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1.
J Pharm Biomed Anal ; 197: 113953, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33618130

RESUMO

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.


Assuntos
Celiprolol , Peróxido de Hidrogênio , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Hidrólise , Oxirredução , Fotólise , Espectrometria de Massas em Tandem
2.
Sci Rep ; 11(1): 452, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33432057

RESUMO

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.


Assuntos
Antagonistas Adrenérgicos beta/efeitos adversos , Progressão da Doença , Ensaios Clínicos Controlados Aleatórios como Assunto , Estado Asmático/induzido quimicamente , Administração Oral , Antagonistas Adrenérgicos beta/administração & dosagem , Atenolol/administração & dosagem , Atenolol/efeitos adversos , Bisoprolol/administração & dosagem , Bisoprolol/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Celiprolol/administração & dosagem , Celiprolol/efeitos adversos , Feminino , Humanos , Incidência , Infusões Intravenosas , Masculino , Practolol/administração & dosagem , Practolol/efeitos adversos , Propranolol/administração & dosagem , Propranolol/efeitos adversos , Risco , Sotalol/administração & dosagem , Sotalol/efeitos adversos , Estado Asmático/epidemiologia , Timolol/administração & dosagem , Timolol/efeitos adversos
3.
Int J Clin Pharmacol Ther ; 59(3): 198-201, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33210993

RESUMO

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.


Assuntos
Celiprolol , Chá , Antagonistas Adrenérgicos beta , Estudos Cross-Over , Voluntários Saudáveis , Humanos
5.
Eur J Vasc Endovasc Surg ; 61(2): 326-331, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33223285

RESUMO

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.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Celiprolol/uso terapêutico , Síndrome de Ehlers-Danlos/tratamento farmacológico , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Síndrome de Ehlers-Danlos/complicações , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
Therapie ; 75(2): 175-181, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32127191

RESUMO

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.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Celiprolol/uso terapêutico , Reposicionamento de Medicamentos , Síndrome de Ehlers-Danlos/tratamento farmacológico , Doenças Vasculares/tratamento farmacológico , Ensaios Clínicos como Assunto , Humanos , Doenças Raras
7.
Cardiovasc Res ; 116(2): 457-465, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31056650

RESUMO

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.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Aneurisma Dissecante/prevenção & controle , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aorta Torácica/efeitos dos fármacos , Aneurisma da Aorta Torácica/prevenção & controle , Ruptura Aórtica/prevenção & controle , Celiprolol/farmacologia , Síndrome de Ehlers-Danlos/tratamento farmacológico , Losartan/farmacologia , Remodelação Vascular/efeitos dos fármacos , Aneurisma Dissecante/patologia , Aneurisma Dissecante/fisiopatologia , Animais , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/patologia , Aneurisma da Aorta Torácica/fisiopatologia , Ruptura Aórtica/patologia , Ruptura Aórtica/fisiopatologia , Colágeno Tipo III/genética , Doxiciclina/farmacologia , Síndrome de Ehlers-Danlos/patologia , Síndrome de Ehlers-Danlos/fisiopatologia , Heterozigoto , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos Endogâmicos C57BL , Mutação , Estudo de Prova de Conceito , Estresse Mecânico
9.
J Am Coll Cardiol ; 73(15): 1948-1957, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30999998

RESUMO

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.


Assuntos
Celiprolol/uso terapêutico , Síndrome de Ehlers-Danlos/tratamento farmacológico , Monitorização Fisiológica/métodos , Adulto , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/mortalidade , Feminino , Seguimentos , Humanos , Assistência de Longa Duração/métodos , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento
10.
Cochrane Database Syst Rev ; 1: CD000458, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29342497

RESUMO

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.


Assuntos
Antidiscinéticos/uso terapêutico , Antipsicóticos/efeitos adversos , Discinesia Induzida por Medicamentos/tratamento farmacológico , Inibidores da Captação Adrenérgica/uso terapêutico , Celiprolol/uso terapêutico , Progressão da Doença , Antagonistas de Dopamina/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Metildopa/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Reserpina/uso terapêutico , Tetrabenazina/uso terapêutico , Cloridrato de Tiapamil/uso terapêutico
11.
Anal Chem ; 89(17): 9491-9501, 2017 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-28795574

RESUMO

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.


Assuntos
Impressão Molecular/métodos , Fosfopeptídeos/química , Triazinas/química , Celiprolol , Modelos Moleculares , Estrutura Molecular , Transição de Fase , Conformação Proteica
12.
J Pharm Sci ; 106(9): 2688-2694, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28322941

RESUMO

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.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Atorvastatina/farmacocinética , Citrus paradisi/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Farmacogenética/métodos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Atorvastatina/química , Atorvastatina/metabolismo , Celiprolol/química , Celiprolol/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Interações Alimento-Droga , Genótipo , Glibureto/química , Glibureto/farmacocinética , Humanos , Absorção Intestinal , Masculino , Proteínas de Neoplasias/metabolismo , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Sulfassalazina/química , Sulfassalazina/farmacocinética , Sumatriptana/química , Sumatriptana/farmacocinética
13.
Arch Pharm (Weinheim) ; 349(9): 733-40, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27417385

RESUMO

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.


Assuntos
Acebutolol/análogos & derivados , Acebutolol/farmacologia , Celiprolol/análogos & derivados , Celiprolol/farmacologia , Propanolaminas/química , Propanolaminas/farmacologia , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/farmacologia , Animais , Cobaias , Átrios do Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Histamina/farmacologia , Isoproterenol/farmacologia , Propanolaminas/síntese química , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos
14.
Am J Hypertens ; 28(7): 858-67, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25577782

RESUMO

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.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Barorreflexo/efeitos dos fármacos , Bisoprolol/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Celiprolol/uso terapêutico , Hipertensão/tratamento farmacológico , Rigidez Vascular/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Adulto , Idoso , Índice Tornozelo-Braço , Anti-Hipertensivos/efeitos adversos , Bisoprolol/efeitos adversos , Monitorização Ambulatorial da Pressão Arterial , Celiprolol/efeitos adversos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Japão , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Estudos Prospectivos , Análise de Onda de Pulso , Fatores de Tempo , Resultado do Tratamento
15.
Pharmacol Rep ; 66(1): 68-73, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24905309

RESUMO

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.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Anti-Hipertensivos/farmacologia , Celiprolol/farmacologia , Citocinas/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Interleucina-6/fisiologia , Lipídeos/sangue , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY
16.
Biol Pharm Bull ; 36(12): 1936-41, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24292052

RESUMO

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.


Assuntos
Bebidas , Celiprolol/farmacocinética , Citrus paradisi , Inibidores do Citocromo P-450 CYP3A , Midazolam/farmacocinética , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Adulto , Celiprolol/sangue , Citocromo P-450 CYP3A , Interações Alimento-Droga , Humanos , Masculino , Midazolam/sangue , Adulto Jovem
17.
Can J Physiol Pharmacol ; 91(10): 791-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24144049

RESUMO

In porcine coronary arteries (PCAs), celiprolol, a selective ß(1)-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. ß(3)-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 ß(3)-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 ß(1)/ß(2)-adrenoceptor antagonist). Cumulative concentration-response curves to SR 58611A and ICI 215001 (2 ß(3)-adrenoceptor agonists) and to celiprolol were constructed. We also used semiquantitative reverse transcription - polymerase chain reaction, which clearly showed the presence of ß(3)-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 ß(3)-adrenoceptor antagonists). We showed (i) that PCAs possess functional ß(3)-adrenoceptors mediating endothelium- and NO-dependent relaxation, and (ii) that celiprolol exerts a ß(3)-adrenoceptor agonistic activity in this vascular bed.


Assuntos
Agonistas de Receptores Adrenérgicos beta 3/farmacologia , Celiprolol/farmacologia , Vasos Coronários/efeitos dos fármacos , Receptores Adrenérgicos beta 3/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Antagonistas de Receptores Adrenérgicos beta 3/farmacologia , Animais , Vasos Coronários/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , RNA Mensageiro/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Suínos
19.
Hypertens Res ; 36(11): 934-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23784509

RESUMO

We have previously reported that intermittent hypoxic stress, which is relevant to sleep apnea syndrome (SAS), increases oxidative stress and induces left ventricular (LV) remodeling. Celiprolol, a ß1-selective adrenoreceptor blocker, is known to have not only an antihypertensive effect but also an antioxidant effect through releasing nitric oxide. The aim of this study was to examine the hypothesis that celiprolol might ameliorate the LV remodeling induced by intermittent hypoxia through its antioxidant effect. Male C57BL/6J mice (8 weeks old) were exposed to intermittent hypoxia (30 s of 5% oxygen followed by 30 s of 21% oxygen) for 8 h day(-1) during the daytime for 10 consecutive days or were maintained under normoxic conditions. Animals were treated with either celiprolol (100 mg kg(-1) day(-1) by gavage) or vehicle. Hypoxic stress caused fluctuations in blood pressure (BP), an increase in the mean cardiomyocyte diameter, perivascular fibrosis and a decrease in endothelial nitric oxide synthase (eNOS) expression. These changes were associated with increased levels of 4-hydroxy-2-nonenal protein, superoxide, tumor necrosis factor-α mRNA and brain natriuretic peptide mRNA in the LV myocardium. Celiprolol significantly suppressed BP fluctuation, restored eNOS expression and reduced oxidative stress and superoxide production, thus ameliorating hypoxia-induced LV remodeling in mice. These findings suggest that treatment with celiprolol might prevent cardiovascular events in borderline hypertensive patients with SAS.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Celiprolol/farmacologia , Hipóxia/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Celiprolol/uso terapêutico , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Superóxidos/metabolismo
20.
Drug Metab Pharmacokinet ; 28(4): 356-61, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23419354

RESUMO

The aim of the present study was to clarify the involvement of P-glycoprotein (P-gp) or organic anion transporting polypeptide (Oatp) 1a5 in the pharmacokinetics of nadolol (NDL), a non-metabolized hydrophilic ß-adrenoceptor blocker, in rats. Pretreatment with itraconazole (ICZ, P-gp inhibitor, 50 mg/kg) for 30 min before oral administration of NDL (10 mg/kg) significantly increased the area under the plasma concentration-time curve (AUC0₋∞)of NDL by 1.7-fold compared with control. Intragastric administration of dexamethasone (DEX, 8 mg/kg) for 4 consecutive days increased P-gp level in the intestine and the liver. In line with this, DEX pre-treatment decreased maximum plasma concentration (C(max)) of NDL by 28% of control. To inhibit the intestinal Oatp1a5, naringin (NRG, 0.145 mg/kg) was preadministered orally for 30 min before the oral administrations of NDL or celiprolol (CEL, 10 mg/kg, Oatp1a5 substrate). Although NRG markedly reduced C(max) and AUC0₋∞ of CEL by 60% and 65% of control, respectively, little difference was observed in the plasma concentration of NDL between NRG and control. These results suggest that P-gp is greatly involved in the pharmacokinetics of NDL, while the involvement of Oatp1a5 in the pharmacokinetics of NDL may be less than that of celiprolol in rats.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Dexametasona/farmacologia , Flavanonas/farmacologia , Itraconazol/farmacologia , Nadolol/farmacocinética , Antagonistas Adrenérgicos beta/farmacocinética , Animais , Celiprolol/farmacocinética , Absorção Intestinal/efeitos dos fármacos , Masculino , Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley
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