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Purpose The aim of this prospective study was to compare in non-Asian subjects the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of two short-acting cardioselective β1-adrenergic antagonists, landiolol and esmolol, after administration of three different bolus dosages. Materials and methods We conducted a single-center, prospective, double-blinded, randomized study in three cross-over periods with 12 healthy subjects (7 women and 5 men, mean age of 24.5 ± 6.9 years) each receiving three doses of landiolol (0.1, 0.2, and 0.3 mg/kg BW) either in a newly developed concentrate i.v. formulation (Rapibloc® 20 mg/2 mL concentrate) or a lyophilized formulation, or three doses of esmolol (0.5, 1, and 1.5 mg/kg BW) in an i.v. formulation (Brevibloc® 100 mg/10 mL). PK and PD parameters, safety, and tolerability were assessed. Findings Results of the two landiolol formulations were reported previously and were similar. For the landiolol concentrate formulation and esmolol, maximum blood concentrations were rapidly reached (mean t max ranged between 1.8 and 3.0 min for landiolol and 1.8 to 2.4 min for esmolol). The parent drugs disappeared very fast from the blood stream, with a t 1/2 of 3.2 ± 1.2 (SD) minutes and 3.7 ± 2.1 (SD) minutes for the low doses of landiolol and esmolol, respectively. Despite comparable injection rates (0.1 or 0.5 mg/kg/15 s for landiolol and esmolol, respectively), the onset of significant heart rate reduction occurred earlier in response to landiolol (1 min) than in response to esmolol (2 min). In addition, significantly lower heart rate values were obtained at every dose level of landiolol, in comparison to esmolol ( p  < 0.05). Both compounds reduced the systolic blood pressure to a comparable degree. Especially at the highest dose, the duration of blood pressure reduction was longer under esmolol compared to landiolol. Seven mild to moderate adverse events occurred after administration of landiolol, and five occurred after administration of esmolol. No serious adverse events were reported in this study. Implications Heart rate reduction induced by a new liquid formulation of landiolol occurred faster, was more pronounced, and lasted longer than the effects of corresponding standard esmolol doses. Both agents reduced systolic blood pressure to a comparable degree, but the blood pressure decrease lasted longer after esmolol infusion. The local tolerance and safety profiles of the two formulations were similar. In summary, compared to esmolol, landiolol shows a more prominent and pronounced bradycardic effect in relation to its blood pressure-lowering effect, an action profile that might be of specific advantage in the perioperative setting. Trial registration NCT01652898 and 2012-002127-14. https://clinicaltrials.gov/ct2/show/NCT01652898?term=landiolol&rank=7

Background and aimsCarvedilol is effective in the primary prophylaxis for large oesophageal varices. We investigated its use in preventing progression of small to large oesophageal varices.MethodsConsecutive cirrhotics with small oesophageal varices were prospectively randomised to either carvedilol (n=70) or placebo (n=70) and followed up for a minimum of 24 months. Endoscopy was done at baseline and six monthly intervals. Hepatic vein pressure gradient (HVPG) was measured at baseline and at 12 months. The primary endpoint was development of large varices.ResultsBaseline characteristics in two groups were comparable. The predominant aetiology of cirrhosis was non-alcoholic fatty liver disease in both the groups. The mean dose of carvedilol administered was 12±1.67 mg/day and the target heart rate achieved was 58±3 bpm. A higher proportion of patients in carvedilol group had non-progression to large varices than placebo (79.4% vs 61.4%; p=0.04); the mean time of non-progression to large varices was 20.8 months (95% CI 19.4 to 22.4) in carvedilol group and 18.7 months (95% CI 17.1 to 20.4) in placebo group (p=0.04). There was a modest reduction of HVPG at 1 year in carvedilol group (−8.64%) compared with placebo (+0.33%) (p=0.22). None of the patients in either group died of variceal bleeding or liver-related causes. No major adverse events were observed in either group.ConclusionsCarvedilol is safe and effective in delaying the progression of small to large oesophageal varices in patients with cirrhosis.Trial registration numberNCT01196507; post-results.

β blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II–IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0·35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. The mean study duration was 58 months (SD 6). The mean ejection fraction was 0·26 (0·07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0·83 [95% CI 0·74–0–93], p=0–0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0·94 [0·86–1–02], p=0·122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. Our results suggest that carvedilol extends survival compared with metoprolol.

As compared with placebo, carvedilol reduced the risk of death by 35 percent and the combined risk of death or hospitalization by 24 percent. Beta-blocking agents have been shown to reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, 1 – 4 but little is known about the efficacy or safety of these agents in severe heart failure. Earlier large-scale studies with bisoprolol, carvedilol, and metoprolol enrolled primarily patients with New York Heart Association class II or III symptoms, and thus they did not provide meaningful information about the effects of these drugs in patients who have symptoms at rest or on minimal exertion. Only one large-scale study of beta-blockade (with bucindolol) focused on patients with severe heart failure; it did not . . .

Background and Objective As a β-adrenoceptor antagonist (β-blocker), esmolol can reduce cardiac output and the phosphodiesterase III inhibitor milrinone has been shown to improve heart contractility in patients with septic shock. This study was performed to assess the effects of esmolol combined with milrinone in patients with severe sepsis. Methods This prospective randomized study was conducted in patients with severe sepsis in the intensive care unit of the Jiangxi Provincial People’s Hospital (Nanchang, Jiangsu, China) between June 2013 and June 2014. Patients were randomly divided into control (C), milrinone (M), and milrinone–esmolol (ME) groups. The primary outcome was the rate of controlling the heart rate (HR) to achieve target levels. Secondary outcomes included the 28-day survival rate and changes in hemodynamic variables, organ function variables, myocardial injury markers, and the serum levels of proinflammatory factors. Result A total of 90 patients with severe sepsis were included in this study (30 per group). The HR in the ME group was lower than in the M and C groups after 12 h. The rate of successful HR control during the first 96 h was significantly higher in the ME group (60.0 vs. 33.3 % in the M group, vs. 26.7 % in the C group). Also, patients in the ME group had higher 28-day overall survival compared with the M (Log rank statistic = 5.452; P  = 0.020) and C groups (Log rank statistic = 10.206; P  = 0.001). Additionally, several variables showed significant improvement in the ME group 96 h after treatment compared with the M and C groups ( P  < 0.05). Conclusion Combination therapy with milrinone and esmolol could improve cardiac function and the 28-day survival rate in patients with severe sepsis.

The beneficial effects of β-blockers on longterm outcome after acute myocardial infarction were shown before the introduction of thrombolysis and angiotensin-converting-enzyme (ACE) inhibitors. Generally, the patients recruited to these trials were at low risk: few had heart failure, and none had measurements of left-ventricular function taken. We investigated the long-term efficacy of carvedilol on morbidity and mortality in patients with leftventricular dysfunction after acute myocardial infarction treated according to current evidence-based practice. Methods In a multicentre, randomised, placebo-controlled trial, 1959 patients with a proven acute myocardial infarction and a left-ventricular ejection fraction of ≤40% were randomly assigned 6·25 mg carvedilol (n=975) or placebo (n=984). Study medication was progressively increased to a maximum of 25 mg twice daily during the next 4–6 weeks, and patients were followed up until the requisite number of primary endpoints had occurred. The primary endpoint was all-cause mortality or hospital admission for cardiovascular problems. Analysis was by intention to treat. Although there was no difference between the carvedilol and placebo groups in the number of patients with the primary endpoint (340 [35%] vs 367 [37%], hazard ratio 0·92 [95% CI 0·80–1·07]), all-cause mortality alone was lower in the carvedilol group than in the placebo group (116 [12%] vs 151 [15%], 0·77 [0·60–0·98], p=0·03). Cardiovascular mortality, non-fatal myocardial infarctions, and all-cause mortality or non-fatal myocardial infarction were also lower on carvedilol than on placebo. In patients treated long-term after an acute myocardial infarction complicated by left-ventricular systolic dysfunction, carvedilol reduced the frequency of all-cause and cardiovascular mortality, and recurrent, non-fatal myocardial infarctions. These beneficial effects are additional to those of evidence-based treatments for acute myocardial infarction including ACE inhibitors.

Purpose Ventricular–arterial (V–A) decoupling decreases myocardial efficiency and is exacerbated by tachycardia that increases static arterial elastance (Ea). We thus investigated the effects of heart rate (HR) reduction on Ea in septic shock patients using the beta-blocker esmolol. We hypothesized that esmolol improves Ea by positively affecting the tone of arterial vessels and their responsiveness to HR-related changes in stroke volume (SV). Methods After at least 24 h of hemodynamic optimization, 45 septic shock patients, with an HR ≥95 bpm and requiring norepinephrine to maintain mean arterial pressure (MAP) ≥65 mmHg, received a titrated esmolol infusion to maintain HR between 80 and 94 bpm. Ea was calculated as MAP/SV. All measurements, including data from right heart catheterization, echocardiography, arterial waveform analysis, and norepinephrine requirements, were obtained at baseline and at 4 h after commencing esmolol. Results Esmolol reduced HR in all patients and this was associated with a decrease in Ea (2.19 ± 0.77 vs. 1.72 ± 0.52 mmHg l −1 ), arterial d P /d t max (1.08 ± 0.32 vs. 0.89 ± 0.29 mmHg ms −1 ), and a parallel increase in SV (48 ± 14 vs. 59 ± 18 ml), all p  < 0.05. Cardiac output and ejection fraction remained unchanged, whereas norepinephrine requirements were reduced (0.7 ± 0.7 to 0.58 ± 0.5 µg kg −1  min −1 , p  < 0.05). Conclusions HR reduction with esmolol effectively improved Ea while allowing adequate systemic perfusion in patients with severe septic shock who remained tachycardic despite standard volume resuscitation. As Ea is a major determinant of V–A coupling, its reduction may contribute to improving cardiovascular efficiency in septic shock.

In this study of a non-selective beta-blocker, bucindolol, there was no effect of treatment on overall mortality. Beta-blockers have emerged as an important treatment for chronic heart failure. Two recently completed trials, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure 1 and the Cardiac Insufficiency Bisoprolol Study II, 2 demonstrated statistically significant and clinically relevant decreases in the rates of hospitalization and death with beta-adrenergic–receptor antagonists in patients with New York Heart Association (NYHA) class II, III, or IV heart failure. However, mortality in the placebo group in these trials was only 11 to 13 percent annually, suggesting that the proportion of high-risk, severely ill patients was low. Furthermore, both studies were performed in largely white European . . .

Heart failure is a substantial public health problem among black Americans. It is more common in the black population than in other populations in the United States, affecting approximately 3 percent of all black adults in this country. 1 , 2 Symptoms of heart failure develop in blacks at an earlier age than they do in nonblacks, 3 – 5 possibly because blacks are more likely to have hypertension and diabetes and to have ventricular hypertrophy and vascular injury than nonblacks. 5 – 8 Once diagnosed, heart failure progresses more rapidly in black patients than in white patients, as evidenced by the higher risk of initial . . .

G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β adrenergic receptor (β AR) that was recently isolated from a DNA-encoded small-molecule library. Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the β AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the β AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.