Bisoprolol versus celiprolol on dynamic hyperinflation, cardiopulmonary exercise and domiciliary safety in COPD: a single-centre, randomised, crossover study.

BACKGROUND: Chronic 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. METHODS: We 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. RESULTS: Clinically 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. CONCLUSIONS: Significant 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 NUMBER: NCT02380053.

Vascular Ehlers-Danlos Syndrome: Pathological Variants, Recent Discoveries, and Theoretical Approaches.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare autosomal dominant genetic disorder. It is the most fatal among all types of EDS. In addition to typical EDS characteristics, vEDS patients are at risk of blood vessel rupture due to possession of pathogenic variants of the COL3A1 gene, which encodes type III collagen. Type III collagen is a major component of humans' vascular walls. The management of this disease is possible; however, there is no cure as of present. Recently, discoveries with potential impact on the management of vEDS have been elucidated. Mice with vEDS traits treated with a beta-blocker celiprolol showed significant improvements in their thoracic aorta biomechanical strength. Moreover, it has been demonstrated that the specifically designed small interference RNAs (siRNA) can effectively silence the pathogenic variant allele. To enhance the normal allele expression, an intracellularly expressed lysyl oxidase is shown to regulate the transcription rate of the COL3A1 promoter. Similarly, an embryonic homeobox transcription factor Nanog upregulates the wild-type COL3A1 expression through activation of the transforming growth factor-beta pathway, which increases type III collagen synthesis. Despite numerous advancements, more studies are to be performed to incorporate these discoveries into clinical settings, and eventually, more personalized treatments can be created.

Pharmacogenomics of celiprolol - evidence for a role of P-glycoprotein and organic anion transporting polypeptide 1A2 in celiprolol pharmacokinetics.

The aim of this study was to search for associations of genetic variants with celiprolol pharmacokinetics in a large set of pharmacokinetic genes, and, more specifically, in a set of previously identified candidate genes ABCB1, SLCO1A2, and SLCO2B1. To this end, we determined celiprolol single-dose (200 mg) pharmacokinetics and sequenced 379 pharmacokinetic genes in 195 healthy volunteers. Analysis with 46,064 common sequence variants in the 379 genes did not identify any novel genes associated with celiprolol exposure. The candidate gene analysis showed that the ABCB1 c.3435T>C and c.2677T/G>A, and the SLCO1A2 c.516A>C variants were associated with reduced celiprolol area under the plasma concentration-time curve (AUC0-∞ ). An alternative analysis with ABCB1 haplotypes showed that, in addition to SLCO1A2 c.516A>C, three ABCB1 haplotypes were associated with reduced celiprolol AUC0-∞ . A genotype scoring system was developed based on these variants and applied to stratify the participants to low and high celiprolol exposure genotype groups. The mean AUC0-∞ of celiprolol in the low exposure genotype group was 55% of the mean AUC0-∞ in the high exposure group (p = 1.08 × 10-11 ). In addition, the results showed gene-gene interactions in the effects of SLCO1A2 and ABCB1 variants on celiprolol AUC0-∞ (p < 5 × 10-6 ) suggesting an interplay between organic anion transporting polypeptide 1A2 and P-glycoprotein in celiprolol absorption. Taken together, these data indicate that P-glycoprotein and organic anion transporting polypeptide 1A2 play a role in celiprolol pharmacokinetics. Furthermore, patients with ABCB1 and SLCO1A2 genotypes associated with low celiprolol exposure may have an increased risk of poor blood-pressure lowering response to celiprolol.

Characterization of degradation products of celiprolol hydrochloride using hyphenated mass and NMR techniques.

Stress degradation studies were carried out on celiprolol hydrochloride under the ICH prescribed hydrolysis (acidic, basic and neutral), photolytic, oxidative and thermal conditions. Maximum degradation was observed upon hydrolysis, especially in the basic condition. In oxidative condition, the drug degraded only upon severe exposure to H2O2, but it remained stable when challenged with AIBN. It also degraded significantly under photolytic conditions. However, the drug was stable to thermal stress. A total of seven degradation products were formed, whose separation was successfully achieved on an Inertsil ODS-3V C-18 HPLC column employing a gradient mobile phase. A comprehensive mass fragmentation pattern of the drug was initially established through the support of high resolution mass spectrometry (HR-MS), multi-stage tandem mass spectrometry (MSn) and on-line H/D exchange MS data. The same approach was then extended to characterization of the degradation products. Additionally, two degradation products were isolated and subjected to 1D/2D NMR studies for their structural confirmation. One of the degradation products showed instability during isolation, therefore, it was subjected to LC-NMR studies for its structural confirmation.

Do beta-adrenergic blocking agents increase asthma exacerbation? A network meta-analysis of randomized controlled trials.

Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04-10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29-80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04-4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02-11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02-11.65)], oral atenolol [RR = 0.51 (95% CI 0.20-1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03-25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08-10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma.Trial registration: PROSPERO CRD42020190540.

Celiprolol Treatment in Patients with Vascular Ehlers-Danlos Syndrome.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Impact of green tea intake on the pharmacokinetics of celiprolol in healthy subjects.

OBJECTIVE: To assess the effect of green tea intake on the pharmacokinetics of the ß-blocker celiprolol. MATERIALS AND METHOD: In an open-label crossover study, 3 healthy subjects were given water or a green tea beverage daily for 3 days. On day 4, each subject received a single oral dose of 200 mg celiprolol with water or green tea. Serum and urinary concentrations of celiprolol were measured for up to 24 hours. RESULTS: Green tea intake decreased the area under the serum concentration-time curve and urinary excretion of celiprolol by 98.6 and 98.0%, respectively. CONCLUSION: Green tea intake might have a negative impact on the clinical effectiveness of celiprolol.

An old drug for a rare disease: The example of celiprolol for vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome (OMIM 130050, 1/150,000 birth) is caused by mutations in collagen 3A1 gene. It is associated with severe phenotype associating early arterial dissection and rupture, digestive and uterine perforations, and skin and joints fragility. Until recently, no treatment was available. Celiprolol, a beta1 antagonist with beta2 partial antagonist properties betablocker was tested in a randomized, controlled trial. We could show that this compound was associated with a 3-fold decrease in major events related to the disease. This effect was similar in molecular-proven patients. Administration of celiprolol in a cohort of patients followed routinely in France was accompanied to similar benefit. Celiprolol is unavailable in the USA. The ACER Therapeutics company applied for new drug application (NDA) to the Food and Drug Administration.

Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome.

AIMS: Antihypertensive drugs are included in the medical therapy of vascular Ehlers-Danlos syndrome (vEDS). The ß-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta. METHODS AND RESULTS: We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment. CONCLUSIONS: In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS.

Vascular Ehlers-Danlos Syndrome: Long-Term Observational Study.

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.

Non-antipsychotic catecholaminergic drugs for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures. OBJECTIVES: 1. To determine the effects of any of the following drugs for antipsychotic-induced TD in people with schizophrenia or other chronic mental illnesses.i. Drugs which influence the noradrenergic system.ii. Dopamine receptor agonists.iii. Dopamine receptor antagonists.iv. Dopamine-depletor drugs.v. Drugs that increase the production or release of dopamine.2. To examine whether any improvement occurred with short periods of intervention (less than 6 weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.3. To examine if there was a differential effect for the various compounds.4. To examine whether the use of non-antipsychotic catecholaminergic drugs are most effective in those with more recent onset TD (less than five years). SEARCH METHODS: We retrieved 712 references from searching the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information. SELECTION CRITERIA: We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses and antipsychotic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo, no intervention, or any other intervention for the treatment of antipsychotic-induced tardive dyskinesia. DATA COLLECTION AND ANALYSIS: We independently extracted data from these trials and we estimated risk ratios (RRs) with 95% confidence intervals (CIs). We assumed that people who left the studies early had no improvement. MAIN RESULTS: There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating.One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events.For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00). AUTHORS' CONCLUSIONS: Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.

Molecularly Imprinted Porous Monolithic Materials from Melamine-Formaldehyde for Selective Trapping of Phosphopeptides.

Thirty-five melamine-formaldehyde (MF) monolithic materials with bimodal pore distributions were synthesized in fused silica capillaries by catalyst-free polycondensation, starting with an aqueous MF precondensate, using acetonitrile as the macroporogen and a variety of aliphatic polyethers and triblock copolymeric surfactants as porogens and mesoporogens, respectively. By varying the prepolymer composition and the type and molecular weight of the polymeric porogen components, a library of porous monolithic materials was produced, covering a range of meso- and macroporous properties. A multivariate evaluation revealed that the amount of surfactant was the strongest contributor to specific surface area and pore volume and to the inversely related mesopore size, whereas the macropore dimensions were controlled mainly by the amount of aliphatic polyether porogen. One of these capillary monoliths, chosen based on the combination of meso- and macropores providing optimal percolative flow and accessible surface area, was synthesized in the presence of N-Fmoc and O-Et protected phosphoserine and phosphotyrosine to prepare molecularly imprinted monoliths with surface layers selective for phosphopeptides. These imprinted monoliths were characterized alongside nonimprinted monoliths by a variety of techniques and finally evaluated by liquid chromatography-mass spectrometry in the capillary format to assess their abilities to trap and release phosphorylated amino acids and peptides from partly aqueous media. Selective enrichment of phosphorylated targets was demonstrated, suggesting that these materials could be useful as trapping media in affinity-based phosphoproteomics.

Small-Dosing Clinical Study: Pharmacokinetic, Pharmacogenomic (SLCO2B1 and ABCG2), and Interaction (Atorvastatin and Grapefruit Juice) Profiles of 5 Probes for OATP2B1 and BCRP.

The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 µg sulfasalazine, 250 µg rosuvastatin, 300 µg glibenclamide, 1200 µg celiprolol, and 600 µg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.

Synthesis and In Vitro Pharmacological Evaluation of 5-(Alkoxymethyl)-2-(3-alkylamino-2-hydroxypropoxy)phenylethanones Related to Acebutolol and Celiprolol.

The structure-activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2-hydroxyphenylethanone as potential ß-blockers are described. The synthesized compounds possess an isopropyl or a tert-butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four-step method and their structures were confirmed by interpretation of their UV, IR, (1) H NMR and (13) C NMR spectra, and by elemental analysis. The ß-adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (ß1 ) and trachea (ß2 ) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as ß1 /ß2 ratio and the values of compounds with an alkoxy group (CH3 O, iC3 H5 O, C5 H11 O, CH2 CHCH2 O, CH3 OCH2 CH2 O) in the lipophilic part and with tert-butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10(-7) mol/dm(3) showed also negative chronotropic effects.

Effects of Celiprolol and Bisoprolol on Blood Pressure, Vascular Stiffness, and Baroreflex Sensitivity.

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.

The effects of celiprolol on serum concentrations of proinflammatory cytokines in hypertensive (SHR) and normotensive (WKY) rats.

BACKGROUND: A growing body of evidence suggests that some cardiovascular drugs could modulate the level of proinflammatory cytokines. Therefore, the aim of the present study was to investigate whether celiprolol, a third generation ß-adrenoceptor blocker, affects lipopolysaccharide (LPS)-induced serum concentrations of TNF-α, IL-1ß, IL-6 in normotensive (WKY) and spontaneously hypertensive (SHR) rats. METHODS: Celiprolol (150 mgkg(-1)) or vehicle was administered by gavage once daily for 21 days. Arterial blood pressure was measured in conscious rats, using the tail-cuff method. Serum concentrations of proinflammatory cytokines were measured with enzyme-linked immunosorbent assay kits. Additionally, plasma concentrations of total cholesterol, HDL-cholesterol and triglycerides were evaluated. RESULTS: In normotensive WKY rats celiprolol did not affect heart rate, blood pressure, or the serum concentrations of triglycerides, total cholesterol or HDL-cholesterol. In hypertensive animals the drug decreased lipid parameters, increased diastolic and mean blood pressure after the first week of administration, and produced a small but significant decrease in heart rate after the first two weeks of the treatment. In both groups of animals, celiprolol decreased LPS-stimulated serum concentration of IL-6 but did not affect levels of TNF-α and IL-1ß. CONCLUSIONS: It is suggested that the IL-6-modulating properties of celiprolol could provide additional value to the therapeutic effectiveness of the drug in the treatment of hypertension.

Comparison of inhibitory duration of grapefruit juice on organic anion-transporting polypeptide and cytochrome P450 3A4.

Recently, a new type of interaction has been reported in which fruit juices diminish oral drug bioavailability through inhibition of organic anion-transporting polypeptide (OATP). In this study, we aimed to clarify the duration of OATP inhibition by grapefruit juice (GFJ), and to compare it with the duration of GFJ-induced inhibition of cytochrome P450 (CYP) 3A4 activity. Seven healthy volunteers were enrolled in this open-label, single-sequence study. They were orally administered celiprolol (100 mg) and midazolam (15 µg/kg) with water on the control day. Three days later, they ingested GFJ (200 mL) 3 times a day for 3 d. On day 1, the same drugs were administered with GFJ. On days 3 and 7, the same drugs were administered with water. Pharmacokinetics of both drugs were evaluated on each trial day. The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve from 0 to 8 h (AUC0-8) of celiprolol significantly decreased on day 1, and the mean ratios of these values and the corresponding control-day values were 0.18 and 0.25, respectively. The Cmax and AUC0-8 returned to the control levels on days 3 and 7. In contrast, AUC0-8 of midazolam were higher on days 1 and 3 than on the control day (mean ratio, 2.12 and 1.47, respectively). The AUC0-8 returned to the control level on day 7. In conclusion, results of this study indicated that the OATP inhibition caused by GFJ dissipated faster than GFJ-mediated alterations in CYP3A4 activity, which were sustained for at least 48 h.