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Vascular Ehlers-Danlos syndrome is a rare severe disease that causes arterial dissections and ruptures that can lead to early death. No preventive treatment has yet been validated. Our aim was to assess the ability of celiprolol, a β1-adrenoceptor antagonist with a β2-adrenoceptor agonist action, to prevent arterial dissections and ruptures in vascular Ehlers-Danlos syndrome. Our study was a multicentre, randomised, open trial with blinded assessment of clinical events in eight centres in France and one in Belgium. Patients with clinical vascular Ehlers-Danlos syndrome were randomly assigned to 5 years of treatment with celiprolol or to no treatment. Randomisation was done from a centralised, previously established list of sealed envelopes with stratification by patients' age (≤32 years or >32 years). 33 patients were positive for mutation of collagen 3A1 (COL3A1). Celiprolol was administered twice daily and uptitrated every 6 months by steps of 100 mg to a maximum of 400 mg per day. The primary endpoints were arterial events (rupture or dissection, fatal or not). This study is registered with ClinicalTrials.gov, number NCT00190411. 53 patients were randomly assigned to celiprolol (25 patients) or control groups (28). Mean duration of follow-up was 47 (SD 5) months, with the trial stopped early for treatment benefit. The primary endpoints were reached by five (20%) in the celiprolol group and by 14 (50%) controls (hazard ratio [HR] 0·36; 95% CI 0·15–0·88; p=0·040). Adverse events were severe fatigue in one patient after starting 100 mg celiprolol and mild fatigue in two patients related to dose uptitration. We suggest that celiprolol might be the treatment of choice for physicians aiming to prevent major complications in patients with vascular Ehlers-Danlos syndrome. Whether patients with similar clinical presentations and no mutation are also protected remains to be established. French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001.

BackgroundChronic obstructive pulmonary disease (COPD) is frequently associated with cardiovascular disease. The utility of beta-blockers for treating patients with COPD may be beneficial, but their safety remains uncertain, including worsening of dynamic hyperinflation (DH) during exercise. We hypothesised that among cardioselective beta-blockers celiprolol, due to its partial beta-2 agonist activity, may be safer than bisoprolol on exercise DH.MethodsWe measured isotime inspiratory capacity (IC) during cycle endurance testing in eleven moderate-severe COPD subjects, alongside other non-invasive cardiopulmonary exercise, bioreactance cardiac output, pulmonary function, biomarkers and daily domiciliary measures. Participants received titrated doses of either bisoprolol (maximim 5 mg) or celiprolol (maximum 400 mg) in randomised crossover fashion, each over 4 weeks.ResultsClinically relevant DH occurred between resting and exercise isotime IC but showed no significant difference with either beta-blocker compared with post-run-in pooled baseline or between treatments. There were no other significant differences observed for remaining exercise ventilatory; non-invasive cardiac output; resting pulmonary function; beta-2 receptor and cardiac biomarkers; domiciliary pulmonary function, oxygen saturation and symptom outcomes, either between treatments or compared with baseline. No significant adverse effects occurred.ConclusionsSignificant DH in moderate-severe COPD subjects was no different between bisoprolol or celiprolol or versus baseline. A broad spectrum of other non-invasive cardiopulmonary and domiciliary safety outcomes was equally reassuring. Bronchoprotection with a concomitant long-acting muscarinic antagonist might be an important safety measure in this context.Trial registration numberNCT02380053.

BACKGROUND We tested the hypothesis that celiprolol and bisoprolol have differential effects on blood pressure (BP), flow-mediated dilation (FMD), and vascular stiffness. METHODS We analyzed 102 hypertensives (mean age: 59±14 years) who were being treated other than beta-blockers. They were randomized to receive add-on treatment with either celiprolol 100–200mg (C group) or bisoprolol 2.5–5mg (B group), and followed up for 3 months. In addition to clinic, home, and ambulatory BP monitoring, the FMD, radial augmentation index (AI), brachial–ankle pulse wave velocity (baPWV), urine albumin-to-creatinine ratio, and baroreflex sensitivity (BRS) were measured at baseline and at the end of the study. RESULTS Compared to the baseline values, home and 24-hour BP were significantly lowered in the third month in both groups (all Ps < 0.05). Pulse rate (PR) and baPWV were reduced (P < 0.001), and BRS was increased significantly only in the B group (P = 0.02). Radial AI was unchanged in the C group but was significantly increased in the B group (P < 0.001). Central BP was significantly reduced in the C group (P = 0.003) but was unchanged in the B group. FMD was significantly increased in both groups (both P < 0.01). CONCLUSION Bisoprolol achieved the greater reduction of PR and improved BRS and vascular stiffness, whereas, celiprolol reduced the central BP level. In treated hypertensive patients, add-on use of celiprolol may be favorable in uncomplicated stage of hypertension. On the other hand, bisoprolol may be useful in hypertensives with cardiac or vascular diseases who have advanced atherosclerotic changes and sympathetic nervous system activation.

beta-Blockers are known to worsen FEV(1) and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment. To determine the effects of beta-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]), FEV(1), and response to formoterol in patients with COPD. A double-blind, placebo-controlled, randomized, cross-over study. An ambulatory, hospital outpatient clinic of pulmonary diseases. Patients with mild-to-moderate irreversible COPD and AHR. Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period >/= 3 days. On day 4 of treatment, FEV(1) and PC(20) were assessed. Immediately hereafter, formoterol (12 microg) was administered and FEV(1) was measured for up to 30 min. PC(20) was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV(1) deteriorated only after propranolol treatment (2.08 +/- 0.31 L) [mean +/- SD] compared with placebo (2.24 +/- 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV(1) at 3 min, 6.7 +/- 8.9%) but was unaffected by the other beta-blockers (16.9 +/- 9.8%, 22 +/- 11.6%, and 16.9 +/- 9.0% for placebo, metoprolol, and celiprolol, respectively). Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV(1) and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of beta-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a beta-blocker must be weighted against the putative detrimental pulmonary effects, ie, effect on FEV(1), AHR, and response to additional beta(2)-agonists.

The significance of β-blockers in the treatment of cardiovascular diseases is well established. The effect of vasodilating β-blockers on endothelial function and prothrombotic state has not been investigated. The study comprised 550 consecutive patients with uncomplicated essential hypertension. They were treated with celiprolol, carvedilol or nebivolol monotherapy (171, 179, and 200 patients, respectively), achieving comparable blood pressure reduction. Plasma levels of fibrinogen and homocystine and serum levels of plasminogen activator inhibitor–1 (PAI-1) were obtained before and 6 months after initiation of treatment. The three drugs differentiated in regard to homocystine ( P < .00001) and fibrinogen level changes ( P = .00003), but not ( P = NS) in PAI-1 change. In smokers, differentiation was found in all three parameters ( P = .0002, P = .001, and P = .006 for fibrinogen, PAI-1, and homocystine, respectively), but in nonsmokers differentiation was found only in homocystine change ( P = .00003). In smokers, fibrinogen, PAI-1, and homocystine were reduced more ( P = .002, P = .0009, and P <.0001, respectively) than in nonsmokers in the whole study cohort. The effect of nebivolol was more prominent in smokers than nonsmokers in reducing all three parameters ( P = .0001, .003, and .003, respectively), whereas in celiprolol and carvedilol-treated groups, differentiation between smokers and nonsmokers was significant ( P = .00003 and .01, respectively) only in homocystine level change. In hypertensive smokers, nebivolol resulted in a significant decrease of plasma PAI-1, fibrinogen and homocystine. Celiprolol also significantly affected these parameters but to a lesser degree, whereas carvedilol had no significant favorable action. In nonsmokers, homocystine was reduced significantly by nebivolol. We conclude that smoking status should be a determinant of antihypertensive treatment choice.

Objectives: Ehlers–Danlos syndrome (EDS) is a group of connective tissue disorders characterized by mutations affecting collagen and extracellular matrix proteins. Vascular EDS (vEDS) stands out for its severe prognosis due to the heightened risk of arterial and organ rupture which significantly increase mortality rates. Limited strategies for treating vEDS are prompting exploration for alternatives such as celiprolol, a cardioselective beta-blocker with potential to reduce vascular stress and improve collagen integrity. This review aims to evaluate current evidence on the impact of celiprolol in managing vEDS. Methods: A comprehensive literature search was conducted across scientific databases for studies comparing celiprolol with placebo or other treatments, focusing on relevant outcomes. Results: A total of 323 participants were included across studies published from 2010 to 2023, primarily conducted in European settings. Celiprolol administration, starting at 100 mg daily and titrated up to 400 mg, significantly reduced the incidence of major vascular events such as arterial dissections and ruptures. Most studies reported improved survival rates and fewer hospitalizations due to acute arterial events. Variations in treatment response and side effects such as dizziness and hypotension were noted across studies, occasionally leading to treatment. Conclusions: Celiprolol appears to be a promising treatment for reducing vascular events in vEDS patients, potentially improving quality of life and mitigating the substantial morbidity and mortality associated with vEDS. Future research should focus on refining treatment protocols, exploring mechanisms of action, and establishing comprehensive clinical guidelines to optimize patient outcomes.

IntroductionVascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol is a β1-adrenoceptor antagonist with partial β2 agonist activity that has been shown to reduce rates of vascular events in this setting, though the underlying mechanisms are not yet fully understood. Moreover, very few echocardiographic data are available in patients with vEDS.AimTo perform a comprehensive echocardiographic assessment of a cohort of patients with vEDS with or without celiprolol therapy compared with healthy subjects.MethodsTwenty patients with genetically confirmed diagnosis of vEDS followed at our Institution (University Hospital of Brescia, Italy) were divided into two groups according to whether or not they were on celiprolol therapy at the maximum recommended dose (400 mg daily) for at least 12 months. Both groups were compared to 10 healthy individuals matched for sex, age, body mass index (BMI), and office blood pressure (BP) values. Each participant underwent transthoracic echocardiography with tissue Doppler analysis (TDI) for a comprehensive evaluation of cardiac structure and function.ResultsMean age was 35 years and mean BMI was 21.6 kg/m2. Female sex was prevalent (60%). Left ventricular (LV) internal diameter values tended to be lower in patients with untreated vEDS than in healthy controls (4.33 vs 4.74 cm, respectively), though this difference was not statistically significant. Similar data were observed for LV mass index (56.9 vs 68.6 g/m2), stroke volume (56.6 vs 71.6 mL), and E/A ratio (1.26 vs 1.66), whereas an opposite trend was observed for e’ lateral (13.2 vs 12.2 cm/s). No statistically significant difference was found between groups in terms of other parameters of LV mass, systolic and diastolic function. A normal LV geometry was found in all the cases. Indices of mechano-energetic efficiency and ventricular-arterial coupling were also similar between groups. No patient presented with aortic root dilation, mitral valve prolapse, valve insufficiency of more than mild degree, or valve stenosis of any degree.ConclusionOur study suggests that patients with vEDS have normal cardiac mass and geometry, as well as normal systolic and diastolic function. Celiprolol therapy does not seem to significantly influence such aspects. Compared with vascular imaging, less stringent follow-up with echocardiography seems reasonable in this setting. Future studies with prospective design should confirm these aspects.

The respiratory effects of nebivolol, a newselective β1-adrenergic blocking agent, and celiprolol, aβ-blocker possessing strong β1-adrenoceptor antagonistand mild β2-agonist properties, were investigated in 12patients with mild asthma. Changes in severalspirometric indexes (FVC, FEV1, and forced expiratory flowrate at 50% of FVC) were measured. The interaction with thebronchodilator effect of the β2-adrenoceptor-selectiveagonist albuterol also was investigated. Theeffect of both nebivolol and celiprolol on FEV1 wasconsidered to be significant (p < 0.05). The administration ofnebivolol and celiprolol, but not of placebo, elicited a decrease inFEV1: mean maximum difference for nebivolol, −0.272 L(95% confidence interval [CI], −0.402 to −0.142); mean maximumdifference for celiprolol, −0.193 L (95% CI, −0.316 to −0.071);mean maximum difference for placebo, −0.0001 L (95% CI, −0.087 to0.085). The inhalation of albuterol, up to a dose of 800 μg,significantly (p < 0.05) improved FEV1, but the valuesafter nebivolol and celiprolol administration were lower than theinitial values. Both β-blockers caused equal changes in heart rate,systolic BP, and diastolic BP. There wereno significant differences between the respiratory actions of the twoactive drugs.

OBJECTIVES--This study examines the acute effects of two differing beta adrenergic blocking agents (metoprolol and a third generation vasodilating beta blocker) on plasma concentrations of atrial natriuretic factor (ANF), brain (ventricular) natriuretic factor (BNF), and haemodynamic variables in patients with heart failure. SETTING--University teaching hospital. METHODS--20 patients with impaired left ventricular systolic function [ejection fraction 32 (SEM 2.3)%] were randomised in a double blind manner to receive either oral metoprolol 6.25 mg twice daily or celiprolol 25 mg daily. Haemodynamic variables were evaluated by Swan-Ganz pulmonary artery catheter over 24 hours. ANF and BNF concentrations were measured at baseline, 5 h, and 24 h by radioimmunoassay. RESULTS--At baseline ANF and BNF concentrations were considerably raised compared to the normal range. Treatment with metoprolol caused ANF to rise further to 147% of the basal level at 5 h (P = 0.017) and 112% at 24 h (P = 0.029). This was associated with a small but non-significant rise in pulmonary capillary wedge pressure. Cardiac output and systemic vascular resistance were unchanged at 24 h. In contrast, after celiprolol ANF fell to 90% of basal levels at 5 h and to 74% of basal level at 24 h (P = 0.019), associated with a small but non-significant fall in pulmonary capillary wedge pressure [-3.3 (2.7) mm Hg] and systemic vascular resistance, and rise in cardiac output from 3.2 (0.2) to 4.0 (0.4) l/min (P = 0.04). BNF concentrations rose to 112% of baseline at 5 h (P = 0.09) after metoprolol but fell slightly, to 91% of baseline values, after celiprolol (NS). CONCLUSIONS--Metoprolol, even in very low doses (6.25 mg), produced a rise in ANF and BNF, although minimal haemodynamic changes were detected. In contrast, a vasodilating beta blocker was associated with a significant fall in ANF and BNF and a small rise in cardiac output. This study confirms both the advantages of vasodilating beta blockers over metoprolol for initial treatment of heart failure and the usefulness of ANF and BNF measurements for the assessment of drug effects in heart failure compared to traditional haemodynamic measurements.

Objective To determine whether a third generation vasodilating β blocker (celiprolol) has long term clinical advantages over metoprolol in patients with chronic heart failure. Design A double blind placebo controlled randomised trial. Setting University teaching Hospital. Patients 50 patients with stable chronic heart failure (NYHA class II-IV) due to idiopathic dilated, ischaemic, or hypertensive cardiomyopathy, with left ventricular ejection fraction < 0.45. Interventions Celiprolol 200 mg daily (n = 21), metoprolol 50 mg twice daily (n = 19), or placebo (n = 10) for three months with a four week dose titration period. After the double blind period, patients entered an open label study (with placebo group receiving β blockers) and were assessed after one year. Main outcome measures Clinical response, efficacy, and tolerance were assessed by the Minnesota heart failure symptom questionnaire, six minute walk test, Doppler echocardiography (systolic and diastolic function), radionuclide ventriculography, and atrial and brain natriuretic peptides measured at baseline and after three months. Results In the metoprolol group at 12 weeksv baseline there was a 47% reduction in symptom score (p < 0.001), improvement of NYHA class (mean (SEM), 2.6 (0.12) to 1.9 (0.13), p = 0.001), exercise distance (1246 (54) to 1402 (52) feet, p < 0.001), and left ventricular ejection fraction (26.9(3.1)% to 31(3.0)%, p = 0.016), and a fall in heart rate (resting, 79 (3) to 62 (3) beats/min, p < 0.001). In the celiprolol group there was a 38% reduction in symptom score (p = 0.02), less improvement in exercise distance (1191 (55) to 1256 (61) feet, p = 0.05), and no significant changes in NYHA class, left ventricular ejection fraction, or heart rate. Mortality at one year was 11% in metoprolol and 19% in the celiprolol group, and symptomatic improvement was maintained in the survivors. Conclusions Both drugs were well tolerated but the vasodilator properties of celiprolol do not seem to provide any obvious additional benefit in the long term treatment of heart failure.