Search

Introduction: Vascular 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. Aim: To perform a comprehensive echocardiographic assessment of a cohort of patients with vEDS with or without celiprolol therapy compared with healthy subjects. Methods: Twenty 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. Results: Mean 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. Conclusion: Our 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. [ABSTRACT FROM AUTHOR]

Vascular Ehlers–Danlos syndrome (vEDS) is a rare autosomal dominant connective tissue disease resulting from pathogenic variants in the collagen type III alpha 1 chain (COL3A1) gene, encoding type III procollagen. Patients with vEDS present with severe tissue fragility that can result in arterial aneurysm, dissection, or rupture, especially of medium-caliber vessels. Although early reports have indicated a very high mortality rate in affected patients, with an estimated median survival of around 50 years, recent times have seen a remarkable improvement in outcomes in this population. This shift could be related to greater awareness of the disease among patients and physicians, with improved management both in terms of follow-up and treatment of complications. Increasing use of drugs acting on the cardiovascular system may also have contributed to this improvement. In particular, celiprolol, a β1 cardio-selective blocker with a β2-agonist vasodilator effect, has been shown to reduce rates of vascular events in patients with vEDS. However, the evidence on the true benefits and possible mechanisms responsible for the protective effect of celiprolol in this specific setting remains limited. Drugs targeting the extracellular matrix organization and autophagy–lysosome pathways are currently under investigation and could play a role in the future. This narrative review aims to summarize current evidence and future perspectives on vEDS medical treatment, with a specific focus on vascular prevention. [ABSTRACT FROM AUTHOR]

Background: Vascular Ehlers–Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol has been suggested to significantly reduce rates of vascular events in this setting, though real-world evidence is limited. The aim of this study was to report our experience with celiprolol therapy in vEDS management. Methods: Patients with a genetically confirmed diagnosis of vEDS who were referred for outpatient consultation at the Brescia University Hospital between January 2011 and July 2023 were included. At each visit, patients' medical history, results of vascular imaging, and office blood pressure measurements were recorded. Celiprolol therapy was progressively titrated to the maximum tolerated dose of up to 400 mg daily, according to the patients' tolerance. Results: Overall, 26 patients were included. Female sex was prevalent (62%). Mean (SD) age was 37 (16) years. Follow-up duration was 72 (41) months. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose. The yearly risk of symptomatic vascular events was 8.8%, the majority of which occurred after reaching the maximum recommended dose of celiprolol. No significant predictor of symptomatic vascular events was identified among patients' clinical characteristics. Conclusion: In our cohort, rates of celiprolol use were high and the drug was well tolerated overall. Nonetheless, the risk of symptomatic vascular events remained nonnegligible. Future studies should identify reliable predictors of major adverse events and explore additional therapeutic strategies that could further lower the risk of life-threatening events in this population. [ABSTRACT FROM AUTHOR]

Type IV Ehlers-Danlos syndrome (vascular) is a rare connective tissue disease caused by COL3A1 gene mutation on type III collagen. Clinical presentation is related to vascular fragility and risk of rupture of the arterial wall. Definite diagnosis is given by genetic study and the approach to these patients requires a multidisciplinary team and effective blood pressure control. There is currently only one medication with potential benefit in prevention of cardiovascular events: celiprolol. This article describes the case of a 41-year-old female patient, diagnosed with vascular Ehlers-Danlos syndrome after multiple major cardiovascular events: aortic, coronary and carotid dissections and venous and arterial thrombosis. These required multiple surgical interventions and long-term admission in intensive care units leading to complete functional recovery. This case report seeks to stress the need for an early diagnosis to prevent the severe cardiovascular complications of this rare syndrome. Resumo: A síndrome de Ehlers-Danlos tipo IV (vascular) é uma doença rara do tecido conjuntivo, caracterizada por uma mutação no gene COL3A1 do colagénio tipo III. A apresentação clínica cursa com fragilidade vascular e risco de rutura da parede arterial em idades jovens. O diagnóstico definitivo é estabelecido pelo estudo genético e a abordagem destes doentes assenta numa equipa multidisciplinar e num eficaz controlo da pressão arterial, existindo atualmente um único fármaco com aparente benefício na prevenção de eventos vasculares, o celiprolol. Este artigo descreve o caso de uma doente, cujo diagnóstico de síndrome de Ehlers-Danlos vascular foi feito aos 41 anos, na sequência múltiplos eventos cardiovasculares major, a saber: dissecção aórtica, coronária, carotídea, tromboses arteriais e venosas, que implicaram múltiplas intervenções cirúrgicas e internamento prolongado em Unidade de Cuidados Intensivos, com total recuperação funcional. Pretende-se, com este caso, salientar a gravidade das manifestações cardiovasculares desta síndrome e a necessidade do diagnóstico precoce, com o objectivo de prevenção das mesmas.

Background: Vascular Ehlers-Danlos syndrome is a rare genetic disorder characterized by defective type III collagen and a high risk of arterial morbidity and mortality. Several cardiovascular drugs are used for treatment, including celiprolol, but no controlled trial in this condition has been conducted to date. We hypothesized the benefit of the addition of an angiotensin II receptor blocker., Methods: A multicenter, randomized, placebo-controlled trial was conducted to assess the efficacy and safety of the angiotensin II receptor blocker irbesartan in adults with vascular Ehlers-Danlos syndrome on stable background celiprolol therapy. Patients were randomized 1:1 to receive irbesartan (150 mg/day titrated to 300 mg/day) or placebo for 2 years. The composite primary outcome was defined as any vascular Ehlers-Danlos syndrome-related fatal or nonfatal arterial event or any new or worsening arterial lesions detected by systematic head-to-pelvis computed tomography angiography or peripheral arterial duplex ultrasound at different time points, using a time-to-first-event analysis., Results: Twenty-nine participants (62% female; 40.3±11.3 years of age) were randomized to irbesartan, and 28 (64% female; 40.7±11.0 years of age) were randomized to placebo. The composite primary outcome occurred in 8 of 29 patients (27.6%) receiving irbesartan versus 15 of 28 patients (53.6%) receiving placebo (hazard ratio, 0.42 [95% CI, 0.17, 0.99]; P <0.05). The risk of recurrent symptomatic or nonsymptomatic arterial events was lower with irbesartan than with placebo (risk ratio, 0.37 [95% CI, 0.19, 0.68]; P =0.002). A reduction of progression of arterial lesions was observed at all sites. Irbesartan significantly reduced systolic blood pressure compared with placebo (baseline-adjusted difference of 5.4 mm Hg [ P <0.001]), but no relation was observed with the reduction of the primary composite outcome. Eleven episodes of irbesartan-related hypotension were recorded, leading to a downtitration in 4 patients., Conclusions: Compared with placebo, irbesartan reduced the risk of severe symptomatic and asymptomatic arterial events in patients with vascular Ehlers-Danlos syndrome on background celiprolol therapy., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02597361.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare monogenetic disease caused by pathogenic variants in procollagen 3A1. Arterial rupture is the most serious clinical manifestation. A randomised controlled trial, the Beta-Blockers in Ehlers-Danlos Syndrome Treatment (BBEST) trial, reported a significant protective effect of the beta blocker celiprolol. The aim was to study the outcome of celiprolol treatment in a cohort of Swedish patients with vEDS. Uppsala is a national referral centre for patients with vEDS. They are assessed by vascular surgeons, angiologists, and clinical geneticists. Family history, previous and future clinical events, medication, and side effects are registered. Celiprolol was administered twice daily and titrated up to a maximum dose of 400 mg daily. Logistic regression was used to analyse predictors of vascular events. Forty patients with pathogenic sequence variants in COL3A1 were offered treatment with celiprolol in the period 2011–2019. The median follow up was 22 months (range 1–98 months); total follow up was 106 patient years. In two patients, uptitration of the dose is ongoing. Of the remaining 38, 26 (65%) patients reached the target dose of 400 mg daily. Dose uptitration was unsuccessful in six patients because of side effects; one died before reaching the maximum dose, and five terminated the treatment. Five major vascular events occurred; four were fatal (ruptured ascending aorta; aortic rupture after type B dissection; ruptured cerebral aneurysm; and ruptured pulmonary artery). One bled from a branch of the internal iliac artery, which was successfully coiled endovascularly. The annual risk of a major vascular event was 4.7% (n = 5/106), similar to the treatment arm of the BBEST trial (5%) and lower than in the control arm of the same trial (12%). No significant predictor of vascular events was identified. Treatment with celiprolol is tolerated in most patients with vEDS. Despite fatal vascular events, these observations suggest that celiprolol may have a protective effect in vEDS. Image 1 [ABSTRACT FROM AUTHOR]

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare genetic connective tissue disorder secondary to pathogenic variants within the COL3A1 gene, resulting in exceptional arterial and organ fragility and premature death. The only published clinical trial to date demonstrated the benefit of celiprolol on arterial morbimortality.Objectives: The authors herein describe the outcomes of a large cohort of vEDS patients followed ≤17 years in a single national referral center.Methods: All patients with molecularly confirmed vEDS were included in a retrospective cohort study. After an initial work-up, patients were treated or recommended for treatment with celiprolol (≤400 mg/day) in addition to usual care and scheduled for yearly follow-up. vEDS-related events and deaths were collected and recorded for each patient.Results: Between 2000 and 2017, 144 patients (median age at diagnosis 34.5 years, 91 probands) were included in this study. After a median follow-up of 5.3 years, overall patient survival was high (71.6%; 95% confidence interval: 50% to 90%) and dependent on the type of COL3A1 variant, age at diagnosis, and medical treatment. At the end of the study period, almost all patients (90.3%) were treated with celiprolol alone or in combination. More than two-thirds of patients remained clinically silent, despite a large number (51%) with previous arterial events or arterial lesions at molecular diagnosis. Patients treated with celiprolol had a better survival than others (p = 0.0004). The observed reduction in mortality was dose-dependent: the best protection was observed at the dose of 400 mg/day versus <400 mg/day (p = 0.003). During the period surveyed, the authors observed a statistically significant difference in the ratio of hospitalizations for acute arterial events/hospitalizations for regular follow-up before and after 2011.Conclusions: In this long-term survey, vEDS patients exhibited a low annual occurrence of arterial complications and a high survival rate, on which the overall medical care seems to have a positive influence. [ABSTRACT FROM AUTHOR]

The present study was oriented to synthesis radioiodinated celiprolol (Cel) for a potential cardiac imaging. Celiprolol has been labeled using 125I with chloramine-T (Ch-T) as an oxidizing agent. The key effective factors such as amount of oxidizing agent, amount of substrate, pH, reaction temperature and reaction time, have been systematically studied to optimize the iodination. The biological distribution indicates the suitability of radioiodinated Cel as a novel tracer to image heart. [ABSTRACT FROM AUTHOR]

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 100-200 mg (C group) or bisoprolol 2.5-5 mg (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. [ABSTRACT FROM AUTHOR]

In porcine coronary arteries (PCAs), celiprolol, a selective β1-adrenoceptors antagonist, induces vasodilatation by an endothelium- and nitric oxide (NO)-dependent pathway. However, the mechanisms of that vascular effect have not been precisely established. β3-Adrenoceptors have been shown to be involved in the relaxation per se of various vascular beds, including coronary vessels. Thus, we evaluated ( i) the presence of β3-adrenoceptors in the PCA and ( ii) their role in celiprolol-induced vasodilatation. PCA rings were placed in organ baths and preconstricted with KCl. All experiments were performed in the presence of nadolol (a β1/β2-adrenoceptor antagonist). Cumulative concentration-response curves to SR 58611A and ICI 215001 (2 β3-adrenoceptor agonists) and to celiprolol were constructed. We also used semiquantitative reverse transcription - polymerase chain reaction, which clearly showed the presence of β3-adrenoceptor transcripts. SR 58611A, ICI 215001, and celiprolol induced concentration-dependent relaxations in PCA rings. SR 58611A-induced relaxation was almost abolished after removal of endothelium or pretreatment with L-NAME (a NO synthase inhibitor). The vasorelaxations induced by SR 58611A and celiprolol were inhibited in the presence of SR 59230A and L-748337 (2 selective β3-adrenoceptor antagonists). We showed ( i) that PCAs possess functional β3-adrenoceptors mediating endothelium- and NO-dependent relaxation, and ( ii) that celiprolol exerts a β3-adrenoceptor agonistic activity in this vascular bed. [ABSTRACT FROM AUTHOR]

A sensitive and selective high performance liquid chromatography (HPLC) method has been developed for the simultaneous determination of celiprolol enantiomers in human plasma, urine, and pharmaceutical formulation. Enantiomeric resolution was achieved on cellulose tris(3,5- dichlorophenyl carbamate) immobilized onto spherical porous silica chiral stationary phase known as Chiralpak IC with a fluorescence detection. The mobile phase consisted of n-hexane:ethanol:triethylamine (70:30:0.4%, v/v/v) has been used with a flow rate of 0.5 mL/min. S-(-)-acebutolol was used as the internal standard. The assay involved the use of acetonitrile for deproteinization of human plasma, and solid phase extraction (SPE) method for human urine samples prior to HPLC analysis. The method was validated in compliance with the international conference on harmonization (ICH) guidelines. The calibration curves were linear over the range of 5-250 ng/mL for each enantiomer. The detection limits of each enantiomer were 1.5 and 2.5 ng/mL in plasma and urine, respectively. The developed method applied for the determination of celiprolol enantiomers in urine, plasma and pharmaceutical formulations. Stress degradation studies as well as assay method indicated that, the method can be used as stability-indicating method and chiral quality control for celiprolol enantiomers by HPLC. [ABSTRACT FROM AUTHOR]

Although nonvasodilating β1 blockers increase the levels of uric acid in serum, it is not known whether vasodilating β1 blockers have a similar eff ect. In the present study, we evaluated the eff ect of celiprolol on the release of hypoxanthine, a uric acid precursor, from muscles after an exercise. We used the semi-ischemic forearm test to examine the release of lactate (▵ LAC), ammonia (▵ Amm), and hypoxanthine (▵ HX) before and 4, 10, and 60 min after an exercise in 18 hypertensive patients as well as 4 normotensive subjects. Before celiprolol treatment, all the levels of ▵ HX and ▵ Amm, and ▵ LAC were increased by semi-ischemic exercise in hypertensive patients, and the increases were remarkably larger than those in normotensive subjects. Celiprolol decreased both systolic and diastolic pressure. It also decreased the levels of ▵ HX and ▵ Amm without changes in ▵ LAC after an exercise. These fi ndings also were confi rmed by summation of each metabolite (Σ▵ Metabolites). Celiprolol caused a marginal decrease of serum uric acid, but the diff erence was not statistically signifi cant. On the other hand, nonvasodilating β1 blockers did not suppress the levels of ▵ HX and ▵ Amm, whereas they signifi cantly increased ▵ LAC after an exercise. Celiprolol improved energy metabolism in skeletal muscles. It suppressed HX production and consequently did not adversely aff ect serum uric acid levels. [ABSTRACT FROM AUTHOR]

Abstract: A new method of analysis has been developed and validated for the determination of plasma celiprolol concentration. Plasma samples (1ml) were pre-purified by solid-phase extraction with Bond Elut® C18. The separation was achieved with XBridge™ C18 column (150mm×3.0mm i.d., 3.5μm) at 35°C using a mixture of acetonitrile and 10mM ammonium acetate buffer (pH 10.5) (34:66, v/v) under isocratic conditions at a flow rate of 0.4ml/min. The peak was detected using a fluorescence detector at excitation 250nm and emission 482nm. Retention times for the internal standard (acebutolol) and celiprolol were 4.2min and 6.3min, respectively. Calibration curves were linear over the range of 1.0–1000ng/ml (r >0.999), with a limit of quantification at 1.0ng/ml. Intra- and inter-assay precision (relative standard deviation) were less than 13.3% and the accuracy (relative error) was −5.1% to 11.5% at four different concentrations. This proposed method was successfully applied to a study of pharmacokinetic interactions between celiprolol and apple juice in humans. [Copyright &y& Elsevier]

Two sensitive fluorometric methods were developed for the determination of both bopindolol malonate (BOP) and celiprolol HCl (CLP) based on measuring their native fluorescence in methanol and acetonitrile, respectively. For BOP, the fluorescence was measured at 316 nm after excitation at 278 nm. The proposed method was successfully applied to the assay of commercial tablets as well as content uniformity testing. For CLP, the fluorescence was enhanced by the addition of carboxymethylcellulose solution and measured at 455 nm after excitation at 339 nm. The method was successfully applied to the analysis of CLP in tablets and biological fluids. In both methods, interference likely to be introduced from co-formulated, co-administered, or chemically related drugs was studied. The results were statistically compared with those obtained by reference methods and were found to be in good agreement. [ABSTRACT FROM AUTHOR]

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC0-24 of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems. [ABSTRACT FROM PUBLISHER]

Abstract: We evaluated celiprolol-induced vasodilatation in aorta taken from 12-week-old spontaneously hypertensive rats (SHR) and the effect of AT1 angiotensin II receptor antagonism on the vasodilatory action of celiprolol in Wistar Kyoto (WKY) rats and SHR. In WKY rats, the celiprolol-induced relaxation was greatly decreased in denuded aorta, and completely abolished in intact aorta by Nω-nitro-l-arginine methyl ester (l-NAME, 100μM). In SHR, celiprolol-induced relaxation was reduced compared to WKY rats (E max (value obtained for the highest concentration, 300μM)=39.1±3.78%, n =21 vs. 80.4±3% in WKY rats, n =10; P <0.0001). Endothelium removal or pre-treatment with l-NAME did not alter celiprolol-induced relaxation in SHR. In both strains, relaxation to celiprolol was decreased in the presence of nadolol (a β1/β2-adrenoceptor antagonist, 10μM). N-[[3-[(2S)-2-hydroxy-3-[[2-[4-[(phenylsulfonyl)amino] phenyl]ethyl]amino] propoxy]phenyl]methyl]-acetamide (L748337, a β3-adrenoceptor antagonist, 7μM) had no effect. A 12-day treatment with candesartan cilexetil (an AT1 receptor antagonist, 0.37 or 1mg/kg/day) reduced systolic blood pressure in both strains, but only improved relaxation to celiprolol in SHR, and only at the highest dose (E max =64.2±3.9%, n =10, P <0.0001 vs. SHR control). In both strains, local aortic AT1 receptor antagonism with candesartan CV11974 (100μM) had no effect. The endothelial β1/β2 relaxation induced by celiprolol was therefore impaired in SHR aorta and AT1 receptor antagonism improved the response to celiprolol, in conjunction with a reduction in blood pressure. This work highlights the need to analyse the potential benefit of a combination of celiprolol/AT1 receptor antagonist in the treatment of hypertension. [Copyright &y& Elsevier]

Abstract: The recently reported X-ray structure of the Beta2-adrenergic receptor, the first reported crystal structure of a ligand-mediated GPCR, is used to explore its utility in computer-aided drug design. Validations were conducted with known beta blockers. This was followed by high-throughput docking studies with proprietary and commercial databases to further validate the X-ray structure’s usefulness as a design tool and to explore the potential for discovery of novel chemical classes acting as Beta2 inhibitors. Our results include the finding of ligands with traditional beta-blocker motifs as well as new motifs, thereby serving to both validate the approach and project its usefulness in the finding and design of novel compounds. [Copyright &y& Elsevier]

Objectives. The most important risk factors for coronary heart disease are hypercholesterolemia, smoking and hypertension. To find out which one – lowering cholesterol concentration or using antihypertensive treatment-is more effective in modifying the total risk, we conducted a parallel group placebo-controlled study. The goal of the study was to assess the effect of two drugs on the calculated CHD Framingham risk score in subjects with both moderate hypertension and moderate hypercholesterolemia. Design. Celiprolol for hypertension and simvastatin for cholesterol-lowering were given as monotherapy or as combination treatment. The effects of the treatments on the CHD risk scores were calculated after 3 months. A total of 112 patients were randomized. Results. The total CHD risk decreased in simvastatin and combination groups from 26% to 19% and from 26% to 17%, respectively. Celiprolol alone decreased the risk from 25% to 21%, which was not statistically different from placebo. Conclusions. It can be concluded that subjects with moderate hypercholesterolemia and hypertension benefit more from lipid-lowering treatment with simvastatin than from blood pressure-lowering with beta blocker celiprolol. [ABSTRACT FROM AUTHOR]

The efflux transporter, P-glycoprotein (P-gp), located in the apical membranes of intestinal absorptive cells, can reduce the bioavailability of a wide range of orally administered drugs. A number of surfactants/excipients have been shown to inhibit P-gp, and thus potentially enhance drug absorption. In this study, the improved everted gut sac technique was used to screen excipients for their ability to enhance the absorption of digoxin and celiprolol in vitro. The most effective excipients with digoxin were (at 0.5%, w/v): Labrasol > Imwitor 742 > Acconon E = Softigen 767 > Cremophor EL > Miglyol > Solutol HS 15 > Sucrose monolaurate > Polysorbate 20 > TPGS > Polysorbate 80. With celiprolol, Cremophor EL and Acconon E had no effect, but transport was enhanced by Softigen 767 > TPGS > Imwitor 742. In vivo, the excipients changed the pharmacokinetic profile of orally administered digoxin or celiprolol, but without increasing the overall AUC. The most consistent change was an early peak of absorption, probably due to the higher concentration of excipient in the proximal intestine where the expression of P-gp is lower. These studies show that many excipients/surfactants can modify the pharmacokinetics of orally administered drugs that are P-gp substrates. [Copyright &y& Elsevier]

A simple, rapid method for the simultaneous determination of cardiovascular drugs: celiprolol, bisoprolol and irbesartan in human plasma is described. The two main features of the proposed method deal first, with a simultaneous solid phase extraction of weakly basic beta-blockers derivatives and irbesartan which exhibit weak acidic properties; second with an absorbance monitoring using diode array detection in order to insure an improved selectivity. The separation is performed on a C18 Kromasil® 4.6 mm×150 mm column using a linear gradient to achieve an entire separation of the four species in less than 20 min. The full analytical validation is performed according to guidance for industry for bioanalytical method validation. Linearity of the response was demonstrated for each drug for a range fulfilling the reported plasma levels, that is 10–500, 5–250 and 20–1000 ng l−1 for celiprolol, bisoprolol and irbesartan respectively. Intra- and inter-day relative standard deviations for all compounds were, in any case, lower than 11% and the method exhibits a convenient accuracy (percentage of relative error lower than 6% for each drug). In each case, the LOD were sufficient to detect post dose trough concentrations for checking patient’s observance. Moreover, selectivity towards either endogenous species or co-administered drugs was demonstrated by combination of the use of the solid phase extraction process, gradient elution and diode array detection facilities, making thus, the proposed technique especially suitable for routine drug monitoring of resistant hypertensive patients. [Copyright &y& Elsevier]

Objective. The β-adrenoceptor-blocking agent celiprolol undergoes negligible metabolism, but is a substrate for P-glycoprotein. Our objective was to investigate the effects of rifampicin on the pharmacokinetics of celiprolol in healthy subjects. Methods. In a randomized cross-over study with two phases and a washout of 4 weeks, ten healthy volunteers received a 5-day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 200-mg dose of celiprolol was administered orally. The plasma concentrations of celiprolol and the excretion of celiprolol into urine were measured up to 33 h after its dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the administration of celiprolol and 2, 4, 6, and 10 h later. MDR1 (P-glycoprotein) genotype was assessed with respect to polymorphisms in exon 21 (G2677T/A) and in exon 26 (C3435T). Results. Rifampicin pretreatment reduced the median area under the plasma celiprolol concentration–time curve AUC0–33 h to 0.44-fold [90% confidence interval (CI), 0.27–0.86], relative to the placebo. The median peak plasma concentration, the time of peak concentration, and the elimination half-life of celiprolol were not significantly changed by rifampicin. During the rifampicin phase, the median amount of celiprolol excreted into urine was decreased by 47% (P<0.05) and celiprolol renal clearance increased by 19% (P<0.05) compared with the placebo phase. There were great inter-individual differences in the extent of rifampicin–celiprolol interaction. However, no association was found between the MDR1 polymorphisms and the degree of interaction between rifampicin and celiprolol. No significant differences were observed in hemodynamic parameters between the phases. Conclusion. Rifampicin pretreatment reduces plasma celiprolol concentrations, possibly by induction of the efflux transporter P-glycoprotein, particularly in the intestinal wall, which leads to decreased absorption of celiprolol. [ABSTRACT FROM AUTHOR]

Purpose: Impaired insulin sensitivity has been linked with chronic heart failure (CHF). Exercise has a beneficial effect on insulin sensitivity in healthy subjects. It is used also as an adjunctive therapy in patients with CHF. We studied the effect of randomized treatment with celiprolol, a vasodilating beta(1)-adrenoceptor antagonist, 200 mg once daily (n=20) or placebo (n=11) on serum lipid levels and insulin sensitivity in patients with CHF. In addition, all subjects participated in a 6-month exercise training protocol. Thirteen subjects in the celiprolol and eight subjects in the control group were on additional beta(1)-adrenoceptor antagonist as part of their tailored CHF therapy. Insulin sensitivity was determined using the hyperinsulinemic euglycemic clamp test (diabetic subjects excluded, n=11 for the celiprolol group and n=8 for the placebo group).Results: Insulin sensitivity index (ISI) increased by 33% (P<0.05) in the celiprolol group and by 17% (NS) in the control group. The mean increase in the whole group was 20% [from 68.2+/-11.5 to 81.7+/-10.7 ml/min/kg (mU/l), P<0.05]. No change was found in the total cholesterol level. HDL cholesterol levels increased by 12% (from 0.98+/-0.05 to 1.10+/-0.05 mmol/l, P<0. 005), and HDL/total cholesterol and HDL/LDL cholesterol ratios by 15% and 16%, respectively (P<0.005). The increase in serum fasting HDL cholesterol level was greater in the celiprolol-treated group (P<0.05). At baseline ISI correlated with maximal oxygen uptake (r=0. 65, P<0.0001) and body mass index (r=-0.55, P<0.001). The change in ISI correlated weakly with the improvement in muscle exercise capacity (r=0.53, P<0.05).Conclusions: Insulin sensitivity and serum lipid levels may be favorably affected by exercise training in subjects with mild-to-moderate CHF. Celiprolol, a vasodilating beta1- selective adrenoceptor antagonist, potentiates this effect. [ABSTRACT FROM AUTHOR]

The effects of celiprolol on fasting plasma leptin levels, glucose tolerance, and insulin sensitivity were studied in a randomized, investigator-masked, and parallel clinical trial. Modified oral glucose tolerance tests (OGTT) were performed during the previous antihypertensive monotherapy (β- or Ca-blocker, or ACE inhibitor), and 6 and 12 months after randomization to celiprolol (200–400 mg daily) or to control group, where the therapy was kept unchanged. One hundred and sixty-nine dyslipidemic and hypertensive nondiabetics with an age range of 42–65 years and an average body mass index of 28.4 kg/m2 completed the study according to the protocol. The mean circulating leptin level decreased from 7.5 to 6.6 ng/mL in men (p < 0.05) and from 23.0 to 19.7 ng/mL in women during the 12-month celiprolol treatment. The incremental glucose area under the curve (AUC) in the 2-hour OGTT decreased from 3.8 to 3.0 h* mmol/L (p < 0.01), and insulin AUC decreased from 134 to 99 h* mU/L (p < 0.01). The insulin sensitivity index increased by 22% (p < 0.001) and the serum triglyceride level decreased by 15% in the celiprolol group. Changes in serum cholesterol were clinically insignificant. In the control group, no significant change was seen in any measured variable. A decrease in leptin levels in the celiprolol group was associated with improved insulin sensitivity, while the weight of the moderately obese patients did not change. The clinical significance of a 14% decrease in fasting plasma leptin level remains to be elucidated. The results suggest amelioration of leptin resistance during long-term celiprolol therapy. [ABSTRACT FROM AUTHOR]