalized area under the plasma concentration-time curve from time zero to 4 hours (AUC0-4) for subjects with mild and moderate hepatic impairment compared to healthy subjects were 97% (75%-125%) and 105% (79%-140%), respectively. Corresponding values for dose-normalized maximum concentration (C max) were 112% (84%-151%) (mild impairment) and 99% (73%-135%) (moderate impairment). The geometric mean ratio (90% confidence interval) of AUC0-4 for subjects with severe renal impairment compared to healthy subjects was 135% (94%-195%), and for C max was 137% (84%-222%). There was no significant relationship between creatinine clearance and AUC0-4 or C max. Renal clearance of olodaterol was reduced to 20% of normal in severe renal impairment. CONCLUSION: Mild to moderate hepatic function impairment or severe renal function impairment did not result in a clinically relevant increase of olodaterol systemic exposure after a single inhaled dose.

Influence of chronic kidney disease and haemodialysis treatment on pharmacokinetics of nebivolol enantiomers.

AIM: The present study evaluated the pharmacodynamics and pharmacokinetics of nebivolol enantiomers in patients with chronic kidney disease (CKD) and in patients undergoing haemodialysis. METHODS: Forty-three adult patients were distributed into three groups: healthy volunteers and hypertensive patients with normal kidney function (n = 22); patients with stage 3 and 4 CKD (n = 11); and patients with stage 5 CKD undergoing haemodialysis (n = 10). The subjects received a single oral dose of 10 mg racemic nebivolol. Serial blood samples were collected up to 48 h after administration of the drug and heart rate variation was measured over the same interval during the isometric handgrip test. The nebivolol enantiomers in plasma were analysed by liquid chromatography-tandem mass spectrometry. RESULTS: The pharmacokinetics of nebivolol is enantioselective, with a greater plasma proportion of l-nebivolol. CKD increased the area under the concentration-time curve (AUC) of l-nebivolol (6.83 ng.h ml(-1) vs. 9.94 ng.h ml(-1) ) and d-nebivolol (4.15 ng.h ml(-1) vs. 7.30 ng.h ml(-1) ) when compared with the control group. However, the AUC values of l-nebivolol (6.41 ng.h ml(-1) ) and d-nebivolol (4.95 ng.h ml(-1) ) did not differ between the haemodialysis and control groups. The administration of a single dose of 10 mg nebivolol did not alter the heart rate variation induced by isometric exercise in the investigated patients. CONCLUSIONS: Stage 3 and 4 CKD increases the plasma concentrations of both nebivolol enantiomers, while haemodialysis restores the pharmacokinetic parameters to values similar to those observed in the control group. No significant difference in heart rate variation induced by isometric exercise was observed between the investigated groups after the administration of a single oral dose of 10 mg nebivolol.

A Review of Nebivolol Pharmacology and Clinical Evidence.

Nebivolol is a highly selective ß1-adrenergic receptor antagonist with a pharmacologic profile that differs from those of other drugs in its class. In addition to cardioselectivity mediated via ß1 receptor blockade, nebivolol induces nitric oxide-mediated vasodilation by stimulating endothelial nitric oxide synthase via ß3 agonism. This vasodilatory mechanism is distinct from those of other vasodilatory ß-blockers (carvedilol, labetalol), which are mediated via α-adrenergic receptor blockade. Nebivolol is approved for the treatment of hypertension in the US, and for hypertension and heart failure in Europe. While ß-blockers are not recommended within the current US guidelines as first-line therapy for treatment of essential hypertension, nebivolol has shown comparable efficacy to currently recommended therapies in lowering peripheral blood pressure in adults with hypertension with a very low rate of side effects. Nebivolol also has beneficial effects on central blood pressure compared with other ß-blockers. Clinical data also suggest that nebivolol may be useful in patients who have experienced erectile dysfunction while on other ß-blockers. Here we review the pharmacological profile of nebivolol, the clinical evidence supporting its use in hypertension as monotherapy, add-on, and combination therapy, and the data demonstrating its positive effects on heart failure and endothelial dysfunction.