Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications

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Miroslav Radenkovic

2016-01-01

Full Text Available The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation.

ANGIOTENSIN RECEPTOR BLOCKERS WITH PLEIOTROPIC PROPERTIES: A NEW STANDARD IN CARDIOVASCULAR RISK MANAGEMENT AND TREATMENT OF HYPERTENSION

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V. I. Podzolkov

2017-01-01

Full Text Available An increase in the activity of the renin-angiotensin-aldosterone system is one of the most important mechanisms for the realization of the cardiovascular continuum. The role that angiotensin receptor blockers play in achieving target figures of blood pressure and reducing cardiovascular risk is discussed. The importance of pleiotropic properties of angiotensin receptor blockers (in particular, activation of peroxisome proliferator-activated receptors gamma – PPAR-γ in the management of patients with insulin resistance, obesity, dyslipidemia is also covered. The evidence base for the use of telmisartan as a drug with pleiotropic effect in patients with arterial hypertension and associated diseases (diabetes mellitus, obesity, renal dysfunction is discussed. 

The modulation of radiosensitivity by combined treatment of selective COX-2 inhibitor, NS 398 and EGF receptor blocker AG 1478 in HeLa cell line

International Nuclear Information System (INIS)

Youn, Seon Min; Oh, Young Kee; Kim, Joo Heon; Park, Mi Ja; Seong, In Ock; Kang, Ki Mun; Chai, Gyu Yong

2005-01-01

Selective inhibition of multiple molecular targets may improve the antitumor activity of radiation. Two specific inhibitors of selective cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) were combined with radiation on the HeLa cell line. To investigate cooperative mechanism with selective COX-2 inhibitor and EGFR blocker, in vitro experiments were done. Antitumor effect was obtained by growth inhibition and apoptosis analysis by annexin V-Flous method. Radiation modulation effects were determined by the clonogenic cell survival assay. Surviving fractions at 2 Gy (SF 2 ) and dose enhancement radio at a surviving fraction of 0.25 were evaluated. To investigate the mechanism of the modulation of radiosensitivity, the cell cycle analyses were done by flow cytometry. The bcl-2 and bax expressions were analyzed by western blot. A cooperative effect were observed on the apoptosis of the HeLa cell line when combination of the two drugs, AG 1478 and NS 398 with radiation at the lowest doses, apoptosis of 22.70% compare with combination of the one drug with radiation, apoptosis of 8.49%. In cell cycle analysis, accumulation of cell on G 0 /G 1 phase and decrement of S phase fraction was observed from 24 hours to 72 hours after treatment with radiation, AG 1478 and NS 398. The combination of NS 398 and AG 1478 enhanced radiosensitivity in a concentration-dependent manner in HeLa cells with dose enhancement ratios of 3.00 and SF 2 of 0.12 but the combination of one drug with radiation was not enhanced radiosensitivity with dose enhancement ratios of 1.12 and SF2 of 0.68 (ρ = 0.005). The expression levels of bcl-2 and bax were reduced when combined with AG 1478 and NS 398. Our results indicate that the selective COX-2 inhibitor and EGFR blocker combined with radiation have potential additive or cooperative effects on radiation treatment and may act through various mechanisms including direct inhibition of tumor cell proliferation, suppression of tumor cell

THE ROLE OF S-AMLODIPINE IN ARTERIAL HYPERTENSION THERAPY WITH COMBINATION OF CALCIUM CHANNEL BLOCKERS AND BETA-BLOCKERS

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M. A. Maksimova

2013-01-01

Full Text Available Aim. To study efficacy and safety of calcium channel blocker, S-amlodipine, in combination with β-blocker, atenolol, in patients with arterial hypertension (HT 1-2 degree com- pared to fixed combination of racemic amlodipine and atenolol.Material and methods. Patients (n=31, 7 men and 24 women with HT 1–2 degree were included into the study. The patients were randomized into two groups by the com- binations sequence. Treatment with each combination lasted 4 weeks. Office blood pressure (BP was assessed at baseline and at the end of the treatment periods, possible side effects were registered.Results. All patients completed the study. Both combination of S-amlodipine+atenolol and fixed combination of racemic amlodipine+atenolol reduced systolic (in average, -15.9 and -12.7 mm Hg, respectively and diastolic (in average, -7.3 and -5.3 mmHg, respectively BP significantly. Heart rate also decreased during therapy (in average, -3 and -4 bt/min, respectively. The differences between combinations BP and heart rate effects were not significant. 8 and 16 adverse events were registered during S-amlodipine+atenolol and racemic amlodipine+atenolol therapies, respectively Conclusion. Combination of S-amlodipine+atenolol, as well as combination of racemic amlodipine+atenolol are effective in the treatment of patients with HT 1-2 degree, however combination with S-amlodipine has less number of adverse events.

Trends in co-prescribing of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in Ireland.

LENUS (Irish Health Repository)

Wan Md Adnan, Wan A H

2011-03-01

(i) To examine the trends in co-prescribing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) therapy and (ii) to examine the influence of major clinical trials (CALM, COOPERATE, VALIANT and ONTARGET) on co-prescribing.

The modulation of radiosensitivity by combined treatment of selective COX-2 inhibitor, NS 398 and EGF receptor blocker AG 1478 in HeLa cell line

Energy Technology Data Exchange (ETDEWEB)

Youn, Seon Min; Oh, Young Kee; Kim, Joo Heon; Park, Mi Ja; Seong, In Ock [Eulji University School of Medicine, Daejeon (Korea, Republic of); Kang, Ki Mun; Chai, Gyu Yong [Gyeongsang National University College of Medicine, Jinju (Korea, Republic of)

2005-03-15

Selective inhibition of multiple molecular targets may improve the antitumor activity of radiation. Two specific inhibitors of selective cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) were combined with radiation on the HeLa cell line. To investigate cooperative mechanism with selective COX-2 inhibitor and EGFR blocker, in vitro experiments were done. Antitumor effect was obtained by growth inhibition and apoptosis analysis by annexin V-Flous method. Radiation modulation effects were determined by the clonogenic cell survival assay. Surviving fractions at 2 Gy (SF{sub 2}) and dose enhancement radio at a surviving fraction of 0.25 were evaluated. To investigate the mechanism of the modulation of radiosensitivity, the cell cycle analyses were done by flow cytometry. The bcl-2 and bax expressions were analyzed by western blot. A cooperative effect were observed on the apoptosis of the HeLa cell line when combination of the two drugs, AG 1478 and NS 398 with radiation at the lowest doses, apoptosis of 22.70% compare with combination of the one drug with radiation, apoptosis of 8.49%. In cell cycle analysis, accumulation of cell on G{sub 0}/G{sub 1} phase and decrement of S phase fraction was observed from 24 hours to 72 hours after treatment with radiation, AG 1478 and NS 398. The combination of NS 398 and AG 1478 enhanced radiosensitivity in a concentration-dependent manner in HeLa cells with dose enhancement ratios of 3.00 and SF{sub 2} of 0.12 but the combination of one drug with radiation was not enhanced radiosensitivity with dose enhancement ratios of 1.12 and SF2 of 0.68 ({rho} = 0.005). The expression levels of bcl-2 and bax were reduced when combined with AG 1478 and NS 398. Our results indicate that the selective COX-2 inhibitor and EGFR blocker combined with radiation have potential additive or cooperative effects on radiation treatment and may act through various mechanisms including direct inhibition of tumor cell proliferation

Combination monoamine oxidase inhibitor and beta-blocker treatment of migraine, with anxiety and depression.

Science.gov (United States)

Merikangas, K R; Merikangas, J R

1995-11-01

This paper presents the results of a study comparing the effectiveness of a beta-adrenergic blocking agent, atenolol, a monoamine oxidase inhibitor (MAO-I), phenelzine, and the combination in treatment of 61 adults with migraine headache. The goals of the study are (1) to investigate the safety of concomitant treatment of migraine with beta-blockers and phenelzine, (2) to assess whether orthostatic hypertension and other side effects would be relieved, and (3) to compare the results of this open trial of phenelzine to those of a previous study using similar methods. Phenelzine was associated with a large decrease in the frequency and severity of migraine attacks. Anxiety and depression were also reduced by phenelzine both alone, and in combination with a beta-blocker. The results show that the combination of MAO-I's and beta-blockers can be administered safely, and can lead to the reduction in the side effects with either drug alone.

The Effect of Combined Treatment with the (ProRenin Receptor Blocker HRP and Quinapril in Type 1 Diabetic Rats

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Gábor Kökény

2017-04-01

Full Text Available Background/Aims: Diabetic nephropathy remains a major clinical problem. The effects of prorenin might be adverse, but the literature data are controversial. We compared the renal effects of the (prorenin receptor ((PRR blockade and angiotensin converting enzyme (ACE inhibition on the progression of diabetic nephropathy in rats. Methods: Diabetes (DM was induced by ip. streptozotocin administration in adult male Sprague-Dawley rats, followed by eight weeks of treatment with the (PRR blocker „handle region” decoy peptide (HRP, 0,1 mg/kg/day or with the ACE inhibitor Quinapril (Q, 50 mg/kg/day and grouped as follows: 1. Control (n=10; 2. DM (n=8; 3. DM+HRP (n=6; 4. DM+Q (n=10; 5. DM+Q+HRP (n=10. Renal functional parameters, histology and gene expressions were evaluated. Results: HRP reduced glomerulosclerosis and podocyte desmin expression, but did not affect proteinuria and tubular ERK(1/2 phosphorylation. Both Q and Q+HRP treatment reduced proteinuria, glomerular and tubular damage, tubular TGF-ß1 expression and ERK(1/2 phosphorylation to the same extent. Conclusion: The effects of HRP were partially beneficial on diabetic kidney lesions as HRP reduced damage but did not improve tubular damage and failed to reduce ERK(1/2 phosphorylation in rats. The combination of HRP with Quinapril had no additive effects over Quinapril monotherapy on the progression of diabetic nephropathy.

Pre-injury beta blocker use does not affect the hyperdynamic response in older trauma patients

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David C Evans

2014-01-01

Full Text Available Purpose: Trauma dogma dictates that the physiologic response to injury is blunted by beta-blockers and other cardiac medications. We sought to determine how the pre-injury cardiac medication profile influences admission physiology and post-injury outcomes. Materials and Methods: Trauma patients older than 45 evaluated at our center were retrospectively studied. Pre-injury medication profiles were evaluated for angiotensin-converting enzyme inhibitors / angiotensin receptor blockers (ACE-I/ARB, beta-blockers, calcium channel blockers, amiodarone, or a combination of the above mentioned agents. Multivariable logistic regression or linear regression analyses were used to identify relationships between pre-injury medications, vital signs on presentation, post-injury complications, length of hospital stay, and mortality. Results: Records of 645 patients were reviewed (mean age 62.9 years, Injury Severity Score >10, 23%. Our analysis demonstrated no effect on systolic and diastolic blood pressures from beta-blocker, ACE-I/ARB, calcium channel blocker, and amiodarone use. The triple therapy (combined beta-blocker, calcium channel blocker, and ACE-I/ARB patient group had significantly lower heart rate than the no cardiac medication group. No other groups were statistically different for heart rate, systolic, and diastolic blood pressure. Conclusions: Pre-injury use of cardiac medication lowered heart rate in the triple-agent group (beta-blocker, calcium channel blocker, and ACEi/ARB when compared the no cardiac medication group. While most combinations of cardiac medications do not blunt the hyperdynamic response in trauma cases, patients on combined beta-blocker, calcium channel blocker, and ACE-I/ARB therapy had higher mortality and more in-hospital complications despite only mild attenuation of the hyperdynamic response.

Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers

DEFF Research Database (Denmark)

Lambers Heerspink, Hiddo J; Holtkamp, Frank A; Parving, Hans-Henrik

2012-01-01

Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of...

The Impact of Type 2 Diabetes on the Efficacy of ADP Receptor Blockers in Patients with Acute ST Elevation Myocardial Infarction: A Pilot Prospective Study

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Matej Samoš

2016-01-01

Full Text Available Background. The aim of this study was to validate the impact of type 2 diabetes (T2D on the platelet reactivity in patients with acute ST elevation myocardial infarction (STEMI treated with adenosine diphosphate (ADP receptor blockers. Methods. A pilot prospective study was performed. Totally 67 patients were enrolled. 21 patients had T2D. Among all study population, 33 patients received clopidogrel and 34 patients received prasugrel. The efficacy of ADP receptor blocker therapy had been tested in two time intervals using light transmission aggregometry with specific inducer and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P flow cytometry assay. Results. There were no significant differences in platelet aggregability among T2D and nondiabetic (ND group. The platelet reactivity index of VASP-P did not differ significantly between T2D and ND group (59.4±30.9% versus 60.0±25.2% and 33.9±25.3% versus 38.6±29.3% in second testing. The number of ADP receptor blocker nonresponders did not differ significantly between T2D and ND patients. The time interval from ADP receptor blocker loading dosing to the blood sampling was similar in T2D and ND patients in both examinations. Conclusion. This prospective study did not confirm the higher platelet reactivity and higher prevalence of ADP receptor blocker nonresponders in T2D acute STEMI patients.

[Assessment of the utilization of angiotensin receptor blockers in hypertension].

Science.gov (United States)

Peña Cabia, S; Ricote Lobera, I; Santos Mena, B; Hidalgo Correas, F J; Climent Florez, B; García Díaz, B

2013-01-01

To assess the degree in which the utilization of angiotensin receptor blockers (ARBs) in our Healthcare Area fits the criteria proposed by the Autonomous Community of Madrid (CAM) before setting «Plan de Actuación de ARA-II» («Action Plan ARA-II»). To study the indications for which are prescribed and to identify those factors that can show influence in prescription. Drug utilization study of the type indication-prescription, descriptive and transversal, for which ARBs-treated and hypertensive patients admitted to a University General Hospital for a study period of 3 months were selected. Based on the clinical situations summarized in the CAM Document «Criterios para establecer el lugar en la terapéutica de los antagonistas de los receptores de la angiotensina II» («Criteria for the place of angiotensin receptor blockers in the therapeutic»), a percentage of patients with «appropriate prescription» and «inadequate prescription« of ARBs was calculated and analyzed in order to determine if the age and the sex were related to the type of prescription or the main indications for which they had been prescribed. Out of the 153 patients included in the study, 67.3% had a «inadequate prescription«, 47.6% of them due to an ARBs prescription as the first drug inhibitor of the reninangiotensin- aldosterone system and 34.0% owing to a poor control of blood pressure with angiotensin-converting enzyme inhibitors (ACEi). There were no statistically significant differences found either by age or sex in the type of prescription or in the main indications for which they were prescribed. The adequacy of the criteria for the utilisation of ARBs Document occurred in 32.7% of cases. In addition, factors such as age and sex did not seem to affect the type of prescription. Misconceptions of superiority of ARBs versus ACEi were evidenced as well. Copyright © 2013 SEFH. Published by AULA MEDICA. All rights reserved.

Preadmission use of renin-angiotensin blockers and rupture of abdominal aortic aneurysm

DEFF Research Database (Denmark)

Wemmelund, Holger; Høgh, Annette; Hundborg, Heidi H.

2016-01-01

PURPOSE: Rupture of abdominal aortic aneurysms (rAAA) is associated with high mortality. Use of angiotensin converting enzyme inhibitors (ACE-inhibitors) and angiotensin receptor blockers (ARBs) has been suggested to reduce the risk of rAAA. This nationwide, combined case-control and follow-up st...

Long-term use of angiotensin receptor blockers and the risk of cancer.

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Laurent Azoulay

Full Text Available The association between angiotensin receptor blockers (ARBs and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs and 95% confidence intervals (CIs of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years. When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96-1.03 or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06-1.20 and RR: 1.19; 95% CI: 1.12-1.27, respectively. This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.

Hinge-deleted IgG4 blocker therapy for acetylcholine receptor myasthenia gravis in rhesus monkeys.

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Losen, Mario; Labrijn, Aran F; van Kranen-Mastenbroek, Vivianne H; Janmaat, Maarten L; Haanstra, Krista G; Beurskens, Frank J; Vink, Tom; Jonker, Margreet; 't Hart, Bert A; Mané-Damas, Marina; Molenaar, Peter C; Martinez-Martinez, Pilar; van der Esch, Eline; Schuurman, Janine; de Baets, Marc H; Parren, Paul W H I

2017-04-20

Autoantibodies against ion channels are the cause of numerous neurologic autoimmune disorders. Frequently, such pathogenic autoantibodies have a restricted epitope-specificity. In such cases, competing antibody formats devoid of pathogenic effector functions (blocker antibodies) have the potential to treat disease by displacing autoantibodies from their target. Here, we have used a model of the neuromuscular autoimmune disease myasthenia gravis in rhesus monkeys (Macaca mulatta) to test the therapeutic potential of a new blocker antibody: MG was induced by passive transfer of pathogenic acetylcholine receptor-specific monoclonal antibody IgG1-637. The effect of the blocker antibody (IgG4Δhinge-637, the hinge-deleted IgG4 version of IgG1-637) was assessed using decrement measurements and single-fiber electromyography. Three daily doses of 1.7 mg/kg IgG1-637 (cumulative dose 5 mg/kg) induced impairment of neuromuscular transmission, as demonstrated by significantly increased jitter, synaptic transmission failures (blockings) and a decrease in the amplitude of the compound muscle action potentials during repeated stimulations (decrement), without showing overt symptoms of muscle weakness. Treatment with three daily doses of 10 mg/kg IgG4Δhinge-637 significantly reduced the IgG1-637-induced increase in jitter, blockings and decrement. Together, these results represent proof-of principle data for therapy of acetylcholine receptor-myasthenia gravis with a monovalent antibody format that blocks binding of pathogenic autoantibodies.

Molecule-specific Effects of Angiotensin II–Receptor Blockers Independent of the Renin–Angiotensin System

Czech Academy of Sciences Publication Activity Database

Kurtz, T. W.; Pravenec, Michal

2008-01-01

Roč. 21, č. 8 (2008), s. 852-859 ISSN 0895-7061 R&D Projects: GA MŠk(CZ) 1M0520; GA MZd(CZ) NR8545 Grant - others:EURATOOLS(XE) LSHG-CT-2005-019015; HHMI(US) 55005624 Institutional research plan: CEZ:AV0Z50110509 Keywords : angiotensin-receptor blockers * cardiovascular protection * renin-angiotensin system Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.122, year: 2008

Combination inhibition of the renin-angiotensin system: is more better?

Science.gov (United States)

Krause, Michelle W; Fonseca, Vivian A; Shah, Sudhir V

2011-08-01

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are considered the standard of care for treatment of cardiovascular disease and chronic kidney disease. Combination therapy with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers effectively inhibits the renin-angiotensin system as well as potentiates the vasodilatory effects of bradykinin. It has been advocated that this dual blockade approach theoretically should result in improved clinical outcomes in both cardiovascular disease and chronic kidney disease. Clinical trial evidence for the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in cardiovascular disease has provided conflicting results in hypertension, congestive heart failure, and ischemic heart disease. Clinical trial evidence to support combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease has largely been based on proteinuria reduction as a surrogate marker for clinically meaningful outcomes. Recent large-scale randomized clinical trials have not been able to validate protection in halting progression in chronic kidney disease with a dual blockade approach. This review serves as an appraisal on the clinical evidence of combination angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in both cardiovascular disease and chronic kidney disease.

Angiotensin receptor blockers: Focus on cardiac and renal injury.

Science.gov (United States)

Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Karuppagounder, Vengadeshprabhu; Krishnamurthy, Prasanna; Suzuki, Kenji; Nakamura, Masahiko; Watanabe, Kenichi

2016-04-01

Angiotensin II, an important component of renin angiotensin system, is a potent vasopressor and its actions are mostly mediated via angiotensin II type 1 receptor (AT1R) and role of AT2R in counterbalancing the actions of AT1R stimulation are under extensive research. In addition to its physiological actions, angiotensin II plays important roles in the pathogenesis of atherosclerosis, hypertension, left ventricular hypertrophy, and heart failure. The effects of angiotensin II can be blocked by either suppressing its production by blocking angiotensin converting enzyme or by antagonizing its actions on AT1R using angiotensin II receptor blockers (ARBs). Instead of the extensive use of ARBs in the treatment of various cardiovascular diseases, proper selection of a particular ARB is crucial as the clinical condition of individual patient is different and also their economic status would play an essential role in medication compliance. Thus a critical review of the proven and promising actions of ARBs against various pathological conditions will be of great importance for the clinicians as well as for the researchers. Copyright © 2016 Elsevier Inc. All rights reserved.

Imidazole derivatives as angiotensin II AT1 receptor blockers: Benchmarks, drug-like calculations and quantitative structure-activity relationships modeling

Science.gov (United States)

Alloui, Mebarka; Belaidi, Salah; Othmani, Hasna; Jaidane, Nejm-Eddine; Hochlaf, Majdi

2018-03-01

We performed benchmark studies on the molecular geometry, electron properties and vibrational analysis of imidazole using semi-empirical, density functional theory and post Hartree-Fock methods. These studies validated the use of AM1 for the treatment of larger systems. Then, we treated the structural, physical and chemical relationships for a series of imidazole derivatives acting as angiotensin II AT1 receptor blockers using AM1. QSAR studies were done for these imidazole derivatives using a combination of various physicochemical descriptors. A multiple linear regression procedure was used to design the relationships between molecular descriptor and the activity of imidazole derivatives. Results validate the derived QSAR model.

Current concepts in combination therapy for the treatment of hypertension: combined calcium channel blockers and RAAS inhibitors

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Alberto F Rubio-Guerra

2009-11-01

Full Text Available Alberto F Rubio-Guerra1, David Castro-Serna2, Cesar I Elizalde Barrera2, Luz M Ramos-Brizuela21Metabolic and Research Clinic, 2Internal Medicine Department, Hospital General de Ticomán SS DF, MéxicoAbstract: Recent guidelines for the management of hypertension recommend target blood pressures <140/90 mmHg in hypertensive patients, or <130/80 mmHg in subjects with diabetes, chronic kidney disease, or coronary artery disease. Despite the availability and efficacy of antihypertensive drugs, most hypertensive patients do not reach the recommended treatment targets with monotherapy, making combination therapy necessary to achieve the therapeutic goal. Combination therapy with 2 or more agents is the most effective method for achieving strict blood pressure goals. Fixed-dose combination simplifies treatment, reduces costs, and improves adherence. There are many drug choices for combination therapy, but few data are available about the efficacy and safety of some specific combinations. Combination therapy of calcium antagonists and inhibitors of the renin-angiotensin-aldosterone system (RAAS are efficacious and safe, and have been considered rational by both the JNC 7 and the 2007 European Society of Hypertension – European Society of Cardiology guidelines for the management of arterial hypertension. The aim of this review is to discuss some relevant issues about the use of combinations with calcium channel blockers and RAAS inhibitors in the treatment of hypertension.Keywords: hypertension, calcium channel blockers, renin-angiotensin-aldosterone system inhibitors, fixed-dose combination, adherence

Fracture risk in perimenopausal women treated with beta-blockers

DEFF Research Database (Denmark)

Rejnmark, Lars; Vestergaard, Peter; Kassem, M.

2004-01-01

beta2-Adrenergic receptors have been identified on human osteoblastic and osteoclastic cells, raising the question of a sympathetic regulation of bone metabolism. We investigated effects of treatment with beta-adrenergic receptor antagonists (beta-blockers) on bone turnover, bone mineral density...... (BMD), and fracture risk. Within the Danish Osteoporosis Prevention Study (DOPS) a population based, comprehensive cohort study of 2016 perimenopausal women, associations between treatment with beta-blockers and bone turnover and BMD were assessed in a cross-sectional design at the start of study....... Moreover, in a nested case-control design, fracture risk during the subsequent 5 years was assessed in relation to treatment with beta-blockers at baseline. Multiple regression- and logistic regression-analyses were performed. Treatment with beta-blockers was associated with a threefold increased fracture...

Feasibility and Association of Neurohumoral Blocker Up-titration After Cardiac Resynchronization Therapy.

Science.gov (United States)

Martens, Pieter; Verbrugge, Frederik H; Nijst, Petra; Bertrand, Philippe B; Dupont, Matthias; Tang, Wilson H; Mullens, Wilfried

2017-08-01

Cardiac resynchronization therapy (CRT) improves mortality and morbidity on top of optimal medical therapy in heart failure with reduced ejection fraction (HFrEF). This study aimed to elucidate the association between neurohumoral blocker up-titration after CRT implantation and clinical outcomes. Doses of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta-blockers were retrospectively evaluated in 650 consecutive CRT patients implanted from October 2008 to August 2015 and followed in a tertiary multidisciplinary CRT clinic. All 650 CRT patients were on a maximal tolerable dose of ACE-I/ARB and beta-blocker at the time of CRT implantation. However, further up-titration was successful in 45.4% for ACE-I/ARB and in 56.8% for beta-blocker after CRT-implantation. During a mean follow-up of 37 ± 22 months, a total of 139 events occurred for the combined end point of heart failure admission and all-cause mortality. Successful, versus unsuccessful, up-titration was associated with adjusted hazard ratios of 0.537 (95% confidence interval 0.316-0.913; P = .022) for ACE-I/ARB and 0.633 (0.406-0.988; P = .044) for beta-blocker on the combined end point heart failure admission and all-cause mortality. Patients in the up-titration group exhibited a similar risk for death or heart failure admission as patients treated with the maximal dose (ACE-I/ARB: P = .133; beta-blockers: P = .709). After CRT, a majority of patients are capable of tolerating higher dosages of neurohumoral blockers. Up-titration of neurohumoral blockers after CRT implantation is associated with improved clinical outcomes, similarly to patients treated with the guideline-recommended target dose at the time of CRT implantation. Copyright © 2017 Elsevier Inc. All rights reserved.

Transcranial Random Noise Stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive

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Leila eChaieb

2015-04-01

Full Text Available Background: Application of transcranial random noise stimulation (tRNS between 0.1 and 640 Hz of the primary motor cortex (M1 for 10 minutes induces a persistent excitability increase lasting for at least 60 minutes. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1mA for 10mins stimulation duration and a pharmacological agent (or sham on 8 healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency towards inhibiting MEPs 5-60 mins poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS.Conclusions: In contrast to transcranial direct current stimulation (tDCS, aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.

The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial

DEFF Research Database (Denmark)

Sandset, Else Charlotte; Bath, Philip M W; Boysen, Gudrun

2011-01-01

BACKGROUND: Raised blood pressure is common in acute stroke, and is associated with an increased risk of poor outcomes. We aimed to examine whether careful blood-pressure lowering treatment with the angiotensin-receptor blocker candesartan is beneficial in patients with acute stroke and raised bl...

Role of olmesartan in combination therapy in blood pressure control and vascular function

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Carlos M Ferrario

2010-08-01

Full Text Available Carlos M Ferrario, Ronald D SmithWake Forest University School of Medicine, Winston-Salem, North Carolina, USAAbstract: Angiotensin receptor blockers have emerged as a first-line therapy in the management of hypertension and hypertension-related comorbidities. Since national and international guidelines have stressed the need to control blood pressure to <140/90 mmHg in uncomplicated hypertension and <130/80 mmHg in those with associated comorbidities such as diabetes or chronic kidney disease, these goal blood pressures can only be achieved through combination therapy. Of several drugs that can be effectively combined to attain the recommended blood pressure goals, fixed-dose combinations of angiotensin receptor blockers and the calcium channel blocker amlodipine provide additive antihypertensive effects associated with a safe profile and increased adherence to therapy. In this article, we review the evidence regarding the beneficial effects of renin–angiotensin system blockade with olmesartan medoxomil and amlodipine in terms of blood pressure control and improvement of vascular function and target organ damage.Keywords: amlodipine, angiotensin receptor blockers, angiotensin-converting enzyme 2, hypertension, renin–angiotensin system

Beta-Blockers and Nitrates: Pharmacotherapy and Indications.

Science.gov (United States)

Facchini, Emanuela; Degiovanni, Anna; Cavallino, Chiara; Lupi, Alessandro; Rognoni, Andrea; Bongo, Angelo S

2015-01-01

Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina.

Angiotensin Receptor Blockers: Cardiovascular Protection in the Metabolic Syndrome

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Prakash C Deedwania

2006-03-01

Full Text Available It is well recognised that the metabolic syndrome, a constellation of risk factors including obesity, hypertension, insulin resistance and dyslipidaemia, is associated with an increased risk of cardiovascular complications and the development of Type 2 diabetes. Consequently, timely identification and management of all components of the metabolic syndrome is warranted. In particular, guidelines have emphasised the importance of targeting elevated blood pressure (BP and dyslipidaemia as a method of reducing global cardiovascular risk.Findings from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE trial show that the angiotensin receptor blocker, valsartan, reduces cardiovascular events and the development of Type 2 diabetes in high-risk individuals. This profile is being further explored in the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR trial.Given the potential advantages to patients and physicians of tackling more than one of the components of the metabolic syndrome, antihypertensive agents such as valsartan would appear to be an important addition to the management of vulnerable patients at high risk of cardiovascular events.

Severe iatrogenic bradycardia related to the combined use of beta-blocking agents and sodium channel blockers

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Kawabata M

2015-02-01

Full Text Available Mihoko Kawabata,1 Yasuhiro Yokoyama,1 Takeshi Sasaki,1 Susumu Tao,1 Kensuke Ihara,1 Yasuhiro Shirai,1 Tetsuo Sasano,2 Masahiko Goya,1 Tetsushi Furukawa,3 Mitsuaki Isobe,4 Kenzo Hirao1 1Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan; 2Department of Biofunctional Informatics, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 3Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; 4Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan Purpose: Drug-induced bradycardia is common during antiarrhythmic therapy; the major culprits are beta-blockers. However, whether other antiarrhythmic drugs are also a significant cause of this, alone or in combination with beta-blockers, is not well known. Methods: We retrospectively investigated the records of all patients hospitalized at our institution for drug-related bradycardia from the years 2004 to 2012. Patients with cardiac disease and electrolytic or hormonal abnormalities that could cause bradyarrhythmias were excluded. Results: Eight patients were identified (mean age, 79±5 years; range, 71–85 years; 6 women. Three patients were taking only beta-blockers (hereafter referred to as the BB group, while five patients were on both beta-blockers and Na channel blockers (hereafter referred to as the BB + Na group. Heart rates ranged from 20~49 beats/minute on arrival. The initial electrocardiogram showed sinus bradycardia (n=6 or sinus arrest with escape beats (n=2. QRS duration was 80–100 ms. The clinical presentation of the BB + Na group was considerably worse than that of the BB group, and included cardiogenic shock and heart failure. Four of the BB + Na patients had been on their medications for over 300 days. The BB group recovered solely with drug discontinuation, while 4 of the 5 patients in the BB + Na group needed additional

Analysis of hydrophobic interactions of antagonists with the beta2-adrenergic receptor.

Science.gov (United States)

Novoseletsky, V N; Pyrkov, T V; Efremov, R G

2010-01-01

The adrenergic receptors mediate a wide variety of physiological responses, including vasodilatation and vasoconstriction, heart rate modulation, and others. Beta-adrenergic antagonists ('beta-blockers') thus constitute a widely used class of drugs in cardiovascular medicine as well as in management of anxiety, migraine, and glaucoma. The importance of the hydrophobic effect has been evidenced for a wide range of beta-blocker properties. To better understand the role of the hydrophobic effect in recognition of beta-blockers by their receptor, we carried out a molecular docking study combined with an original approach to estimate receptor-ligand hydrophobic interactions. The proposed method is based on automatic detection of molecular fragments in ligands and the analysis of their interactions with receptors separately. A series of beta-blockers, based on phenylethanolamines and phenoxypropanolamines, were docked to the beta2-adrenoceptor binding site in the crystal structure. Hydrophobic complementarity between the ligand and the receptor was calculated using the PLATINUM web-server (http://model.nmr.ru/platinum). Based on the analysis of the hydrophobic match for molecular fragments of beta-blockers, we have developed a new scoring function which efficiently predicts dissociation constant (pKd) with strong correlations (r(2) approximately 0.8) with experimental data.

Ivabradine in combination with beta-blocker therapy for the treatment of stable angina pectoris in every day clinical practice.

Science.gov (United States)

Koester, Ralf; Kaehler, Jan; Ebelt, Henning; Soeffker, Gerold; Werdan, Karl; Meinertz, Thomas

2010-10-01

The anti-anginal efficacy of the selective I(f) inhibitor ivabradine has been demonstrated in controlled clinical trials. However, there is limited information about the safety and efficacy of a combined treatment of ivabradine with beta-blockers, particularly outside of clinical trials in every day practice. This analysis from the REDUCTION study evaluated the safety and efficacy of a combined therapy of beta-blockers and ivabradine in every day practice. In this multi-center study 4,954 patients with stable angina pectoris were treated with ivabradine in every day routine practice and underwent a clinical follow-up for 4 months. 344 of these patients received a co-medication with beta-blockers. Heart rate (HR), angina pectoris episodes, nitrate consumption, overall efficacy and tolerance were analyzed. After 4 months of treatment with ivabradine HR was reduced by 12.4 ± 11.6 bpm from 84.3 ± 14.6 to 72.0 ± 9.9 bpm, p every day practice.

Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-γ activation

International Nuclear Information System (INIS)

Moriuchi, Akie; Yamasaki, Hironori; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Fujishima, Keiichiro; Satoh, Tsuyoshi; Fukushima, Keiko; Fukushima, Tetsuya; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Abiru, Norio; Kawasaki, Eiji; Eguchi, Katsumi

2007-01-01

Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-γ

Cholinesterases: structure of the active site and mechanism of the effect of cholinergic receptor blockers on the rate of interaction with ligands

Energy Technology Data Exchange (ETDEWEB)

Antokhin, A M; Gainullina, E T; Taranchenko, V F [Federal State Agency ' 27 Scientific Centre of Ministry of Defence of the Russian Federation' (Russian Federation); Ryzhikov, S B; Yavaeva, D K [Department of Physics, M.V.Lomonosov Moscow State University (Russian Federation)

2010-10-19

Modern views on the structure of cholinesterase active sites and the mechanism of their interaction with organophosphorus inhibitors are considered. The attention is focused on the mechanism of the effect of cholinergic receptor blockers, acetylcholine antagonists, on the rate of interaction of acetylcholine esterase with organophosphorus inhibitors.

Cholinesterases: structure of the active site and mechanism of the effect of cholinergic receptor blockers on the rate of interaction with ligands

International Nuclear Information System (INIS)

Antokhin, A M; Gainullina, E T; Taranchenko, V F; Ryzhikov, S B; Yavaeva, D K

2010-01-01

Modern views on the structure of cholinesterase active sites and the mechanism of their interaction with organophosphorus inhibitors are considered. The attention is focused on the mechanism of the effect of cholinergic receptor blockers, acetylcholine antagonists, on the rate of interaction of acetylcholine esterase with organophosphorus inhibitors.

Association between spironolactone added to beta-blockers and ACE inhibition and survival in heart failure patients with reduced ejection fraction: a propensity score-matched cohort study.

Science.gov (United States)

Frankenstein, L; Katus, H A; Grundtvig, M; Hole, T; de Blois, J; Schellberg, D; Atar, D; Zugck, C; Agewall, S

2013-10-01

Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification. We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients' clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone. During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64-1.07; HR 1.03; 95 % CI 0.88-1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82-1.18). In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers.

Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial

DEFF Research Database (Denmark)

NN, NN; Yusuf, S; Teo, K

2008-01-01

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular...

Comparative effectiveness of recommended versus less intensive drug combinations in secondary prevention of acute coronary syndrome

NARCIS (Netherlands)

Bezin, Julien; Groenwold, Rolf; Ali, M Sanni; Lassalle, Régis; Robinson, Philip; de Boer, Anthonius; Moore, Nicholas; Klungel, Olaf H; Pariente, Antoine

2017-01-01

PURPOSE: The secondary prevention treatment for acute coronary syndrome (ACS) is based on the combined use of drugs from four therapeutic classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers). The objective of this study

Comparative effectiveness of recommended versus less intensive drug combinations in secondary prevention of acute coronary syndrome

NARCIS (Netherlands)

Bezin, Julien; Groenwold, Rolf H H; Ali, M. Sanni; Lassalle, Régis; Robinson, Philip; de Boer, A.; Moore, Nicholas; Klungel, Olaf H.; Pariente, Antoine

Purpose: The secondary prevention treatment for acute coronary syndrome (ACS) is based on the combined use of drugs from four therapeutic classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers). The objective of this study

Energy expenditure estimation in beta-blocker-medicated cardiac patients by combining heart rate and body movement data

NARCIS (Netherlands)

Kraal, Jos J.; Sartor, Francesco; Papini, Gabriele; Stut, Wim; Peek, Niels; Kemps, Hareld Mc; Bonomi, Alberto G.

2016-01-01

Accurate assessment of energy expenditure provides an opportunity to monitor physical activity during cardiac rehabilitation. However, the available assessment methods, based on the combination of heart rate (HR) and body movement data, are not applicable for patients using beta-blocker medication.

Olmesartan medoxomil combined with hydrochlorothiazide for the treatment of hypertension

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Mark Greathouse

2006-12-01

Full Text Available Mark GreathouseSouth Hills Cardiology Associates of Pittsburgh, Pittsburgh, PA, USAAbstract: In most patients with hypertension, especially Stage 2 hypertension, adequate control of blood pressure (BP is only achieved with combination drug therapy. When using combination therapy, antihypertensive agents with complementary mechanisms of action are recommended, for example, an angiotensin receptor blocker (ARB in combination with hydrochlorothiazide (HCTZ, a β-blocker + HCTZ, an ACE inhibitor + HCTZ, or a calcium channel blocker + an ACE inhibitor. One such combination is olmesartan medoxomil + HCTZ, which is available as fixed-dose, single-tablet combinations for once-daily administration. In clinical trials, olmesartan medoxomil/HCTZ reduced systolic BP (SBP and diastolic BP (DBP to a greater extent than either component as monotherapy. A clinical study in patients with Stage 1 or 2 hypertension showed that olmesartan medoxomil/HCTZ achieved a similar mean reduction in DBP, but a significantly greater mean reduction in SBP and higher rate of BP control (<140/90 mmHg than observed with losartan/HCTZ, at US/European-approved starting doses. In a non-inferiority trial, the antihypertensive efficacy of olmesartan medoxomil/HCTZ was comparable to that of atenolol/HCTZ. Furthermore, indirect comparisons have shown that olmesartan medoxomil/HCTZ compares favorably with other antihypertensive combination therapies, including other ARB/HCTZ combinations and amlodipine besylate/benazepril. Olmesartan medoxomil/HCTZ is generally well tolerated. In conclusion, olmesartan medoxomil/HCTZ is an effective and well-tolerated combination antihypertensive therapy that results in significant BP reductions and BP control in many patients. Keywords: olmesartan medoxomil, hydrochlorothiazide, angiotensin II receptor blocker, hypertension

Ramelteon combined with an α1-blocker decreases nocturia in men with benign prostatic hyperplasia.

Science.gov (United States)

Kawahara, Takashi; Morita, Satoshi; Ito, Hiroki; Terao, Hideyuki; Sakata, Ryoko; Ishiguro, Hitoshi; Tanaka, Katsuyuki; Miyamoto, Hiroshi; Matsuzaki, Junichi; Kubota, Yoshinobu; Uemura, Hiroji

2013-06-12

Nocturia is defined as waking one or more times during the night due to the urge to void. Recently, the effectiveness of several sedatives and analgesics for nocturia has been reported. We herein investigated the effects of ramelteon, an antioxidant and sleep inducer, on nocturia unresponsive to α1-blocker monotherapy in males with lower urinary tract symptoms (LUTS) as a pilot study. Subjects were 19 patients who had LUTS suggestive of benign prostate hyperplasia, received α1-blockers (tamsulosin, silodosin, or naftopidil), and continued to have two or more episodes of nocturia per night before starting ramelteon. Ramelteon at 8 mg once daily for one month was added to the α1-blocker. A self-administered questionnaire including the International Prostate Symptom Score (IPSS), quality of life (QoL) index, Overactive Bladder Symptom Score (OABSS), and Nocturia Quality-of-Life Questionnaire (N-QOL) were assessed before and one month after starting ramelteon. The mean score on IPSS question 7 (nocturia) decreased significantly from 2.88 before starting ramelteon to 2.41 one month after starting the medication (P = 0.03). The mean total OABSS decreased significantly from 6.31 to 5.38 (P = 0.03), and the mean for OABSS question 2 (nighttime frequency of nocturia) also significantly decreased from 2.63 to 2.13 (P = 0.01). The mean total N-QOL score did not change significantly. Two patients had dizziness; the remaining patients had no adverse drug-related events. Ramelteon in combination with an α1-blocker could be a treatment option for reducing nocturia in men with BPH.

The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

International Nuclear Information System (INIS)

Ribeiro, Mariana P.C.; Nunes-Correia, Isabel; Santos, Armanda E.; Custódio, José B.A.

2014-01-01

Recent reports suggest that N-methyl-D-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination. - Highlights: • MK-801 and memantine decrease melanoma cell proliferation. • The combination of MK-801 with antiestrogens inhibits melanoma cell proliferation. • These combinations greatly enhance the effects of the compounds individually. • MK-801 combined with tamoxifen active metabolites induces cell cycle arrest in G1. • The combination of MK-801 and antiestrogens is an innovative strategy for melanoma

Rational design, efficient syntheses and biological evaluation of N,N '-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Czech Academy of Sciences Publication Activity Database

Agelis, G.; Resvani, A.; Koukoulitsa, C.; Tůmová, Tereza; Slaninová, Jiřina; Kalavrizioti, D.; Spyridaki, K.; Afantitis, A.; Melagraki, G.; Siafaka, A.; Gkini, E.; Megariotis, G.; Grdadolnik, S. G.; Papadopoulos, M. G.; Vlahakos, D.; Maragoudakis, M.; Liapakis, G.; Mavromoustakos, T.; Matsoukas, J.

2013-01-01

Roč. 62, Apr (2013), s. 352-370 ISSN 0223-5234 Institutional support: RVO:61388963 Keywords : AT1 receptor blockers * N,N '-Bis-alkylated butylimidazole analogs * synthesis * Wittig reaction * hydroxymethylation * structure elucidation Subject RIV: CC - Organic Chemistry Impact factor: 3.432, year: 2013

Combination of behaviorally sub-effective doses of glutamate NMDA and dopamine D1 receptor antagonists impairs executive function.

Science.gov (United States)

Desai, Sagar J; Allman, Brian L; Rajakumar, Nagalingam

2017-04-14

Impairment of executive function is a core feature of schizophrenia. Preclinical studies indicate that injections of either N-methyl d-aspartate (NMDA) or dopamine D 1 receptor blockers impair executive function. Despite the prevailing notion based on postmortem findings in schizophrenia that cortical areas have marked suppression of glutamate and dopamine, recent in vivo imaging studies suggest that abnormalities of these neurotransmitters in living patients may be quite subtle. Thus, we hypothesized that modest impairments in both glutamate and dopamine function can act synergistically to cause executive dysfunction. In the present study, we investigated the effect of combined administration of "behaviorally sub-effective" doses of NMDA and dopamine D 1 receptor antagonists on executive function. An operant conditioning-based set-shifting task was used to assess behavioral flexibility in rats that were systemically injected with NMDA and dopamine D 1 receptor antagonists individually or in combination prior to task performance. Separate injections of the NMDA receptor antagonist, MK-801, and the dopamine D 1 receptor antagonist, SCH 23390, at low doses did not impair set-shifting; however, the combined administration of these same behaviorally sub-effective doses of the antagonists significantly impaired the performance during set-shifting without affecting learning, retrieval of the memory of the initial rule, latency of responses or the number of omissions. The combined treatment also produced an increased number of perseverative errors. Our results indicate that NMDA and D 1 receptor blockade act synergistically to cause behavioral inflexibility, and as such, subtle abnormalities in glutamatergic and dopaminergic systems may act cooperatively to cause deficits in executive function. Copyright © 2017 Elsevier B.V. All rights reserved.

H2 blockers

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Peptic ulcer disease - H2 blockers; PUD - H2 blockers; Gastroesophageal reflux - H2 blockers; GERD - H2 blockers ... H2 blockers are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

A low-dose β1-blocker in combination with milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum.

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Shigeki Kobayashi

Full Text Available OBJECTIVES: The purpose of this study was to investigate whether adding a low-dose β1-blocker to milrinone improves cardiac function in failing cardiomyocytes and the underlying cardioprotective mechanism. BACKGROUND: The molecular mechanism underlying how the combination of low-dose β1-blocker and milrinone affects intracellular Ca(2+ handling in heart failure remains unclear. METHODS: We investigated the effect of milrinone plus landiolol on intracellular Ca(2+ transient (CaT, cell shortening (CS, the frequency of diastolic Ca(2+ sparks (CaSF, and sarcoplasmic reticulum Ca(2+ concentration ({Ca(2+}SR in normal and failing canine cardiomyocytes and used immunoblotting to determine the phosphorylation level of ryanodine receptor (RyR2 and phospholamban (PLB. RESULTS: In failing cardiomyocytes, CaSF significantly increased, and peak CaT and CS markedly decreased compared with normal myocytes. Administration of milrinone alone slightly increased peak CaT and CS, while CaSF greatly increased with a slight increase in {Ca(2+}SR. Co-administration of β1-blocker landiolol to failing cardiomyocytes at a dose that does not inhibit cardiomyocyte function significantly decreased CaSF with a further increase in {Ca(2+}SR, and peak CaT and CS improved compared with milrinone alone. Landiolol suppressed the hyperphosphorylation of RyR2 (Ser2808 in failing cardiomyocytes but had no effect on levels of phosphorylated PLB (Ser16 and Thr17. Low-dose landiolol significantly inhibited the alternans of CaT and CS under a fixed pacing rate (0.5 Hz in failing cardiomyocytes. CONCLUSION: A low-dose β1-blocker in combination with milrinone improved cardiac function in failing cardiomyocytes, apparently by inhibiting the phosphorylation of RyR2, not PLB, and subsequent diastolic Ca(2+ leak.

A low-dose β1-blocker in combination with milrinone improves intracellular Ca2+ handling in failing cardiomyocytes by inhibition of milrinone-induced diastolic Ca2+ leakage from the sarcoplasmic reticulum.

Science.gov (United States)

Kobayashi, Shigeki; Susa, Takehisa; Ishiguchi, Hironori; Myoren, Takeki; Murakami, Wakako; Kato, Takayoshi; Fukuda, Masakazu; Hino, Akihiro; Suetomi, Takeshi; Ono, Makoto; Uchinoumi, Hitoshi; Tateishi, Hiroki; Mochizuki, Mamoru; Oda, Tetsuro; Okuda, Shinichi; Doi, Masahiro; Yamamoto, Takeshi; Yano, Masafumi

2015-01-01

The purpose of this study was to investigate whether adding a low-dose β1-blocker to milrinone improves cardiac function in failing cardiomyocytes and the underlying cardioprotective mechanism. The molecular mechanism underlying how the combination of low-dose β1-blocker and milrinone affects intracellular Ca(2+) handling in heart failure remains unclear. We investigated the effect of milrinone plus landiolol on intracellular Ca(2+) transient (CaT), cell shortening (CS), the frequency of diastolic Ca(2+) sparks (CaSF), and sarcoplasmic reticulum Ca(2+) concentration ({Ca(2+)}SR) in normal and failing canine cardiomyocytes and used immunoblotting to determine the phosphorylation level of ryanodine receptor (RyR2) and phospholamban (PLB). In failing cardiomyocytes, CaSF significantly increased, and peak CaT and CS markedly decreased compared with normal myocytes. Administration of milrinone alone slightly increased peak CaT and CS, while CaSF greatly increased with a slight increase in {Ca(2+)}SR. Co-administration of β1-blocker landiolol to failing cardiomyocytes at a dose that does not inhibit cardiomyocyte function significantly decreased CaSF with a further increase in {Ca(2+)}SR, and peak CaT and CS improved compared with milrinone alone. Landiolol suppressed the hyperphosphorylation of RyR2 (Ser2808) in failing cardiomyocytes but had no effect on levels of phosphorylated PLB (Ser16 and Thr17). Low-dose landiolol significantly inhibited the alternans of CaT and CS under a fixed pacing rate (0.5 Hz) in failing cardiomyocytes. A low-dose β1-blocker in combination with milrinone improved cardiac function in failing cardiomyocytes, apparently by inhibiting the phosphorylation of RyR2, not PLB, and subsequent diastolic Ca(2+) leak.

Beta-blockers in cirrhosis and refractory ascites

DEFF Research Database (Denmark)

Kimer, Nina; Feineis, Martin; Møller, Søren

2015-01-01

OBJECTIVE: It is currently discussed if beta-blockers exert harmful effects and increase mortality in patients with cirrhosis and refractory ascites. In this study, we provide an overview of the available literature in this field in combination with a retrospective analysis of 61 patients...... trials (9 trials on propranolol, 1 case-control study and 4 retrospective analyses) were identified. One trial suggested an increased mortality in patients treated with beta-blockers and refractory ascites. The results of the remaining trials were inconclusive. No increase in mortality among beta-blocker......-treated patients was found in the present retrospective analysis. CONCLUSIONS: Treatment with beta-blockers may increase mortality in patients with cirrhosis and refractory ascites. However, the current evidence is sparse and high-quality studies are warranted to clarify the matter....

Current role of beta-blockers in the treatment of hypertension.

Science.gov (United States)

Aronow, Wilbert S

2010-11-01

It is important to know which patients with hypertension will benefit from beta-blocker therapy and which beta-blockers should be used in the treatment of hypertension to reduce cardiovascular events and mortality. Studies between 1981 and 2009 using a Medline search are reported. Beta-blockers should be used to treat hypertension in patients with previous myocardial infarction, acute coronary syndromes, angina pectoris, congestive heart failure, ventricular arrhythmias, supraventricular tachyarrhythmias, diabetes mellitus, after coronary artery bypass graft surgery, and in patients who are pregnant, have thyrotoxicosis, glaucoma, migraine, essential tremor, perioperative hypertension, or an excessive blood pressure response after exercise. The use of beta-blockers as first-line therapy in patients with primary hypertension has been controversial. However, the 2009 guidelines of the European Society of Hypertension state that large-scale meta-analyses of available data confirm that diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and calcium channel blockers do not significantly differ in their ability to lower blood pressure and to exert cardiovascular protection both in elderly and in younger patients. The key message of this paper is that atenolol should not be used as an antihypertensive drug and that the degree of reduction of mortality, myocardial infarction, stroke and congestive heart failure by antihypertensive therapy is dependent on the degree of lowering of aortic blood pressure. Newer vasodilator beta-blockers such as carvedilol and nebivolol may be more effective in reducing cardiovascular events than traditional beta-blockers, but this needs to be investigated by controlled clinical trials.

Correlations of plasma renin activity and aldosterone concentration with ambulatory blood pressure responses to nebivolol and valsartan, alone and in combination, in hypertension.

Science.gov (United States)

Giles, Thomas D; Bakris, George; Oparil, Suzanne; Weber, Michael A; Li, Huiling; Mallick, Madhuja; Bharucha, David B; Chen, ChunLin; Ferguson, William G

2015-11-01

After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%-73%) and decreased with nebivolol (51%-65%) and the combination treatment (17%-39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%-22%; nebivolol, 20%-26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P valsartan. Baseline ln(aldosterone) correlated with 24-hour systolic and diastolic BP reductions following combination treatment only (P < .001 and P = .005). The implications of the renin-angiotensin-aldosterone system effects of this beta blocker-angiotensin receptor blocker combination should be explored further. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Management of hypertension: Insights into prescribing behavior with focus on angiotensin receptor blockers

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S Ramakrishnan

2017-01-01

Full Text Available Introduction: Angiotensin receptor blockers (ARBs are emerging as an attractive first choice antihypertensive as recommended by various guidelines. However, choice among the first-line antihypertensive classes and among ARBs differs between practicing physicians. Aims: This survey aimed to understand the usage preferences of ARBs and its place in for treating hypertension (HTN among physicians from various clinical settings in India. Methods: A cross-sectional survey was conducted with a prevalidated survey questionnaire consisting of 25 questions for HTN management. Practicing general physicians and cardiologists were approached for seeking their perception, opinions, and prescribing behavior. Results: Responses of 594 physicians and cardiologists were received. As opined by 90.1% of physicians, newly diagnosed HTN represented more than 10% of their overall patient load. As a monotherapy, 59.9% of the physicians preferred ARB as the first choice in newly diagnosed HTN patients, followed by calcium channel blocker (12.3% and angiotensin-converting-enzyme inhibitor (8.1%. Of all ARBs, telmisartan is preferred by 73% of physicians. Most physicians prefer telmisartan among all ARBs for 24 h blood pressure (BP control, including morning BP surge (76.4% and for prevention of cardiovascular morbidity and mortality (78.8% followed by olmesartan and losartan. Predominantly, majority of physicians (89.1% agreed for the beneficial role of telmisartan in preventing onset of microalbuminuria and nephropathy. Conclusion: Indian physicians prefer ARBs as the first choice in most hypertensive patients, which shows agreement with the guideline recommendations followed globally. Telmisartan has emerged as the most preferred ARB among all, for most of the HTN patients including those with comorbidities.

Beta-blockers

DEFF Research Database (Denmark)

Arboe, Bente; Ulrik, Charlotte Suppli

2013-01-01

Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.......Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma....

Formulary considerations in selection of beta-blockers.

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Yedinak, K C

1993-08-01

Selection of beta-adrenergic blockers for formulary addition can be a difficult task, especially with the increasing availability of new beta-blockers, as well as the numerous differences in pharmacodynamic and pharmacokinetic properties of currently available agents. Nevertheless, appropriate evaluation of the important characteristics of beta-blockers should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in efficacy, product formulation and cost should be carefully considered when making formulary decisions. Notably, evidence from clinical trials indicates differences in efficacy among beta-blockers for post-myocardial infarction prophylaxis, situational anxiety, essential tremor, thyrotoxicosis, migraine prophylaxis and prevention of bleeding associated with oesophageal varices. For many clinical situations, it is also important to select an effective agent that is available in both an oral and intravenous formulation, especially for cardioprotection after acute myocardial infarction and for use in supraventricular arrhythmias. In addition, availability of sustained release products and generic formulations should be considered for their potential to increase compliance and decrease cost, respectively. Comparative drug costs, as well as costs associated with decreased compliance, should also be carefully evaluated. Differences in beta-receptor selectivity, duration of action and presence of intrinsic sympathomimetic activity (ISA) are also important considerations in the selection of beta-blockers for formulary consideration. Although degree of selectivity is relative, beta 1-selective agents may be less likely to induce bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and may be less likely to affect glucose homeostasis in patients with diabetes mellitus. Duration of action of a beta-blocker is an important consideration for evaluation of efficacy throughout the recommended

Effects of gap junction blockers on human neocortical synchronization.

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Gigout, S; Louvel, J; Kawasaki, H; D'Antuono, M; Armand, V; Kurcewicz, I; Olivier, A; Laschet, J; Turak, B; Devaux, B; Pumain, R; Avoli, M

2006-06-01

Field potentials and intracellular recordings were obtained from human neocortical slices to study the role of gap junctions (GJ) in neuronal network synchronization. First, we examined the effects of GJ blockers (i.e., carbenoxolone, octanol, quinine, and quinidine) on the spontaneous synchronous events (duration = 0.2-1.1 s; intervals of occurrence = 3-27 s) generated by neocortical slices obtained from temporal lobe epileptic patients during application of 4-aminopyridine (4AP, 50 muM) and glutamatergic receptor antagonists. The synchronicity of these potentials (recorded at distances up to 5 mm) was decreased by GJ blockers within 20 min of application, while prolonged GJ blockers treatment at higher doses made them disappear with different time courses. Second, we found that slices from patients with focal cortical dysplasia (FCD) could generate in normal medium spontaneous synchronous discharges (duration = 0.4-8 s; intervals of occurrence = 0.5-90 s) that were (i) abolished by NMDA receptor antagonists and (ii) slowed down by carbenoxolone. Finally, octanol or carbenoxolone blocked 4AP-induced ictal-like discharges (duration = up to 35 s) in FCD slices. These data indicate that GJ play a role in synchronizing human neocortical networks and may implement epileptiform activity in FCD.

SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease.

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Zou, Honghong; Zhou, Baoqin; Xu, Gaosi

2017-05-16

Diabetic kidney disease (DKD) is the most common cause of end stage renal disease. The comprehensive management of DKD depends on combined target-therapies for hyperglycemia, hypertension, albuminuria, and hyperlipaemia, etc. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, the most recently developed oral hypoglycemic agents acted on renal proximal tubules, suppress glucose reabsorption and increase urinary glucose excretion. Besides improvements in glycemic control, they presented excellent performances in direct renoprotective effects and the cardiovascular (CV) safety by decreasing albuminuria and the independent CV risk factors such as body weight and blood pressure, etc. Simultaneous use of SGLT-2 inhibitors and renin-angiotensin-aldosterone system (RAAS) blockers are novel strategies to slow the progression of DKD via reducing inflammatory and fibrotic markers induced by hyperglycaemia more than either drug alone. The available population and animal based studies have described SGLT2 inhibitors plus RAAS blockers. The present review was to systematically review the potential renal benefits of SGLT2 inhibitors combined with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, mineralocorticoid receptor antagonists, and especially the angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.

Degarelix: A Novel Gonadotropin-Releasing Hormone (GnRH) Receptor Blocker-Results from a 1-yr, Multicentre, Randomised, Phase 2 Dosage-Finding Study in the Treatment of Prostate Cancer

NARCIS (Netherlands)

van Poppel, Hendrik; Tombal, Bertrand; de la Rosette, Jean J.; Persson, Bo-Eric; Jensen, Jens-Kristian; Kold Olesen, Tine

2008-01-01

Background: Degarelix is a gonadotropin-releasing hormone antagonist (GnRH receptor blocker) with immediate onset of action, suppressing gonadotropins, testosterone, and prostate-specific antigen (PSA) in prostate cancer. Objective: To determine the efficacy and safety of initial doses of 200 mg or

[Influence of ET-1 and ETA receptor blocker (BQ123) on the level of TNF-α in the brain rat].

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Gorąca, Anna; Skibska, Beata

2016-06-01

Endothelin 1 (ET-1) in addition to the vasoconstriction, also has mitogenic, proinflammatory and proagregation activities. The mediators of inflammatory responses are cytokines, including special role attributed to tumor necrosis factor (TNF-α). The aim of this study was to evaluate the effect of ET-1 and its receptor blocker (BQ123) on the level of TNF-α in the brain rat. Experiments were performed on four groups of Wistar-Kyoto rats. Animals were divided into four groups of 8 rats. Group I - control was administered into the tail vein solution of 0.9 % NaCl. Group II - saline followed by ET-1 (3 μg/kg b.w.). Group III - saline followed by BQ123 (1 mg/kg b.w.). Group IV (BQ123/ET-1) - BQ123 (1 mg/kg b.w.) administered 30 min before ET-1 (3 μg/kg b.w.). Administration of ET-1 at doses of 3 μg/kg b.w. resulted in a statistically significant increase in TNF-α concentrations in brain homogenates compared to the control group (pET(A) receptor blocker - BQ123 (1mg/kg b.w.) 30 min before administration of ET-1 significantly decreased in TNF-α concentrations in brain homogenates (p ET-1 is significantly increased in TNF-α levels in brain homogenates, while BQ123 given 30 min before administration of ET-1 caused a significant decrease in TNF-α levels, suggesting that its anti-inflammatory activity. © 2016 MEDPRESS.

Angiotensin Converting-Enzyme Inhibitors, Angiotensin Receptor Blockers, and Calcium Channel Blockers Are Associated with Prolonged Vascular Access Patency in Uremic Patients Undergoing Hemodialysis.

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Fu-An Chen

Full Text Available Vascular access failure is a huge burden for patients undergoing hemodialysis. Many efforts have been made to maintain vascular access patency, including pharmacotherapy. Angiotensin converting enzyme inhibitor (ACE-I, angiotensin receptor blocker (ARB, and calcium channel blocker (CCB are known for their antihypertensive and cardio-protective effects, however, their effects on long-term vascular access patency are still inconclusive.We retrospectively enrolled patients commencing maintenance hemodialysis between January 1, 2000, and December 31, 2006 by using National Health Insurance Research Database in Taiwan. Primary patency was defined as the date of first arteriovenous fistula (AVF or arteriovenous graft (AVG creation to the time of access thrombosis or any intervention aimed to maintain or re-establish vascular access patency. Cox proportional hazards models were used to adjust the influences of patient characteristics, co-morbidities and medications.Total 42244 patients were enrolled in this study, 37771 (89.4% used AVF, 4473 (10.6% used AVG as their first long term dialysis access. ACE-I, ARB, and CCB use were all associated with prolonged primary patency of AVF [hazard ratio (HR 0.586, 95% confidence interval (CI 0.557-0.616 for ACE-I use; HR 0.532, CI 0.508-0.556 for ARB use; HR 0.485, CI 0.470-0.501 for CCB use] and AVG (HR 0.557, CI 0.482-0.643 for ACE-I use, HR 0.536, CI 0.467-0.614 for ARB use, HR 0.482, CI 0.442-0.526 for CCB use.In our analysis, ACE-I, ARB, and CCB were strongly associated with prolonged primary patency of both AVF and AVG. Further prospective randomized studies are still warranted to prove the causality.

Amlodipine and valsartan as components of a rational and effective fixed-dose combination

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Bernard Waeber

2009-03-01

Full Text Available Bernard Waeber1, Luis M Ruilope21Division of Clinical Pathophysiology, University Hospital, Faculty of Biology and Medicine, University of Lausanne, Switzerland; 2Hypertension Unit, Hospital 12 de Octubre, Madrid, SpainAbstract: Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists and blockers of the renin-angiotensin system are widely used today to initiate antihypertensive therapy but, when given as monotherapy, do not suffice in most patients to normalize blood pressure. Combining the two types of agents considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. This is exemplified by the experience accumulated with the recently developed fixed dose combination containing the AT1-receptor blocker valsartan (160 mg and the dihydropyridine amlodipine (5 or 10 mg. In a randomized trial, an 8-week treatment normalized blood pressure (<140/90 mmHg within 8 weeks in a large fraction of hypertensive patients (78.4% and 85.2% using the 5/160 [n = 371] and 10/160 mg [n = 377] dosage, respectively. Like all AT1-receptor blockers valsartan has a placebo-like tolerability. Valsartan prevents to a large extent the occurrence amlodipine-induced peripheral edema. Both amlodipine and valsartan have beneficial effects on cardiovascular morbidity and mortality, as well as protective effects on renal function. The co-administration of these two agents is therefore very attractive, as it enables a rapid and sustained blood pressure control in hypertensive patients. The availability of a fixed-dose combination based on amlodipine and valsartan is expected therefore to facilitate the management of hypertension, to improve long-term adherence with antihypertensive therapy and, ultimately, to have a positive impact on cardiovascular and renal outcomes.Keywords: antihypertensive therapy, fixed-dose combination, calcium antagonists

The discovery of new potent non-peptide Angiotensin II AT1 receptor blockers: A concise synthesis, molecular docking studies and biological evaluation of N-substituted 5-butylimidazole derivatives

Czech Academy of Sciences Publication Activity Database

Agelis, G.; Resvani, A.; Durdagi, S.; Spyridaki, K.; Tůmová, Tereza; Slaninová, Jiřina; Giannopoulos, P.; Vlahakos, D.; Liapakis, G.; Mavromoustakos, T.; Matsoukas, J.

2012-01-01

Roč. 55, Sep (2012), s. 358-374 ISSN 0223-5234 Institutional research plan: CEZ:AV0Z40550506 Keywords : synthesis * angiotensin II receptor blockers * N-substituted 5-butylimidazole derivatives * antihypertensive activity * molecular docking Subject RIV: CC - Organic Chemistry Impact factor: 3.499, year: 2012

Beta blockers and chronic heart failure patients: prognostic impact of a dose targeted beta blocker therapy vs. heart rate targeted strategy.

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Corletto, Anna; Fröhlich, Hanna; Täger, Tobias; Hochadel, Matthias; Zahn, Ralf; Kilkowski, Caroline; Winkler, Ralph; Senges, Jochen; Katus, Hugo A; Frankenstein, Lutz

2018-05-17

Beta blockers improve survival in patients with chronic systolic heart failure (CHF). Whether physicians should aim for target dose, target heart rate (HR), or both is still under debate. We identified 1,669 patients with systolic CHF due to ischemic heart disease or idiopathic dilated cardiomyopathy from the University Hospital Heidelberg and the Clinic of Ludwigshafen, Germany. All patients were treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker and had a history of CHF known for at least 6 months. Target dose was defined as treatment with ≥ 95% of the respective published guideline-recommended dose. Target HR was defined as 51-69 bpm. All-cause mortality during the median follow-up of 42.8 months was analysed with respect to beta blocker dosing and resting HR. 201 (12%) patients met the dose target (group A), 285 (17.1%) met the HR target (group B), 627 (37.6%) met no target (group C), and 556 (33.3%) did not receive beta blockers (Group D). 5-year mortality was 23.7, 22.7, 37.6, and 55.6% for group A, B, C, and D, respectively (p <  0.001). Survival for group A patients with a HR ≥ 70 bpm was 28.8% but 14.8% if HR was 50-70 bpm (p = 0.054). Achieving guidelines recommended beta blocker dose or to HR control has a similar positive impact on survival. When on target dose, supplemental HR control additionally improves survival.

The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers

DEFF Research Database (Denmark)

Smink, P A; Miao, Y; Eijkemans, M J C

2014-01-01

Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes.......98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use...

Pharmacogenetics of β-Blockers

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Shin, Jaekyu; Johnson, Julie A.

2009-01-01

β-Blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a β-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to β-blockers. This review summarizes the pharmacogenetic data for β-blockers in patients with various diseases and discusses the potential implications of β-blocker pharmacogenetics in clinical practice. PMID:17542770

Alpha Blockers

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... quickly, but their effects last only a few hours. Long-acting medications take longer to work, but their effects last longer. Which alpha blocker is best for you depends on your health and the condition being treated. Alpha blockers are ...

A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients.

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Yang, Yue; Wei, Ri-bao; Xing, Yue; Tang, Lu; Zheng, Xiao-yong; Wang, Zi-cheng; Gao, Yu-wei; Li, Min-xia; Chen, Xiang-mei

2013-12-01

This study compared the efficacy of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) in the effect of insulin resistance (IR) as assessed using the homeostasis model assessment of insulin resistance (HOMA-IR) in non-diabetic patients. The MEDLINE, EMBASE, and Cochrane Library databases were searched to identify studies published before December 2012 that investigated the use of ARBs and CCBs to determine the effect on the HOMA-IR index in non-diabetics. Parameters on IR and blood pressure were collected. Review Manager 5.2 and Stata 12.0 were used to perform the meta-analysis. Fixed and random effects models were applied to various aspects of the meta-analysis, which assessed the therapeutic effects of the two types of drug using the HOMA-IR index in non-diabetic patients. The meta-analysis included five clinical trials. Patient comparisons before and after treatment with ARBs and CCBs revealed that ARBs reduced the HOMA-IR index (weighted mean difference (WMD) -0.65, 95% confidence interval (CI) -0.93 to -0.38) and fasting plasma insulin (FPI) (WMD -2.01, 95% CI -3.27 to -0.74) significantly more than CCBs. No significant differences in the therapeutic effects of these two types of drug on blood pressure were observed. Given that there are no significant differences in the therapeutic effects of ARBs and CCBs on blood pressure, as ARBs are superior to CCBs in their effect on the HOMA-IR index in non-diabetics, they might be a better choice in hypertension patients without diabetes. © 2013.

Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

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Nishida Yayoi

2012-05-01

Full Text Available Abstract Background Both angiotensin II type I receptor blockers (ARBs and calcium channel blockers (CCBs are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601 and propensity-score matched new CCB users (n = 601, with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG, total cholesterol (TC, non-fasting blood glucose, hemoglobin A1c (HbA1c, sodium, potassium, creatinine, alanine aminotransferase (ALT, aspartate aminotransferase (AST, gamma-glutamyltransferase (GGT, hemoglobin and hematocrit, and white blood cell (WBC, red blood cell (RBC and platelet (PLT counts up to 12 months after the start of ARB or CCB monotherapy. Results We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions Our study suggested that hematological adverse effects and

Circadian rhythm of urinary potassium excretion during treatment with an angiotensin receptor blocker.

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Ogiyama, Yoshiaki; Miura, Toshiyuki; Watanabe, Shuichi; Fuwa, Daisuke; Tomonari, Tatsuya; Ota, Keisuke; Kato, Yoko; Ichikawa, Tadashi; Shirasawa, Yuichi; Ito, Akinori; Yoshida, Atsuhiro; Fukuda, Michio; Kimura, Genjiro

2014-12-01

We have reported that the circadian rhythm of urinary potassium excretion (U(K)V) is determined by the rhythm of urinary sodium excretion (U(Na)V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U(Na)V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U(K)V during ARB treatment has not been reported. Circadian rhythms of U(Na)V and U(K)V were examined in 44 patients with CKD undergoing treatment with ARB. Whole-day U(Na)V was not altered by ARB whereas whole-day U(K)V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U(Na)V and U(K)V (r=0.56, pcircadian rhythm of U(K)V was determined by the rhythm of UNaV even during ARB treatment. Changes in the circadian U(K)V rhythm were not determined by aldosterone but by U(Na)V. © The Author(s) 2013.

Prospective direct comparison of antihypertensive effect and safety between high-dose amlodipine or indapamide in hypertensive patients uncontrolled by standard doses of angiotensin receptor blockers and amlodipine.

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Okamura, Keisuke; Shirai, Kazuyuki; Totake, Nao; Okuda, Tetsu; Urata, Hidenori

2018-01-01

When hypertension is uncontrolled by routine treatment with an angiotensin II receptor blocker (ARB) and the calcium channel blocker amlodipine (5 mg), the dose of amlodipine can be increased or a diuretic can be added. We investigated the more effective option in a prospective multicenter open-label study. Hypertensive patients were recruited if the target blood pressure (BP) in The Japanese Society of Hypertension 2009 guideline could not be achieved with standard-dose ARB therapy and amlodipine (5 mg). Patients were divided into three groups. Group-1 was switched to a combination of irbesartan (100 mg) and amlodipine (10 mg). Group-2A was changed to a combination of irbesartan (100 mg), amlodipine (5 mg), and indapamide, while Group-2B received a standard-dose ARB and amlodipine (5 mg) plus indapamide. Patients were assigned by their attending physicians and were followed for 6 months. The primary endpoint was the antihypertensive effect of each regimen. Group-1 contained 85 patients, Group-2A had 49 patients, and Group-2B had 4 patients. We only analyzed Group-1 and Group-2A due to the small size of Group-2B. In both groups, systolic BP and diastolic BP were significantly decreased up to 6 months (all p < 0.001). Reduction of systolic BP was greater in Group-1 than Group-2A after 1 month and 6 months (both p < 0.05). Uric acid was increased in Group-2A after 3 months, but not at 6 months. Although both regimens were effective for reducing BP, increasing amlodipine to 10 mg daily controlled hypertension without elevation of serum uric acid.

A retrospective study of treatment persistence and adherence to α-blocker plus antimuscarinic combination therapies, in men with LUTS/BPH in the Netherlands.

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Drake, Marcus J; Bowditch, Sally; Arbe, Emilio; Hakimi, Zalmai; Guelfucci, Florent; Amri, Ikbel; Nazir, Jameel

2017-05-22

To assess treatment persistence and adherence in men ≥45 years of age with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), using prescription records from the Netherlands IMS Lifelink™ LRx database. In this retrospective, observational cohort study, we identified men who received combination therapy with an α-blocker plus an antimuscarinic (e.g. solifenacin or tolterodine) between 1 November 2013 and 31 October 2014. Treatment could be received as a fixed-dose combination (FDC) tablet or as two drugs administered together (concomitant therapy), if both combination drugs were prescribed within 30 days. The primary objective was to assess treatment persistence, defined as the time from initiation of combination therapy until first discontinuation of the FDC or at least one of the drugs given concomitantly (i.e. ≥30 days without prescription renewal). Subgroup and sensitivity analyses were conducted to assess persistence by antimuscarinic agent, and with different gap lengths used to define discontinuation (45, 60 and 90 days), respectively. A total of 1891 men received an α-blocker plus an antimuscarinic (FDC, N = 665; concomitant therapy, N = 1226). Median time to discontinuation was significantly longer with FDC versus concomitant therapy (414 vs. 112 days; adjusted hazard ratio [HR] 2.04, 95% confidence interval 1.77, 2.35; p BPH treated with α-blocker plus antimuscarinic combination therapy in the Netherlands showed that treatment persistence was significantly greater in those who received a FDC tablet compared with combination therapy given concomitantly. The study also shows that treatment persistence was extended in men who received combination therapy containing solifenacin compared with other antimuscarinics. Overall, these findings may be useful for prescribers, as improved persistence on-treatment may translate into improved outcomes for men with LUTS/BPH. Further study is warranted to establish the key

Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

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Lee Robert E

2006-01-01

Full Text Available Abstract Background There have been indications that common Angiotensin Receptor Blockers (ARBs may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone and the Parathyroid Hormone (PTH. Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma, which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b, which recruits monocytes to the site of inflammatory immune challenge. Results Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki≈10 nmol are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki≈30 nmol and Losartan (Ki≈70 nmol may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki≈0.3 nmol, while Losartan (Ki≈3 nmol, Irbesartan (Ki≈6 nmol, Olmesartan and Valsartan (Ki≈12 nmol also seem likely to have significant PPAR modulatory activity. Olmesartan andIrbesartan (Ki≈9 nmol additionally act as antagonists of a theoretical modelof CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the AngiotensinII Type1 receptor (AT2R1 has been presented. Conclusion Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the

Influence of beta blockers on survival in dogs with severe subaortic stenosis.

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Eason, B D; Fine, D M; Leeder, D; Stauthammer, C; Lamb, K; Tobias, A H

2014-01-01

Subaortic stenosis (SAS) is one of the most common congenital cardiac defects in dogs. Severe SAS frequently is treated with a beta adrenergic receptor blocker (beta blocker), but this approach largely is empirical. To determine the influence of beta blocker treatment on survival time in dogs with severe SAS. Retrospective review of medical records of dogs diagnosed with severe, uncomplicated SAS (pressure gradient [PG] ≥80 mmHg) between 1999 and 2011. Fifty dogs met the inclusion criteria. Twenty-seven dogs were treated with a beta blocker and 23 received no treatment. Median age at diagnosis was significantly greater in the untreated group (1.2 versus 0.6 years, respectively; P = .03). Median PG at diagnosis did not differ between the treated and untreated groups (127 versus 121 mmHg, respectively; P = .2). Cox proportional hazards regression was used to identify the influence of PG at diagnosis, age at diagnosis, and beta blocker treatment on survival. In the all-cause multivariate mortality analysis, only age at diagnosis (P = .02) and PG at diagnosis (P = .03) affected survival time. In the cardiac mortality analysis, only PG influenced survival time (P = .03). Treatment with a beta blocker did not influence survival time in either the all-cause (P = .93) or cardiac-cause (P = .97) mortality analyses. Beta blocker treatment did not influence survival in dogs with severe SAS in our study, and a higher PG at diagnosis was associated with increased risk of death. Copyright © 2014 by the American College of Veterinary Internal Medicine.

Efficacy and Safety of Initial Combination Treatment of an Alpha Blocker with an Anticholinergic Medication in Benign Prostatic Hyperplasia Patients with Lower Urinary Tract Symptoms: Updated Meta-Analysis.

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Hyun Jung Kim

Full Text Available There is still controversy as to whether initial combination treatment is superior to serial addition of anticholinergics after maintenance or induction of alpha blockers in benign prostatic hyperplasia (BPH/lower urinary tract symptoms (LUTS.The objective of this study was to determine the benefits and safety of initial combination treatment of an alpha blocker with anticholinergic medication in BPH/LUTS through a systematic review and meta-analysis.We conducted a meta-analysis of improvement in LUTS using International Prostate Symptom Score (IPSS, maximal urinary flow rate (Qmax, post-voided residual volume (PVR, and quality of life (QoL.In total, 16 studies were included in our analysis, with a total sample size of 3,548 subjects (2,195 experimental subjects and 1,353 controls. The mean change in total IPSS improvement from baseline in the combination group versus the alpha blocker monotherapy group was -0.03 (95% CI: -0.14-0.08. The pooled overall SMD change of storage IPSS improvement from baseline was -0.28 (95% CI: -0.40 - -0.17. The pooled overall SMD changes of QoL, Qmax, and PVR were -0.29 (95% CI: -0.50 - -0.07, 0.00 (95% CI: -0.08-0.08, and 0.56 (95% CI: 0.23-0.89, respectively. There was no significant difference in the number of acute urinary retention (AUR events or PVR.Initial combination treatment of an alpha blocker with anticholinergic medication is efficacious for in BPH/ LUTS with improved measures such as storage symptoms and QoL without causing significant deterioration of voiding function.

Beta-blockers and statins in the context of asthma

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Joanna Pawlak

2009-12-01

Full Text Available Asthma is a disease with a complex pathogenesis and differentiated clinical picture with airway inflammation in its background. Many cells and cell-released substances are engaged in the course of the disease. The basic treatment strategy in asthma is based on chronic administration of inhaled glucocorticosteroids (with a strong anti-inflammatory effect and beta2-adrenoreceptor agonists (bronchodilatory effect. Much attention has been recently paid to the effects of other medicines on mechanisms important in the pathogenesis of asthma, including beta-blockers and statins. Many researchers have suggested a potentially useful role of some beta-blockers in chronic asthma therapy, particularly considering their effect on the pharmacodynamics of beta receptors in the bronchi. Moreover, statins, due to their anti-inflammatory and immunomodulatory effects, can also be useful in the management of asthma.

Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction.

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Baroletti, Steven A; Gabardi, Steven; Magee, Colm C; Milford, Edgar L

2003-06-01

Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.

The review of identification and assay methods of β-blockers

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Ольга Олександрівна Віслоус

2015-10-01

Full Text Available Every year the number of β-blockers on the pharmaceutical market is increasing, requiring systematization of their standardization methods.Aim of research. The aim of our research is to study literature data about identification and assay methods of β-blockers with different direction of action – selective (praktolol, metoprolol, atenolol, acebutolol, betaxolol, bevantolol, bisoprolol, celiprolol, esmolol, epanolol, esatenolol, nebivolol, Talinolol, non-selective (alprenolol, Oxprenololum, pindolol, propranolol, timolol, sotalol, nadolol, mepindolol, karteol, tertatolol, bopindolol, bupranolol, penbutolol, kloranolol and combined (labetalol, carvedilol.Methods. The analytical review of literature sources about β-blockers analysis by physical, chemical, and physicochemical methods.Results. After literature sources’ analyzing it was found that physical and physicochemical constants are basically used for β-blockers pharmacopoeial analysis; both physicochemical values and chemical reactions are used in forensic analysis, resulting in the article.It was founded that titration methods, mostly acid-base titration method, are used for β-blockers assay in the analysis of substances. For β-blockers detection in biological fluids and dosage forms, active pharmaceutical ingredients and metabolites mixture separation one should prefer physicochemical methods, such as gas chromatography and liquid chromatography, absorption UV-Visible spectroscopy, fluorometry, etc.Conclusion. The results have shown can be used for the further search of the identification and assay optimal methods of β-blockers both pure and mixed with other active substances and excipients

The Impact of Combination Therapy with a-Blockers and 5ARIs on the Progression of BPH.

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Sountoulides, Petros; Gravas, Stavros

2015-01-01

Benign prostatic hyperplasia (BPH) can be a progressive disease for some men with significant impact on their quality of life due to worsening of symptoms, risk of acute urinary retention (AUR) and surgery. Certain clinical parameters such as age, prostate volume and PSA are able to predict those patients with BPH-associated LUTS that are at risk of disease progression. These patients will likely benefit most from medical therapy that provides symptom relief while at the same time may prevent disease progression. Studies have shown that a-blockers, although able to rapidly alleviate symptoms, have no effect on prostate volume, risk for AUR and BPH-related surgery. On the other hand 5ARIs have proven their efficacy in reducing prostate size, the risk of AUR and prostate surgery. Therefore combination therapy with an a-blocker and a 5ARI can be the mainstay of treatment for those patients at risk of BPH progression. Patients' perspective and their needs and expectations from treatment are other crucial parameters to consider in order selecting the optimal management of BPH. Therefore physicians should take into consideration the drug properties and also the patients' preferences before deciding on the optimal pharmacological treatment for BPH-associated LUTS.

Risk of insomnia attributable to β-blockers in elderly patients with newly diagnosed hypertension.

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Chang, Chia-Hsien; Yang, Yea-Huei Kao; Lin, Swu-Jane; Su, Jyun-Jhong; Cheng, Ching-Lan; Lin, Li-Jen

2013-01-01

Use of β-blockers may cause insomnia and central nervous system and/or psychological side effects, but data are limited on the relative risks of insomnia among β-blockers. This retrospective cohort study used Taiwan's National Health Insurance claims database from 2003 to 2007, where 4,063 patients aged above 65 years with newly diagnosed hypertension and treated with β-blockers were followed for 1 year. The primary endpoint was a new insomnia event within 30 days of treatment initiation. Adjusted odds ratios of insomnia were obtained by logistic regressions, controlling for baseline risk factors of insomnia. Using propranolol therapy as the reference, the adjusted odds ratio (95% confidence interval) for the insomnia risk was 0.47 (0.35-0.63) for non-propranolol users, 0.31 (0.19-0.50) for bisoprolol, and 0.46 (0.33-0.66) for atenolol. Compared to the patients using non-selective β-blockers, the adjusted odds ratio was 0.48 (0.36-0.34) for those using selective β(1)-blockers. Additionally, the adjusted odds ratio was 0.72 (0.53-0.96) for β-blockers with low lipophilicity when compared to those with high lipophilicity. The use of bisoprolol and atenolol was associated with the lowest risk of insomnia in elderly patients, as compared to propranolol. β-Blockers with high selectivity in β(1)-receptors and/or low lipophilicity were associated with a lower risk of insomnia.

Energy expenditure estimation in beta-blocker-medicated cardiac patients by combining heart rate and body movement data.

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Kraal, Jos J; Sartor, Francesco; Papini, Gabriele; Stut, Wim; Peek, Niels; Kemps, Hareld Mc; Bonomi, Alberto G

2016-11-01

Accurate assessment of energy expenditure provides an opportunity to monitor physical activity during cardiac rehabilitation. However, the available assessment methods, based on the combination of heart rate (HR) and body movement data, are not applicable for patients using beta-blocker medication. Therefore, we developed an energy expenditure prediction model for beta-blocker-medicated cardiac rehabilitation patients. Sixteen male cardiac rehabilitation patients (age: 55.8 ± 7.3 years, weight: 93.1 ± 11.8 kg) underwent a physical activity protocol with 11 low- to moderate-intensity common daily life activities. Energy expenditure was assessed using a portable indirect calorimeter. HR and body movement data were recorded during the protocol using unobtrusive wearable devices. In addition, patients underwent a symptom-limited exercise test and resting metabolic rate assessment. Energy expenditure estimation models were developed using multivariate regression analyses based on HR and body movement data and/or patient characteristics. In addition, a HR-flex model was developed. The model combining HR and body movement data and patient characteristics showed the highest correlation and lowest error (r 2  = 0.84, root mean squared error = 0.834 kcal/minute) with total energy expenditure. The method based on individual calibration data (HR-flex) showed lower accuracy (i 2  = 0.83, root mean squared error = 0.992 kcal/minute). Our results show that combining HR and body movement data improves the accuracy of energy expenditure prediction models in cardiac patients, similar to methods that have been developed for healthy subjects. The proposed methodology does not require individual calibration and is based on the data that are available in clinical practice. © The European Society of Cardiology 2016.

Additive Effect of Qidan Dihuang Grain, a Traditional Chinese Medicine, and Angiotensin Receptor Blockers on Albuminuria Levels in Patients with Diabetic Nephropathy: A Randomized, Parallel-Controlled Trial

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Xiang, Lei; Jiang, Pingping; Zhou, Lin; Sun, Xiaomin; Bi, Jianlu; Cui, Lijuan; Nie, Xiaoli; Luo, Ren; Liu, Yanyan

2016-01-01

Albuminuria is characteristic of early-stage diabetic nephropathy (DN). The conventional treatments with angiotensin receptor blockers (ARB) are unable to prevent the development of albuminuria in normotensive individuals with type 2 diabetes mellitus (T2DM). Purpose. The present study aimed to evaluate the effect of ARB combined with a Chinese formula Qidan Dihuang grain (QDDHG) in improving albuminuria and Traditional Chinese Medicine Symptom (TCMS) scores in normotensive individuals with T2DM. Methods. Eligible patients were randomized to the treatment group and the control group. Results. Compared with baseline (week 0), both treatment and control groups markedly improved the 24-hour albuminuria, total proteinuria (TPU), and urinary albumin to creatinine ratio (A/C) at 4, 8, and 12 weeks. Between treatment and the control group, the levels of albuminuria in the treatment group were significantly lower than in the control group at 8 and 12 weeks (p < 0.05). In addition, treatment group markedly decreased the scores of TCMS after treatment. Conclusion. This trial suggests that QDDHG combined with ARB administration decreases the levels of albuminuria and the scores for TCMS in normotensive individuals with T2DM. PMID:27375762

Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin.

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Zhang, Yan; Diao, Teng-Yue; Gu, Sa-Sa; Wu, Shu-Yan; Gebru, Yoseph A; Chen, Xi; Wang, Jing-Yu; Ran, Shu; Wong, Man-Sau

2014-09-01

This study was performed to address the pathological roles of the skeletal renin-angiotensin system (RAS) in type 1 diabetes-induced osteoporosis and the effects of the angiotensin II type 1 receptor blocker losartan on bones in diabetic mice. Bone histomorphology was detected by H&E staining, Safranin O staining and X-ray radiography. Micro-CT was performed for the analysis of bone parameters. Gene and protein expression were determined by RT-PCR and immunoblotting. Type 1 diabetic mice displayed osteopenia phenotype, and losartan treatment had no osteoprotective effects on diabetic mice as shown by the reduction of bone mineral density and microarchitectural parameters at the proximal metaphysis of the tibia. The mRNA expression of AGT, renin receptor and ACE, and protein expression of renin and AT1R were markedly up-regulated in the bones of vehicle-treated diabetic mice compared to those of non-diabetic mice. The treatment with losartan further significantly increased the expression of AGT, renin, angiotensin II and AT1R, and reduced the expression of AT2R receptor as compared to those of diabetic mice. Local bone RAS functionally played a role in the development of type 1 diabetic osteoporosis, and losartan had no bone-sparing function in diabetes mice because of enhance skeletal RAS activity. © The Author(s) 2013.

Metaflumizone is a novel sodium channel blocker insecticide.

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Salgado, V L; Hayashi, J H

2007-12-15

Metaflumizone is a novel semicarbazone insecticide, derived chemically from the pyrazoline sodium channel blocker insecticides (SCBIs) discovered at Philips-Duphar in the early 1970s, but with greatly improved mammalian safety. This paper describes studies confirming that the insecticidal action of metaflumizone is due to the state-dependent blockage of sodium channels. Larvae of the moth Spodoptera eridania injected with metaflumizone became paralyzed, concomitant with blockage of all nerve activity. Furthermore, tonic firing of abdominal stretch receptor organs from Spodoptera frugiperda was blocked by metaflumizone applied in the bath, consistent with the block of voltage-dependent sodium channels. Studies on native sodium channels, in primary-cultured neurons isolated from the CNS of the larvae of the moth Manduca sexta and on Para/TipE sodium channels heterologously expressed in Xenopus (African clawed frog) oocytes, confirmed that metaflumizone blocks sodium channels by binding selectively to the slow-inactivated state, which is characteristic of the SCBIs. The results confirm that metaflumizone is a novel sodium channel blocker insecticide.

Renal graft failure after addition of an angiotensin II receptor antagonist to an angiotensin-converting enzyme inhibitor

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Kamper, Anne-Lise; Nielsen, Arne Høj; Baekgaard, Niels

2002-01-01

Combined treatment with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor blocker (ARB) has been suggested in order to achieve a more complete blockade of the renin-angiotensin-aldosterone system in cardiovascular and renal disease. The present report descri...

A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.

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Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

2016-10-01

Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease.

Marine Bivalve Cellular Responses to Beta Blocker Exposures ...

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β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent binding of agonists such as catecholamines to β adrenoceptors. In the absence of agonist induced activation of the receptor, adenylate cyclase is not activated which in turn limits cAMP production and protein kinase A activation, preventing increases in blood pressure and arrhythmias. After being taken therapeutically, commonly prescribed β blockers may make their way to coastal habitats via discharge from waste water treatment plants (WWTP) posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular responses of three commercially important marine bivalves - Eastern oysters, blue mussels and hard clams - upon exposure to two β blocker drugs, propranolol and metoprolol, and to find molecular initiating events (MIEs) indicative of the exposure. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas (HP) tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug. Tissues were bathed in 30 parts per thousand (ppt) filtered seawater, antibiotic mix, Leibovitz nutrient media, and the test drug. Exposures were conducted for 24 hours and samples were saved for cellular biomarker assays. A lysosomal destabilization assay, which is a marker of membrane damage, was also performed at the end of each exposure.

Critical appraisal and pooled analysis of telmisartan alone or in combination with hydrochlorothiazide for achieving blood pressure goals

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Satoshi Morimoto

2010-06-01

Full Text Available Satoshi Morimoto, Nobuyuki Takahashi, Tatsuyori Morita, Kazunori Someya, Nagaoki Toyoda, Toshiji IwasakaSecond Department of Internal Medicine, Kansai Medical University 2-3-1, Shinmachi, Hirakata, Osaka 573-1191, JapanAbstract: Rigid control of blood pressure (BP is essential to prevent cardiovascular disease. However, only about 40% of hypertensive patients undergoing pharmacological intervention with a single agent achieve their BP goals in contemporary clinical practice. Combined therapy using currently available agents is effective in maximizing treatment outcome, although it raises medical costs and decreases the drug compliance rate. To overcome such negative consequences, a combination tablet containing an angiotensin II receptor blocker (ARB with a small dose of hydrochlorothiazide (HCTZ is now available on the international market, including Japan. This article briefly describes the unique properties of telmisartan, a highly selective ARB for the angiotensin II type 1 receptor, including its long-acting characteristics and recent prospective multicenter randomized clinical trials, followed by a description of a newly-introduced combination tablet in Japan, which contains telmisartan and HCTZ. This article also reviews its safety and efficacy based on currently available evidence. Finally, evidence comparing telmisartan/HCTZ with other combination therapies is presented.Keywords: angiotensin II receptor blocker, ARB, blood pressure, hypertension, diuretics, PPAR-γ

Effects of Combined Endothelin A Receptor and Renin-Angiotensin System Blockade on the Course of End-Organ Damage in 5/6 Nephrectomized Ren-2 Hypertensive Rats

Czech Academy of Sciences Publication Activity Database

Vaněčková, Ivana; Kujal, P.; Husková, Z.; Vaňourková, Z.; Vernerová, Z.; Čertíková; Chábová, V.; Škaroupková, P.; Kramer, H. J.; Tesař, V.; Červenka, L.

2012-01-01

Roč. 35, č. 5 (2012), s. 382-392 ISSN 1420-4096 Institutional research plan: CEZ:AV0Z50110509 Keywords : 5/6 nephrectomy * Endothelin receptor type A * AT1 receptor blocker * end-organ damage * hypertension Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.596, year: 2012

Calcium channel blocker overdose

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... this page: //medlineplus.gov/ency/article/002580.htm Calcium-channel blocker overdose To use the sharing features on this page, please enable JavaScript. Calcium-channel blockers are a type of medicine used ...

Effect of beta-blocker therapy on functional status in patients with heart failure--a meta-analysis

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Abdulla, Jawdat; Køber, Lars; Christensen, Erik

2005-01-01

BACKGROUND: The results of randomised control trials (RCTs) evaluating the effect of beta-blockers on functional status in patients with chronic heart failure are conflicting. AIM: To perform a systematic review and meta-analysis of RCTs evaluating the effect of beta-blockers on New York Heart...... Association (NYHA) classification and exercise tolerance in chronic heart failure. METHODS AND RESULTS: We selected 28 RCTs evaluating beta-blocker versus placebo in addition to ACE inhibitor therapy. Combined results of 23 RCTs showed that beta-blockers improved NYHA class by at least one class with odds...... ratio (OR) 1.80 (1.33-2.43) pbeta-blockers had no significant effect...

β-Blocker pharmacogenetics in heart failure

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Shin, Jaekyu

2009-01-01

β-Blockers (metoprolol, bisoprolol, and carvedilol) are a cornerstone of heart failure (HF) treatment. However, it is well recognized that responses to a β-blocker are variable among patients with HF. Numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to a β-blocker, including left ventricular ejection fraction improvement, survival, and hospitalization due to HF exacerbation. This review summarizes the pharmacogenetic data for β-blockers in patients with HF and discusses the potential implications of β-blocker pharmacogenetics for HF patients. PMID:18437562

A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers

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Seyed Ali Sadjadi

2009-07-01

Full Text Available Seyed Ali Sadjadi1, James I McMillan1, Navin Jaipaul1, Patricia Blakely1, Su Su Hline21Section of Nephrology (111N, Jerry L Pettis Memorial Veterans Medical Center, Loma Linda, CA, USA; 2Divison of Nephrology, Loma Linda University Medical Center, Loma Linda, CA, USABackground and objectives: Angiotensin-converting enzyme inhibitors (ACEI and angiotensin receptor blockers (ARB are increasingly used in a variety of settings including heart failure, renal failure, arterial hypertension, and diabetic nephropathy. The objective of this study was to investigate the prevalence of hyperkalemia with ACEI and ARB use, in a population of the United States veterans.Design, settings, material, and measurements: Retrospective observational cohort study of 1163 patients on ACEIs and 1168 patients on ARBs in a single Veterans Affairs Medical Center. Electronic medical records were reviewed over a 12-month period with data collected on various demographic, laboratory, comorbidity, and medication related variables. Results: Hyperkalemia (>5 mEq/L was observed in 20.4% of patients on ACEIs and 31.0% on ARBs. Severe hyperkalemia (6 mEq/L or higher, was observed in 0.8% of ACEI and 2.8% of ARB users. In univariate logistic regression analyses, diabetes mellitus; serum glucose, total carbon dioxide content, creatinine, and estimated glomerular filtration rate (GFR were significantly associated with hyperkalemia. ARB use, when compared to ACEI, was associated with a 42% increase in odds of hyperkalemia (odds ratio [OR] = 1.42; p = 0.001 in a model including adjustment for GFR and a 56% increase in odds of hyperkalemia (OR = 1.56; p < 0.001 in a model including adjustment for serum creatinine.Conclusions: Hyperkalemia, associated with the use of ACEIs and ARBs, is usually mild and severe hyperkalemia is rare. Hyperkalemia is more common with ARBs than ACEIs. ARB use, when compared to ACEI use, may significantly and independently be associated with increased odds of

The effect of angiotensin-2 receptor blocker valsartan on circulating level of endothelial progenitor cells in diabetic patients with asymptomatic coronary artery disease.

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Berezin, Alexander E; Kremzer, Alexander A; Martovitskaya, Yulia V; Samura, Tatyana A

2015-01-01

Decreased circulating endothelial progenitor cells (EPCs) are considered as strong and robust biomarkers for the prediction of cardiovascular outcomes in diabetic populations. The perspectives for modulating EPCs levels in T2DM with known coronary artery disease (CAD) with different drugs, affected mechanisms of improving mobilization of EPCs from tissue, are not still understood. To evaluate an effect of angiotensin-2 receptor blocker valsartan on circulating level of EPCs in diabetic patients with asymptomatic CAD. The study population was structured retrospectively after determining the CAD by contrast-enhanced spiral computed tomography angiography in 126 asymptomatic subjects. All subjects were distributed into two cohorts depending on daily doses of valsartan given. Low (80-160 mg daily orally) and high doses (240-320 mg daily orally) of valsartan were used and they were adjusted depending on achieving BP level less than 140/80 mmHg. The change from baseline in CD34(+) subset cells (frequencies and absolute values) was not significantly different between treatment cohorts. We found a significant increase of circulating level of CD14(+)CD309(+) cells in two patient cohorts. But more prominent change of CD14(+)CD309(+) cells was verified in subjects who were given valsartan in high daily doses when compared with persons who were included into cohort with low daily doses of the drug (1.96% versus 2.59%, respectively; Pvalsartan only. We found positive influence of angiotensin-2 receptor blocker valsartan in escalation doses on bone marrow-derived EPCs phenotyped as CD14(+)CD309(+) and CD14(+)CD309(+)Tie(2+) in T2DM patients with known asymptomatic CAD. Copyright © 2014 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.

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Motoharu Hayashi

Full Text Available A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1, tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1 and glucose transporter 4 (GLUT4 in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results

Endoscopic therapy and beta-blockers for secondary prevention in adults with cirrhosis and oesophageal varices

DEFF Research Database (Denmark)

Gluud, Lise Lotte; Morgan, Marsha Y.

2017-01-01

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the beneficial and harmful effects of endoscopic therapy and beta-blockers used as a combination therapy versus monotherapy with either endoscopic therapy or beta-blockers for secondary prevention...

Low-dose β-blocker in combination with milrinone safely improves cardiac function and eliminates pulsus alternans in patients with acute decompensated heart failure.

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Kobayashi, Shigeki; Susa, Takehisa; Tanaka, Takeo; Murakami, Wakako; Fukuta, Seiko; Okuda, Shinichi; Doi, Masahiro; Wada, Yasuaki; Nao, Tomoko; Yamada, Jutaro; Okamura, Takayuki; Yano, Masafumi; Matsuzaki, Masunori

2012-01-01

The purpose of this study was to determine whether a low-dose β-blocker, in combination with milrinone, improves cardiac function in acute decompensated heart failure (ADHF) with tachycardia. Twenty ADHF patients (New York Heart Association classification III, n=1, and IV, n=19; heart rate [HR], 107±12 beats/min; left ventricular ejection fraction, 24±7%; cardiac index [CI], 2.2±0.6 L·min(-1)·m(-2); pulmonary capillary wedge pressure [PCWP], 26±8 mmHg) were enrolled in this study. The patients first underwent conventional therapy with milrinone, vasodilators and diuretics; landiolol (1.5-6.0 µg·kg(-1)·min(-1); i.v.), which is an ultra-short-acting β(1)-selective blocker, was then added to the treatment regimen to study its effect on hemodynamics. Low-dose landiolol (1.5 µg·kg(-1)·min(-1)) significantly reduced HR by 11% without changing blood pressure (BP) and CI, whereas higher doses (≥3.0 µg·kg(-1)·min(-1)) tended to decrease BP and CI while increasing PCWP and systemic vascular resistance. After treatment with landiolol (1.5 µg·kg(-1)·min(-1)), hemodynamic parameters such as PCWP, stroke volume index, SvO(2), rate pressure product, filling time/RR, E/e', and Tei index were significantly improved. A low-dose β-blocker in combination with milrinone improved cardiac function in ADHF patients with tachycardia; therefore, it may be considered as an adjunct therapy for use when standard therapy with milrinone is not effective at slowing HR.

Clinical Efficacy of Jinshuibao Capsules Combined with Angiotensin Receptor Blockers in Patients with Early Diabetic Nephropathy: A Meta-Analysis of Randomized Controlled Trials

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Qiang Lu

2018-01-01

Full Text Available Background. Jinshuibao capsules (JSB have been widely used to treat early diabetic nephropathy (DN, but the specific effects are still inconsistent. A meta-analysis of randomized controlled trials (RCTs was conducted to evaluate the clinical efficacy of JSB for early DN. Methods. Four international databases and four Chinese databases were searched from publication dates to March 1, 2018. The RCTs reporting the results of JSB’s specific effects were included, and comparisons were between JSB combined with Angiotensin Receptor Blockers (ARBs as experimental intervention and ARBs as the control. Included studies’ quality was evaluated and the extracted data were analyzed with RevMan 5.3 software. Results. Twenty-six RCTs including 2198 early DN participants were adopted in the meta-analysis. The results showed that, compared with the ARBs alone, JSB could remarkably improve the ORR (OR = 3.84; 95% CI: 2.37~6.24; P<0.00001 and decrease 24 h UTP (MD = −93.32; 95% CI: −128.60 ~-58.04; P<0.00001, UAER (MD = −24.02; 95% CI: −30.93 ~-17.11; P<0.00001, BUN (MD = −0.26; 95%: −0.44 ~-0.08; P=0.005, Scr (MD = −9.07; 95% CI: −14.26 ~-3.88; P=0.0006, ACR (MD = −17.55; 95% CI: −22.81 ~-12.29; P<0.00001, Cys-C (MD = −0.60; 95% CI: −0.88 ~-0.32; P<0.00001, SBP (MD = −3.08; 95% CI: −4.65 ~-1.52; P=0.0001, DBP (MD = −2.09; 95% CI: −4.00 ~-0.19; P=0.03, and TG (MD = −0.36; 95% CI: −0.50 ~-0.21; P<0.00001. However, it showed no significant differences in TC (MD = −0.32; 95% CI: −0.69~0.04; P=0.08, FBG (MD = 0.04; 95% CI: −0.39~0.47; P=0.87, HbA1c (MD = −0.26; 95% CI: −0.59~0.06; P=0.11, and β2-MG (MD = −15.61; 95% CI: −32.95~1.73; P=0.08. Conclusions. This study indicates that JSB is an effective accessory therapeutic medicine for patients with early DN. It contributes to decreasing blood pressure and the content of triglyceride and improving the renal function of early DN patients. However, there is still a

Efficacy and safety of a therapeutic interchange from high-dose calcium channel blockers to a fixed-dose combination of amlodipine/benazepril in patients with moderate-to-severe hypertension.

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Hilleman, D E; Reyes, A P; Wurdeman, R L; Faulkner, M

2001-08-01

Recent hypertension trials have demonstrated the importance of achieving goal blood pressures to reduce the risk of target organ damage. In patients with moderate to severe hypertension, the use of high-dose monotherapy and/or combinations of drugs are necessary to achieve these goals. Fixed-dose combination products may be useful in these patients by reducing the number of daily doses required to control blood pressure. The objective of the present study was to evaluate the efficacy and safety of a therapeutic interchange between high-dose calcium channel blocker therapy and a fixed-dose combination of amlodipine/ benazepril (Lotrel; Novartis Pharmaceuticals, USA) in patients with moderate to severe hypertension. A total of 75 patients were switched from amlodipine (n = 25), felodipine (n = 25), and nifedipine-GITS (n = 25) to amlodipine/benazepril. Twenty-eight of the 75 patients (37%) were taking either a beta-blocker or a diuretic in addition to the high-dose calcium channel blocker prior to the switch. Blood pressure control, side effects and the cost of the therapeutic interchange were evaluated in the year following the therapeutic interchange. Sixty-six of the 75 (88%) patients were successfully switched with maintenance of blood pressure control and without the development of new dose-limiting side effects. Reasons for treatment failure after the therapeutic interchange included loss of blood pressure control in five patients and the development of new dose-limiting side effects in four patients. These side effects included cough in three patients and rash in one patient. After accounting for differences in drug acquisition cost and costs related to the switch (clinic and emergency room and laboratory tests), a cost savings of $16030 for all 75 patients was realised in the first year. The per patient-per year cost savings was $214. Our data indicate that a therapeutic interchange from selected high-dose calcium channel blockers to a fixed-dose combination

The Effect of an Angiotensin Receptor Blocker on Arterial Stiffness in Type 2 Diabetes Mellitus Patients with Hypertension

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Ji Hyun Kim

2011-06-01

Full Text Available BackgroundHypertension and type 2 diabetes mellitus are major risk factors for cardiovascular disease. This study analyzed the changes in central aortic waveforms and pulse wave velocity as well as related parameters after treatment with valsartan, an angiotensin II type 1 receptor blocker, in patients with type 2 diabetes and hypertension.MethodsWe used pulse wave analysis to measure central aortic waveform in a total of 98 subjects. In 47 of these patients, pulse wave velocity measurements were obtained before and after 12 weeks of treatment with valsartan.ResultsIn the central aortic waveform analysis, the aortic pulse pressure and augmentation index were significantly decreased after valsartan treatment, as was the aortic pulse wave velocity. Factors contributing to the improvement in pulse wave velocity were the fasting blood glucose and haemoglobin A1c levels.ConclusionShort-term treatment with valsartan improves arterial stiffness in patients with type 2 diabetes and hypertension, and the glucose status at baseline was associated with this effect.

Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

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Yuki Hamano

2011-09-01

Full Text Available Background/Aims: Anti-glomerular basement membrane (GBM nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs with distinct peroxisome proliferator-activated receptor (PPAR-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.

Evaluation of risk of falls and orthostatic hypotension in older, long-term topical beta-blocker users

NARCIS (Netherlands)

Ramdas, Wishal D.; van der Velde, Nathalie; van der Cammen, Tischa J. M.; Wolfs, Roger C. W.

2009-01-01

Falls are a serious problem in the elderly, and have recently been described as cardiovascular-mediated side effects of beta-blocker eye drops. Therefore, we investigated the possible association between the long-term use of beta-blockers, prostaglandins and their combinations in eye drops, and

Partial neuromuscular blockade in humans enhances muscle blood flow during exercise independently of muscle oxygen uptake and acetylcholine receptor blockade

DEFF Research Database (Denmark)

Hellsten, Ylva; Krustrup, Peter; Iaia, F Marcello

2009-01-01

This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one-legged k......This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one...... conductance during exercise, events that are not associated with either acetylcholine or an increased oxygen demand. The results do not support an essential role for acetylcholine, released form the neuromuscular junction, in exercise hyperaemia or for the enhanced blood flow during neuromuscular blockade....... The enhanced exercise hyperemia during partial neuromuscular blockade may be related to a greater recruitment of fast-twitch muscle fibres. Key words: blood flow, neuromuscular blockade, exercise, skeletal muscle....

Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects.

Science.gov (United States)

Yahiro, Eiji; Miura, Shin-Ichiro; Suematsu, Yasunori; Matsuo, Yoshino; Arimura, Tadaaki; Kuwano, Takashi; Imaizumi, Satoshi; Iwata, Atsushi; Uehara, Yoshinari; Saku, Keijiro

2015-01-01

While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.

Renoprotective effects of mineralocorticoid receptor blockers in patients with proteinuric kidney diseases.

Science.gov (United States)

Morales, Enrique; Millet, Victor Gutiérrez; Rojas-Rivera, Jorge; Huerta, Ana; Gutiérrez, Eduardo; Gutiérrez-Solís, Elena; Egido, Jesús; Praga, Manuel

2013-02-01

Several studies have demonstrated a short-term antiproteinuric effect of mineralocorticoid receptor blockers (MRB) on proteinuric kidney diseases, but no information is available about the long-term persistence (>1 year) of such reduction in proteinuria and the long-term effects of MRB on renal function. We prospectively studied the effects of adding spironolactone (25 mg/day) to 87 patients who maintained proteinuria higher than 1 g/day in spite of renin-angiotensin system blockade. The mean follow-up was 25 ± 15 (1-84) months. Estimated glomerular filtration rate (eGFR) showed an acute fall in the first month of treatment (5.1 ± 9.4 mL/min/1.73 m(2)), but it remained stable thereafter (+0.04 ± 0.7 mL/min/1.73 m(2)/month), with a significant difference with respect to the eGFR slope during the 12-month pre-treatment period. The initial eGFR fall predicted a more stable course of renal function, the higher the eGFR initial fall, the better the long-term evolution of eGFR. Proteinuria showed an important and sustained reduction since the first month of treatment. At the end of follow-up, it had decreased by 61% (43-77%) with respect to baseline values. The antiproteinuric and renoprotective influence of spironolactone was also observed in diabetic patients and in patients with renal function impairment, although tolerance was poorer among the latter. Spironolactone induces an initial acute fall in eGFR that predicts a later favourable influence on the course of renal function and a remarkable and sustained reduction in proteinuria.

Detecting Anti Ad-blockers in the Wild

Directory of Open Access Journals (Sweden)

Mughees Muhammad Haris

2017-07-01

Full Text Available The rise of ad-blockers is viewed as an economic threat by online publishers who primarily rely on online advertising to monetize their services. To address this threat, publishers have started to retaliate by employing anti ad-blockers, which scout for ad-block users and react to them by pushing users to whitelist the website or disable ad-blockers altogether. The clash between ad-blockers and anti ad-blockers has resulted in a new arms race on the Web. In this paper, we present an automated machine learning based approach to identify anti ad-blockers that detect and react to ad-block users. The approach is promising with precision of 94.8% and recall of 93.1%. Our automated approach allows us to conduct a large-scale measurement study of anti ad-blockers on Alexa top-100K websites. We identify 686 websites that make visible changes to their page content in response to ad-block detection. We characterize the spectrum of different strategies used by anti ad-blockers. We find that a majority of publishers use fairly simple first-party anti ad-block scripts. However, we also note the use of third-party anti ad-block services that use more sophisticated tactics to detect and respond to ad-blockers.

Role of valsartan, amlodipine and hydrochlorothiazide fixed combination in blood pressure control: an update

Directory of Open Access Journals (Sweden)

Maurizio Destro

2010-04-01

Full Text Available Maurizio Destro1, Francesca Cagnoni1, Antonio D’Ospina1, Alessandra Rossi Ricci1, Elena Demichele1, Emmanouil Peros1, Augusto Zaninelli2, Paola Preti31Internal Medicine, Ospedale Unificato Broni-Stradella, Stradella (PV, Italy; 2General Medicine, School of Medicine, University of Florence, Florence, Italy; 3Internal Medicine, University of Pavia, Pavia, ItalyAbstract: The treatment of moderate or severe hypertension in most cases requires the contemporaneous use of multiple antihypertensive agents. The most available two-drug combinations have an agent that addresses renin secretion and another one that is statistically more effective in renin-independent hypertension. The practice of combining agents that counteract different mechanisms is the most likely explanation for the fact that most available two-drug combinations have an agent that addresses renin secretion (beta-blocker, angiotensin converting enzyme inhibitor, angiotensin II receptor blocker or direct renin inhibitor and another one that is more effective in renin-independent hypertension (diuretic, dihydropyridine or non-dihydropyridine calcium channel blocker. Based on these considerations, addition of hydrochlorothiazide to the combination of an antagonist of the renin-angiotensin system with a calcium channel blocker would constitute a logical approach. Inclusion of a diuretic in the triple combination is based on the evidence that these agents are effective and cheap, enhance the effect of other antihypertensive agents, and add a specific effect to individuals with salt-sensitivity of blood pressure. The benefit of triple combination therapy with amlodipine, valsartan and hydrochlorothiazide over its dual component therapies has been demonstrated, and the use of a single pill will simplify therapy resulting in better blood pressure control.Keywords: valsartan, amlodipine, hydrochlorothiazide, HCTZ, blood pressure, hypertension

Rationale for nebivolol/valsartan combination for hypertension: review of preclinical and clinical data.

Science.gov (United States)

Giles, Thomas D; Cockcroft, John R; Pitt, Bertram; Jakate, Abhijeet; Wright, Harold M

2017-09-01

: To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin-angiotensin-aldosterone system inhibitors, when combined, have been deemed 'less effective' based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg - a vasodilatory β1-selective antagonist/β3 agonist - and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I-II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

Beta-blocker therapy for tremor in Parkinson's disease.

Science.gov (United States)

Crosby, N J; Deane, K H O; Clarke, C E

2003-01-01

The tremor of Parkinson's disease can cause considerable disability for the individual concerned. Traditional antiparkinsonian therapies such as levodopa have only a minor effect on tremor. Beta-blockers are used to attenuate other forms of tremor such as Essential Tremor or the tremor associated with anxiety. It is thought that beta-blockers may be of use in controlling the tremor of Parkinson's disease. To compare the efficacy and safety of adjuvant beta-blocker therapy against placebo for the treatment of tremor in patients with Parkinson's disease. Electronic searches of MEDLINE, EMBASE, SCISEARCH, BIOSIS, GEROLIT, OLDMEDLINE, LILACS, MedCarib, PASCAL, JICST-EPLUS, RUSSMED, DISSERTATION ABSTRACTS, SIGLE, ISI-ISTP, Aslib Index to Theses, The Cochrane Controlled Trials Register, Clinicaltrials.gov, metaRegister of Controlled Trials, NIDRR, NRR and CENTRAL were conducted. Grey literature was hand searched and the reference lists of identified studies and reviews examined. The manufacturers of beta-blockers were contacted. Randomised controlled trials of adjuvant beta-blocker therapy versus placebo in patients with a clinical diagnosis of idiopathic Parkinson's disease. Data was abstracted independently by two of the authors onto standardised forms and disagreements were resolved by discussion. Four randomised controlled trials were found comparing beta-blocker therapy with placebo in patients with idiopathic Parkinson's disease. These were double-blind cross-over studies involving a total of 72 patients. Three studies did not present data from the first arm, instead presenting results as combined data from both treatment arms and both placebo arms. The risk of a carry-over effect into the second arm meant that these results were not analysed. The fourth study presented data from each arm. This was in the form of a mean total score for tremor for each group. Details of the baseline scores, the numbers of patients in each group and standard deviations were not

The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome?

Science.gov (United States)

Früh, Andreas; Siem, Geir; Holmström, Henrik; Døhlen, Gaute; Haugaa, Kristina H

2016-11-01

Patients with Jervell and Lange-Nielsen syndrome (JLNS) exhibit severe phenotypes that are characterized by congenital deafness, very long QT intervals, and high risk of life-threatening arrhythmias. Current treatment strategies include high doses of beta-blocker medication, left cardiac sympathetic denervation, and ICD placement, which is challenging in young children. The purpose of this study was to evaluate the safety and effect of pacing in addition to beta-blocker treatment in children with JLNS. All genetically confirmed patients with JLNS born since 1999 in Norway were included in the study. Data on history of long QT syndrome-related symptoms, QT interval, and beta-blocker and pacemaker treatment were recorded. A total of 9 patients with QT intervals ranging from 510 to 660 ms were identified. Eight patients developed long QT syndrome-related symptoms, and 1 patient died before diagnosis. The survivors received beta-blocker medication. Seven patients also received a pacemaker; 1 had a ventricular lead and 6 had atrial leads. The patient with the ventricular lead died during follow-up. The 6 patients with atrial leads survived without events at a mean follow-up of 6.9 years after pacemaker implantation. Two patients received prophylactic upgrade to a 2-chamber ICD. No arrhythmic events occurred in 6 very young JLNS patients who received atrial pacing in combination with increased doses of beta-blockers during 7-year follow-up. If confirmed in additional patients, this treatment strategy may prevent life-threatening arrhythmias in this high-risk patient group and may act as a bridge to insertion of a 2-chamber ICD when left cardiac sympathetic denervation is not available. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Reduction of the protective effect of β-receptor inhibitors on E.coli bacteria

International Nuclear Information System (INIS)

Zywietz, F.; Brueckner, V.; Linden, W.

1974-01-01

Bacteria of E.coli B/r strain were tested with selenium-substituted amino acids for effects concerning radiation protection. Selenium-methionine was used for the tests. The B-receptor blocker Propanolol (Docitonsup(R)) was applied additionally. The irradiation was carried out on a 200 kV-γ-ray unit with a dose rate of 1,000 R/min. For selenium-methionine a maximum dose reduction factor (DRF) of 1.8 was found. The results of the present tests show that the radiation resistance-increasing effect of the protective substances used here, selenium methionine and cystein, was eliminated partially or totally by the β-receptor blocker. To what extent the development of a substance receptor complex important for the efficiency of AMP mechanism is prevented by the receptor blocker must be seen from further experiments. (GSE) [de

Effect of angiotensin II receptor blocker, olmesartan, on turnover of bone metabolism in bedridden elderly hypertensive women with disuse syndrome.

Science.gov (United States)

Aoki, Motokuni; Kawahata, Hirohisa; Sotobayashi, Daisuke; Yu, Hisahiro; Moriguchi, Atsushi; Nakagami, Hironori; Ogihara, Toshio; Morishita, Ryuichi

2015-08-01

Although recent studies suggest that several antihypertensive drugs could reduce the risk of bone fracture, it is still unclear how these drugs act on bone remodeling, especially in elderly women with severe osteoporosis with disuse syndrome. In the present study, we investigated the effects of a calcium channel blocker (CCB) and an angiotensin II receptor blocker (ARB) on bone metabolism in elderly bedridden women with hypertension and disuse syndrome. Elderly bedridden women (aged >75 years) receiving antihypertensive therapy treated with CCB were recruited in the present study. The participants were divided into two groups--CCB group and ARB group--and followed up to 12 months. Markers of bone resorption were markedly increased, suggesting accelerated bone resorption in the participants of the present study. In the follow-up period, the patients treated with a CCB showed a significant decrease in bone mineral density in a time-dependent manner, accompanied by a significant increase in bone resorption markers, whereas treatment with olmesartan inhibited bone loss, associated with attenuation of increased bone resorption markers. Bone mineral density of femoral neck in the CCB group was significantly lower than that in the ARB group at 6 months. The present study showed inhibitory effects of an ARB on bone resorption in hypertensive patients with accelerated bone resorption, such as elderly bedridden women, and indicated an important role of the renin-angiotensin system in bone metabolism. In elderly hypertensive patients, ARB might be expected to have additional beneficial potential to maintain bone health in bedridden patients. © 2014 Japan Geriatrics Society.

Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): A randomised study.

Science.gov (United States)

Hidalgo, Francisco J; Anguita, Manuel; Castillo, Juan C; Rodríguez, Sara; Pardo, Laura; Durán, Enrique; Sánchez, José J; Ferreiro, Carlos; Pan, Manuel; Mesa, Dolores; Delgado, Mónica; Ruiz, Martín

2016-08-15

To analyse the effect of the early coadministration of ivabradine and beta-blockers (intervention group) versus beta-blockers alone (control group) in patients hospitalised with heart failure and reduced left ventricular ejection fraction (HFrEF). A comparative, randomised study was performed to compare the treatment strategies of beta-blockers alone versus ivabradine and beta-blockers starting 24hours after hospital admission, for acute HF in patients with an left ventricular ejection fraction (EF)70bpm. A total of 71 patients were examined, 33 in the intervention group and 38 in the control group. No differences were observed with respect to their baseline characteristics or standard treatment at discharge. HR at 28days (64.3±7.5 vs. 70.3±9.3bpm, p=0.01) and at 4months (60.6±7.5 vs. 67.8±8bpm, p=0.004) after discharge were significantly lower in the intervention group. Significant differences were found with respect to the EF and brain natriuretic peptide levels at 4months. No differences in clinical events (rehospitalisation/death) were reported at 4months. No severe side effects attributable to the early administration of ivabradine were observed. The early coadministration of ivabradine and beta-blockers during hospital admission for acute HFrEF is feasible and safe, and it produces a significant decrease in HR at 28days and at 4months after hospital discharge. It also seemed to improve systolic function and functional and clinical parameters of HF patients at short-term. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

International Nuclear Information System (INIS)

Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

2009-01-01

The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPAR-γ). Although nifedipine did not affect expression levels of PPAR-γ, it increased the PPAR-γ transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-γ activation.

Improving the prognosis of diabetic patients: evaluating the role of intensive versus moderate blood pressure control with selective angiotensin II receptor blocker (ARB therapy

Directory of Open Access Journals (Sweden)

Martin P Bedigian

2000-06-01

Full Text Available The ABCD (Appropriate Blood Pressure Control in Diabetes and ABCD-2V (Part 2 with Valsartan are prospective, randomised clinical trials which will provide important data on the impact of intensive vs. moderate blood pressure (BP control on microvascular and macrovascular complications in normotensive and hypertensive patients with type 2 diabetes mellitus (DM. The ABCD trial was a five-year study that compared the effects of intensive vs. moderate BP control on the endpoints of nephropathy, retinopathy, neuropathy, and cardiovascular disease events using a calcium channel blocker (CCB and an angiotensin-converting enzyme (ACE inhibitor as the primary antihypertensive agents. The recently published results of the hypertensive cohort of ABCD are reviewed herein. The follow-up study, ABCD-2V, is ongoing and was designed to compare intensive vs. moderate BP control on the same endpoints as the ABCD study, using the highly selective angiotensin II receptor blocker (ARB valsartan as the primary antihypertensive agent. First results of ABCD-2V are expected in 2004. The baseline characteristics for the patients enrolled thus far in the hypertensive cohort of ABCD-2V are reviewed. These studies will provide insight into the role of intensive vs. moderate BP control in the management of normotensive and hypertensive patients with type 2 DM.

?1-Blockers in Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Obstruction: Is Silodosin Different?

OpenAIRE

Roehrborn, Claus G.; Cruz, Francisco; Fusco, Ferdinando

2016-01-01

Available ?1-blockers (ABs) have different profiles of receptor selectivity. Silodosin exhibits the highest selectivity for the ?1A adrenergic receptor. This pharmacological feature couples with a singular urodynamic and clinical profile. The magnitude of bladder outlet obstruction improvement in patients receiving silodosin is higher if compared to other ABs. From a clinical point of view, current evidence suggests an advantage in favor of silodosin in terms of nocturia improvement and cardi...

The evolution of systolic blood pressure as a strong predictor of cardiovascular risk and the effectiveness of fixed-dose ARB/CCB combinations in lowering levels of this preferential target

Directory of Open Access Journals (Sweden)

Jean-Jacques Mourad

2008-12-01

Full Text Available Jean-Jacques MouradHypertension Unit, Avicenne Hospital – AP-HP and Paris XIII University Bobigny, FranceAbstract: Elevated blood pressure is an important cardiovascular risk factor. Although targets for both diastolic blood pressure (DBP and systolic blood pressure (SBP are defined by current guidelines, DBP has historically taken precedence in hypertension management. However, there is strong evidence that SBP is superior to DBP as a predictor of cardiovascular events. Moreover, achieving control of SBP is assuming greater importance amongst an aging population. In spite of the growing recognition of the importance of SBP in reducing cardiovascular risk and the emphasis by current guidelines on SBP control, a substantial proportion of patients still fail to achieve SBP targets, and SBP control is achieved much less frequently than DBP control. Thus, new approaches to the management of hypertension are required in order to control SBP and minimize cardiovascular risk. Fixed-dose combination (FDC therapy is an approach that offers the advantages of multiple drug administration and a reduction in regimen complexity that favors compliance. We have reviewed the latest evidence demonstrating the efficacy in targeting SBP of the most recent FDC products; combinations of the calcium channel blocker (CCB, amlodipine, with angiotensin receptor blockers (ARBs, valsartan or olmesartan. In addition, results from studies with new classes of agent are outlined.Keywords: hypertension, systolic blood pressure, angiotensin receptor blocker, calcium channel blocker, combination therapy

How should we manage heart failure developing in patients already treated with angiotensin-converting enzyme inhibitors and beta-blockers for hypertension, diabetes or coronary disease?

DEFF Research Database (Denmark)

Gustafsson, Finn; Segura, Julian; Ruilope, Luis M

2010-01-01

An increasing number of patients in the community are being treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers for hypertension, coronary disease or diabetic renal and vascular complications. Some of these patients will develop heart...... failure despite such treatment. Based on data from hypertension trials it can be estimated that approximately 5% of treated patients will develop heart failure over 5 years. It is unclear whether patients developing heart failure on and off ACE-inhibitors or beta-blockers, respectively, at the time...

Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

Directory of Open Access Journals (Sweden)

Pieter Spincemaille

2014-10-01

Full Text Available The human pathology Wilson disease (WD is characterized by toxic copper (Cu accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp. The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.

Misperceptions About β-Blockers and Diuretics

Science.gov (United States)

Ubel, Peter A; Jepson, Christopher; Asch, David A

2003-01-01

BACKGROUND Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics. METHODS We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients. RESULTS Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes (P diuretics were less effective and β-blockers were less tolerated than other medications. Moreover, their prescription practices were associated with their provision of free samples provided by pharmaceutical representatives, even after adjusting for other demographic characteristics. Efforts to increase physicians' prescribing of β-blockers and diuretics may need to be directed at overcoming misunderstandings about the effectiveness and tolerability of these medicines

Adverse CNS-effects of beta-adrenoceptor blockers.

Science.gov (United States)

Gleiter, C H; Deckert, J

1996-11-01

In 1962 propranolol, the first beta adrenoceptor antagonist (beta blocker), was brought on to the market. There is now a host of different beta blockers available, and these compounds are among the most commonly prescribed groups of drugs. The efficacy of beta blockers has been proven predominantly for the treatment of cardiovascular diseases. Beta blockers are also used for certain types of CNS disorders, such as anxiety disorders, essential tremor and migraine. While low toxicity means that they have a favorable risk-benefit ratio, given the high intensity of use, it is essential to have a comprehensive knowledge of adverse events. Adverse events of beta blockers that can be related to the CNS are quite often neglected, even in textbooks of clinical pharmacology or review articles, and thus often misdiagnosed. The following article, therefore, after summarizing the use of beta blockers for CNS indications, critically reviews the literature on centrally mediated adverse events. General pharmacological features of beta blockers and their molecular basis of action will briefly be addressed to the extent that they are or may become relevant for central nervous pharmacotherapy and side-effects.

Calcium channel blocker poisoning

Directory of Open Access Journals (Sweden)

Miran Brvar

2005-04-01

Full Text Available Background: Calcium channel blockers act at L-type calcium channels in cardiac and vascular smooth muscles by preventing calcium influx into cells with resultant decrease in vascular tone and cardiac inotropy, chronotropy and dromotropy. Poisoning with calcium channel blockers results in reduced cardiac output, bradycardia, atrioventricular block, hypotension and shock. The findings of hypotension and bradycardia should suggest poisoning with calcium channel blockers.Conclusions: Treatment includes immediate gastric lavage and whole-bowel irrigation in case of ingestion of sustainedrelease products. All patients should receive an activated charcoal orally. Specific treatment includes calcium, glucagone and insulin, which proved especially useful in shocked patients. Supportive care including the use of catecholamines is not always effective. In the setting of failure of pharmacological therapy transvenous pacing, balloon pump and cardiopulmonary by-pass may be necessary.

Associations between ACE-Inhibitors, Angiotensin Receptor Blockers, and Lean Body Mass in Community Dwelling Older Women.

Science.gov (United States)

Bea, Jennifer W; Wassertheil-Smoller, Sylvia; Wertheim, Betsy C; Klimentidis, Yann; Chen, Zhao; Zaslavsky, Oleg; Manini, Todd M; Womack, Catherine R; Kroenke, Candyce H; LaCroix, Andrea Z; Thomson, Cynthia A

2018-01-01

Studies suggest that ACE-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) may preserve skeletal muscle with aging. We evaluated longitudinal differences in lean body mass (LBM) among women diagnosed with hypertension and classified as ACE-I/ARB users and nonusers among Women's Health Initiative participants that received dual energy X-ray absorptiometry scans to estimate body composition ( n =10,635) at baseline and at years 3 and 6 of follow-up. Of those, 2642 were treated for hypertension at baseline. Multivariate linear regression models, adjusted for relevant demographics, behaviors, and medications, assessed ACE-I/ARB use/nonuse and LBM associations at baseline, as well as change in LBM over 3 and 6 years. Although BMI did not differ by ACE-I/ARB use, LBM (%) was significantly higher in ACE-I/ARB users versus nonusers at baseline (52.2% versus 51.3%, resp., p =0.001). There was no association between ACE-I/ARB usage and change in LBM over time. Reasons for higher LBM with ACE-I/ARB use cross sectionally, but not longitundinally, are unclear and may reflect a threshold effect of these medications on LBM that is attenuated over time. Nevertheless, ACE-I/ARB use does not appear to negatively impact LBM in the long term.

Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

International Nuclear Information System (INIS)

Wairagu, Peninah M.; Park, Kwang Hwa; Kim, Jihye; Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il; Jung, Soon-Hee; Yong, Suk-Joong; Jeong, Yangsik

2014-01-01

Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs

Effect of nipradilol, a beta-adrenergic blocker with vasodilating activity, on oxotremorine-induced tremor in mice.

Science.gov (United States)

Iwata, S; Nomoto, M; Fukuda, T

1996-10-01

The effect of nipradilol, a nonselective beta-adrenergic receptor blocker with nitroglycerin-like vasodilating activity, on oxotremorine-induced tremor was studied in mice. General tremor in mice was elicited by 0.5 mg/kg oxotremorine. The tremor was quantified using a capacitance transducer, then analyzed by a signal processor. The strength of the tremor was expressed in "points". The point values of the tremor (mean +/- SE) in control mice for 5 mg/kg (+/-)-propranolol, 2.5 mg/kg arotinolol, 0.5 mg/kg nipradilol, 1.0 mg/kg nipradilol and 2.5 mg/kg nipradilol were 87 +/- 16, 42 +/- 6, 38 +/- 6, 99 +/- 28, 28 +/- 6 and 31 +/- 7, respectively. The strength of the tremor was reduced by all beta-blockers. Although 1.0 mg/kg nipradilol significantly reduced the tremor, further inhibition of the tremor was not obtained with dosages up to 2.5 mg/kg of the drug. In conclusion, nipradilol was effective for suppressing oxotremorine-induced tremor, as were other beta-blockers.

Topical beta-blockers and mortality

NARCIS (Netherlands)

Müskens, Rogier P. H. M.; Wolfs, Roger C. W.; Witteman, Jacqueline C. M.; Hofman, Albert; de Jong, Paulus T. V. M.; Stricker, Bruno H. C.; Jansonius, Nomdo M.

2008-01-01

To study the associations between long-term and short-term use of topical beta-blockers and mortality. Prospective population-based cohort study. To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484 incident beta-blocker users and

EFFICACY OF FIXED COMBINATION OF VALSARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE IN COMPLEX THERAPY OF THE PATIENT OF VERY HIGH CARDIOVASCULAR RISK

Directory of Open Access Journals (Sweden)

I. M. Sokolov

2012-01-01

Full Text Available The high prevalence of arterial hypertension in association with high and very high cardiovascular risk requires widespread use of combined therapy. Current approaches to selection of combination components of antihypertensive drugs are based the efficacy of these drugs proven in multicenter randomized clinical trials. The triple combination of calcium antagonist, angiotensin II receptor blocker and thiazide diuretic is regarded as the best option for combined therapy in patients with arterial hypertension and ischemic heart disease to reduce cardiovascular risk.

Beta Blockers

Science.gov (United States)

... may not work as effectively for people of African heritage and older people, especially when taken without ... conditions/high-blood-pressure/in-depth/beta-blockers/ART-20044522 . Mayo Clinic Footer Legal Conditions and Terms ...

Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.

Science.gov (United States)

Feng, Xiaoli; Luo, Zhidan; Ma, Liqun; Ma, Shuangtao; Yang, Dachun; Zhao, Zhigang; Yan, Zhencheng; He, Hongbo; Cao, Tingbing; Liu, Daoyan; Zhu, Zhiming

2011-07-01

Clinical trials have shown that angiotensin II receptor blockers reduce the new onset of diabetes in hypertensives; however, the underlying mechanisms remain unknown. We investigated the effects of telmisartan on peroxisome proliferator activated receptor γ (PPAR-δ) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in cultured myotubes, as well as on the running endurance of wild-type and PPAR-δ-deficient mice. Administration of telmisartan up-regulated levels of PPAR-δ and phospho-AMPKα in cultured myotubes. However, PPAR-δ gene deficiency completely abolished the telmisartan effect on phospho-AMPKαin vitro. Chronic administration of telmisartan remarkably prevented weight gain, enhanced running endurance and post-exercise oxygen consumption, and increased slow-twitch skeletal muscle fibres in wild-type mice, but these effects were absent in PPAR-δ-deficient mice. The mechanism is involved in PPAR-δ-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPKα level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPKα expression in skeletal muscle was unchanged in PPAR-δ-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-δ as a potential therapeutic target for the prevention of type 2 diabetes. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Antihypertensive treatment and stroke prevention: are angiotensin receptor blockers superior to other antihypertensive agents?

Science.gov (United States)

Armario, Pedro; de la Sierra, Alejandro

2009-06-01

Stroke remains a common vascular event with high mortality and morbidity. After heart disease, stroke is the second leading cause of death worldwide in adult persons. Silent or subclinical stroke is likely to occur with even greater frequency than clinical stroke and increases the risk of subsequent cerebrovascular events. Hypertension is by far the single most important controllable risk factor for stroke. The relationship between blood pressure (BP) and stroke mortality is strong, linear, and continuous in subjects with levels of BP higher than 115/75 mm Hg. Blood pressure reduction by antihypertensive treatment is clearly efficacious in the prevention of stroke (both primary and secondary). Although meta-analyses suggest that BP reduction, per se, is the most important determinant for stroke risk reduction, the question is if specific classes of antihypertensive drugs offer special protection against stroke is still controversial. Some studies have suggested that angiotensin receptors blockers (ARBs) appear to offer additional protection against stroke. This has been hypothesized in studies in hypertensives, such as LIFE and SCOPE, and especially in the only comparative trial focused on secondary stroke prevention. In the MOSES trial, the comparison of eprosartan versus nitrendipine in patients with a previous stroke resulted, despite a similar BP reduction, in a significant reduction in the primary composite endpoint of total mortality plus cardiovascular and cerebrovascular events, including recurrent events. These results may suggest a blood pressure-independent effect of ARBs, which can be mediated through several mechanisms, including their ability to counteract other markers of target organ damage, but also through a direct neuroprotective effect.

Induction of parturition in the bitch with the progesterone-receptor blocker aglépristone.

Science.gov (United States)

Baan, M; Taverne, M A M; Kooistra, H S; de Gier, J; Dieleman, S J; Okkens, A C

2005-04-15

The triggering mechanism for parturition in the bitch remains unclear. Consequently, the development of drugs to successfully induce parturition in the dog has been difficult. The aim of this study was to evaluate the efficacy of the progesterone-receptor blocker aglépristone for the induction of parturition in beagle bitches. The course of parturition was therefore investigated in six parturitions induced by aglépristone and in six spontaneous parturitions. In addition, data were collected on pup survival and growth rates. Aglépristone was administered twice with a 9h interval on day 58 of pregnancy. If parturition did not proceed a standard intervention protocol was applied. Expulsion of the first pup occurred between 32 and 56 h after the first treatment with aglépristone, at which time the plasma progesterone concentration was still elevated. Accordingly, the gestation length of the bitches in the induced group (59.5+/-0.2 days) was significantly shorter than that of the spontaneously whelping bitches (62.2+/-0.5 days). The expulsion phase length, the inter-pup interval, the number of puppies born dead, and the number of clinical interventions needed during parturition did not significantly differ between the spontaneously whelping and the induced group. Pup survival and mean birth weights in the two groups did not differ significantly and aglépristone treatment had no significant influence on the growth rates. The results of this study show that aglépristone is an effective drug which can be used safely for the induction of parturition in the dog.

Optimal use of β-blockers in high-risk hypertension: A guide to dosing equivalence

Directory of Open Access Journals (Sweden)

Janet B McGill

2010-05-01

Full Text Available Janet B McGillDepartment of Medicine, Washington University School of Medicine, St. Louis, Missouri, USAAbstract: Hypertension is the number one diagnosis made by primary care physicians, placing them in a unique position to prescribe the antihypertensive agent best suited to the individual patient. In individuals with diabetes mellitus, blood pressure (BP levels > 130/80 mmHg confer an even higher risk for cardiovascular and renal disease, and these patients will benefit from aggressive antihypertensive treatment using a combination of agents. β‑blockers are playing an increasingly important role in the management of hypertension in high-risk patients. β‑blockers are a heterogeneous class of agents, and this review presents the differences between β‑blockers and provides evidence-based protocols to assist in understanding dose equivalence in the selection of an optimal regimen in patients with complex needs. The clinical benefits provided by β‑blockers are only effective if patients adhere to medication treatment long term. β‑blockers with proven efficacy, once-daily dosing, and lower side effect profiles may become instrumental in the treatment of hypertensive diabetic and nondiabetic patients.Keywords: antihypertensive, blood pressure, atenolol, carvedilol, labetalol, metoprolol, nebivolol

Valsartan combination therapy in the management of hypertension – patient perspectives and clinical utility

OpenAIRE

Nash, David T; McNamara, Michael S

2009-01-01

The morbidity and mortality benefits of lowering blood pressure (BP) in hypertensive patients are well established, with most individuals requiring multiple agents to achieve BP control. Considering the important role of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of hypertension, a key component of combination therapy should include a RAAS inhibitor. Angiotensin receptor blockers (ARBs) lower BP, reduce cardiovascular risk, provide organ protection, and are among t...

Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy

NARCIS (Netherlands)

Roscioni, Sara S.; de Zeeuw, Dick; Bakker, Stephan J. L.; Lambers Heerspink, Hiddo J.

2012-01-01

Mineralocorticoid-receptor antagonists (MRAs) reduce blood pressure and albuminuria in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. The use of MRAs, however, is limited by the occurrence of hyperkalaemia, which frequently occurs in patients

Beta-blockers: friend or foe in asthma?

Directory of Open Access Journals (Sweden)

Arboe B

2013-07-01

Full Text Available Bente Arboe, Charlotte Suppli UlrikDepartment of Pulmonary Medicine, Hvidovre Hospital and University of Copenhagen, Hvidovre, DenmarkBackground and aim: Recently, β-blockers have been suggested as a potential maintenance treatment option for asthma. The aim of this review is to provide an overview of the current knowledge of the potential benefits and risks of β-blocker therapy for asthma.Method: Systematic literature review.Results: No significant increase in the number of patients requiring rescue oral corticosteroid for an exacerbation of asthma has been observed after initiation of β-blocker treatment. Patients with mild to moderate reactive airway disease, probably both asthma and chronic obstructive pulmonary disease, may have a limited fall in forced expiratory volume in 1 second (FEV1 following single-dose administration of β-blocker, whereas no change in FEV1 has been reported following long-term administration. In a murine model of asthma, long-term administration of β-blockers resulted in a decrease in airway hyperresponsiveness, suggesting an anti-inflammatory effect. In keeping with this, long-term administration of a nonselective β-blocker to steroid-naïve asthma patients has shown a dose-dependent improvement in airway hyperresponsiveness, and either an asymptomatic fall in FEV1 or no significant change in FEV1. Furthermore, available studies show that bronchoconstriction induced by inhaled methacholine is reversed by salbutamol in patients on regular therapy with a β-blocker. On the other hand, a recent placebo-controlled trial of propranolol and tiotropium bromide added to inhaled corticosteroids revealed no effect on airway hyperresponsiveness and a small, not statistically significant, fall in FEV1 in patients classified as having mild to moderate asthma.Conclusion: The available, although limited, evidence suggests that a dose-escalating model of β-blocker therapy to patients with asthma is well tolerated, does not

How should we manage heart failure developing in patients already treated with angiotensin-converting enzyme inhibitors and beta-blockers for hypertension, diabetes or coronary disease?

DEFF Research Database (Denmark)

Gustafsson, Finn; Segura, Julian; Ruilope, Luis M

2010-01-01

An increasing number of patients in the community are being treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers for hypertension, coronary disease or diabetic renal and vascular complications. Some of these patients will develop heart...... failure despite such treatment. Based on data from hypertension trials it can be estimated that approximately 5% of treated patients will develop heart failure over 5 years. It is unclear whether patients developing heart failure on and off ACE-inhibitors or beta-blockers, respectively, at the time...... of heart failure diagnosis have similar prognosis.Treatment options for patients developing heart failure while already treated with ACE inhibitors/ARBs and beta-blockers are very limited if current heart failure guidelines are followed. In this review possible strategies are outlined and important areas...

Introductory statement: Of receptors and analogs in renin-angiotensin-aldosterone and adrenergic systems

International Nuclear Information System (INIS)

Eliahou, H.E.; Iaina, A.

1980-01-01

This article reports on the role of the octapeptides angiotensin II (A II)-effector and its receptor on hypertensive patients and in animal experiments. By applying the A-II-receptor blockers, vasodilates drugs, β-receptor blockers and by sodium depletion, the behaviour of the blood pressure, the plasmareninactivity, and of the aldosteron were investigated; a comparative investigation between the A II and A III effectors was also carried out. The iodo-hippurate uptake was reduced with an artificially produced renal arterial ischemia. In general, this investigation provided new viewpoints in the understanding of the possible pathogenetic mechanism of essential hypertonism. (APR) [de

Nebivolol and valsartan as a fixed-dose combination for the treatment of hypertension.

Science.gov (United States)

Sander, Gary E; Giles, Thomas D

2015-04-01

The fixed-dose combination of nebivolol and valsartan drug has been clinically evaluated and demonstrated to represent a unique combination of nebivolol, a selective β1-adrenoceptor antagonist and a β3-adrenoceptor agonist; β3 receptor activation increases endothelial nitric oxide and produces vasodilation. Valsartan is highly selective angiotensin AT1 receptor blocker and exerts its major pharmacological effect by decreasing angiotensin II-induced vasoconstriction and production of aldosterone. The addition of nebivolol counteracts the effects of increased angiotensin II concentrations resulting from potent AT1 blockade. This review describes a recently completed trial establishing the efficacy of the nebivolol/valsartan combination. This review provides a literature search of pertinent pharmacological and clinical data that describes the mechanisms of both drugs individually and the results of a clinical trial comparing fixed-dose combinations of nebivolol with valsartan as compared with each drug as monotherapy. Fixed-dose combination drugs are intended to improve patient compliance and reduce drug costs, as well as to reduce long-term cardiovascular event rates and block counter-regulatory effects due to monotherapy. The vast majority of hypertensive patients will require at least two medications. We believe that the clinical evidence suggests that the combination of nebivolol with valsartan offers a definite clinical benefit, combining β1-adrenoceptor and angiotensin AT1 receptor blockade with β3 receptor activation and resultant increase in nitric oxide and vasodilation.

Beta-blocker under-use in COPD patients

Directory of Open Access Journals (Sweden)

Lim KP

2017-10-01

Full Text Available Kuan Pin Lim,1,2 Sarah Loughrey,1 Michael Musk,1,2 Melanie Lavender,1,2 Jeremy P Wrobel1–3 1Advanced Lung Disease Unit, Royal Perth Hospital, Perth, WA, Australia; 2Respiratory Department, Fiona Stanley Hospital, Murdoch, WA, Australia; 3School of Medicine, University of Notre Dame, Fremantle, WA, Australia Background: Cardiovascular (CVS comorbidities are common in COPD and contribute significantly to morbidity and mortality, especially following acute exacerbations of COPD (AECOPD. Beta-blockers (BBs are safe and effective in COPD patients, with demonstrated survival benefit following myocardial infarction. We sought to determine if BBs are under-prescribed in patients hospitalized with AECOPD. We also sought to determine inpatient rates of CVS and cerebrovascular complications, and their impact on patient outcomes. Methods: Retrospective hospital data was collected over a 12-month period. The medical records of all patients >40 years of age coded with a diagnosis of AECOPD were analyzed. Prevalent use and incident initiation of BBs were assessed. Comorbidities including indications and contraindications for BB use were analyzed. Results: Of the 366 eligible patients, 156 patients (42.6% had at least one indication for BB use – of these patients, only 53 (34.0% were on BB therapy and 61 (39.1% were not on BB therapy but had no listed contraindication. Prevalent use of BBs at the time of admission in all 366 patients was 19.7%, compared with 45.6%, 39.6% and 45.9% use of anti-platelets, statins and angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, respectively. CVS and cerebrovascular complications were common in this population (57 patients, 16% and were associated with longer length of stay (p<0.01 and greater inpatient mortality (p=0.02. Conclusions: BBs are under-prescribed in COPD patients despite clear indication(s for their use. Further work is required to explore barriers to BB prescribing in COPD patients

Two novel real time cell-based assays quantify beta-blocker and NSAID specific effects in effluents of municipal wastewater treatment plants.

Science.gov (United States)

Bernhard, Kevin; Stahl, Cordula; Martens, Regina; Köhler, Heinz-R; Triebskorn, Rita; Scheurer, Marco; Frey, Manfred

2017-05-15

Pharmaceuticals, such as beta-blockers, nonsteroidal anti-inflammatory drugs (NSAIDs) as well as their metabolites are introduced into the water cycle via municipal wastewater treatment plant (WWTP) effluents in all industrialized countries. As the amino acid sequences of the biological target molecules of these pharmaceuticals - the beta-1 adrenergic receptor for beta-blockers and the cyclooxygenase for NSAIDs - are phylogenetically conserved among vertebrates it is reasonable that wildlife vertebrates including fish physiologically respond in a similar way to them as documented in humans. Consequently, beta-blockers and NSAIDs both exhibit their effects according to their mode of action on one hand, but on the other hand that may lead to unwanted side effects in non-target species. To determine whether residuals of beta-1 adrenergic receptor antagonists and cyclooxygenase inhibitors may pose a risk to aquatic organisms, one has to know the extent to which such organisms respond to the total of active compounds, their metabolites and transformation products with the same modes of action. To cope with this demand, two cell-based assays were developed, by which the total beta-blocker and cyclooxygenase inhibitory activity can be assessed in a given wastewater or surface water extract in real time. The measured activity is quantified as metoprolol equivalents (MetEQ) of the lead substance metoprolol in the beta-blocker assay, and diclofenac equivalents (DicEQ) in the NSAID assay. Even though MetEQs and DicEQs were found to surpass the concentration of the respective lead substances (metoprolol, diclofenac), as determined by chemical analysis by a factor of two to three, this difference was shown to be reasonably explained by the presence and action of additional active compounds with the same mode of action in the test samples. Thus, both in vitro assays were proven to integrate effectively over beta-blocker and NSAID activities in WWTP effluents in a very sensitive

Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels

DEFF Research Database (Denmark)

Dupuis, Delphine S; Klaerke, Dan A; Olesen, Søren-Peter

2005-01-01

Patients with congenital long QT syndrome may develop arrhythmias under conditions of increased sympathetic tone. We have addressed whether some of the beta-adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether....... These data showed that HERG blockade by beta-adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).......-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the beta1-receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line...

Calcium Channel Blockers

Science.gov (United States)

... Certain calcium channel blockers interact with grapefruit products. Kaplan NM, et al. Treatment of hypertension: Drug therapy. In: Kaplan's Clinical Hypertension. 11th ed. Philadelphia, Pa.: Wolters Kluwer ...

Beta-blocker use and fall risk in older individuals: Original results from two studies with meta-analysis.

Science.gov (United States)

Ham, Annelies C; van Dijk, Suzanne C; Swart, Karin M A; Enneman, Anke W; van der Zwaluw, Nikita L; Brouwer-Brolsma, Elske M; van Schoor, Natasja M; Zillikens, M Carola; Lips, Paul; de Groot, Lisette C P G M; Hofman, Albert; Witkamp, Renger F; Uitterlinden, André G; Stricker, Bruno H; van der Velde, Nathalie

2017-10-01

To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Data from two prospective studies were used, including community-dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B-PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time-varying β-blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β-blocker use, their characteristics - selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism - and fall risk. The results of the studies were combined using meta-analyses. In total 2917 participants encountered a fall during a total follow-up time of 89 529 years. Meta-analysis indicated no association between use of any β-blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 [95% confidence interval (CI) 0.88-1.06]. Use of a selective β-blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83-1.01). Use of a nonselective β-blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01-1.48). Other β-blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk. Our study suggests that use of a nonselective β-blocker, contrary to selective β-blockers, is associated with an increased fall risk in an older population. In clinical practice, β-blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β-blocker in this age group, and the pros and cons for β-blocker classes should be taken into consideration. © 2017 The British Pharmacological Society.

HEART FAILURE, DIABETES, BETA-BLOCKERS AND RISK OF HYPOGLYCEMIA

Directory of Open Access Journals (Sweden)

A. A. Aleksandrov

2008-01-01

Full Text Available Aim. To evaluate an influence of carvedilol on risk of hypoglycemia in patients with diabetes type 2 (D2 and chronic heart failure (CHF treated with angiotensin converting enzyme (ACE inhibitors.Material and methods. 13 patients (10 men, 3 women; aged 59,8±6,7 y.o. with D2 and CHF caused by ischemic heart disease were included in the study. Before inclusion all patients were treated with ACE inhibitors and various beta-blockers (atenolol, metoprolol, bisoprolol. These beta-blockers were changed for carvedilol. Heart ultrasonography, blood pressure control, glycemia monitoring, HbA1c level determination were performed before, during and after carvedilol therapy.Results. Carvedilol reduces frequency and duration of hypoglycaemia episodes. There were not episodes of severe hypoglycaemia during carvedilol therapy.Conclusion. Carvedilol reduces risk of hypoglycemia when it is used in combination with ACE inhiditors in diabetic patients with CHF.

Guideline-recommended therapy, including beta-blocker utilization, in patients with chronic heart failure: results from a Canadian community hospital heart function clinic

Directory of Open Access Journals (Sweden)

Heffernan M

2016-06-01

Full Text Available Michael Heffernan Division of Cardiology, Oakville Trafalgar Memorial Hospital, Oakville, ON, Canada Abstract: A comprehensive analysis of beta-blocker utilization and other guideline-recommended therapies for the treatment of chronic heart failure in a Canadian community hospital heart function clinic has not been undertaken and was, therefore, the focus of this study. The proportion of patients who would be potential candidates for ivabridine and sacubitril–valsartan therapy as a result of fulfilling the criteria for enrollment in either the Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT study (left-ventricular ejection fraction [LVEF] >35%, sinus rhythm, New York Heart Association II–IV or the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI with angiotensin-converting enzyme inhibitor (ACEI to determine impact on global Mortality and Morbidity in Heart Failure (PARADIGM-HF study (LVEF <40%, New York Heart Association II–IV, glomerular filtration rate >30 mL/min, was also assessed. A retrospective cross-sectional analysis was carried out in all 371 patients treated in this community heart function clinic for at least a 12-month period. The patients were elderly (mean age 74±13.3 years and predominately male (61.5% with symptomatic (82.5% moderate left-ventricular dysfunction (LVEF 45.4%±15.6%. A substantial proportion of the patients also had a diagnosis of atrial fibrillation (52.8%. The total use of beta blockers exceeded 87%, while 100% of patients without a documented contraindication or intolerance to a beta blocker received therapy. Adherence to other guideline-recommended pharmacotherapies specifically for heart failure with reduced left ventricular ejection was high: 86.1% of the eligible patients were treated with an ACEI/angiotensin receptor blocker and 61.9% received a mineralcorticoid receptor antagonist. We determined that 13.7% of the complement of this heart

Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson's Disease

National Research Council Canada - National Science Library

Schwarzschild, Michael A; Xu, Kui

2008-01-01

...) that are leading candidate modulators of PD risk. In Year 4 we have obtained and reported evidence that the adenosine receptor blocker caffeine as well as specific genetic depletion of the A2A subtype of adenosine receptor...

An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

Directory of Open Access Journals (Sweden)

Masaya Koshizaka

2012-01-01

Full Text Available Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1 is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway.

In vivo imaging of oxidative stress in the kidney of diabetic mice and its normalization by angiotensin II type 1 receptor blocker

International Nuclear Information System (INIS)

Sonta, Toshiyo; Inoguchi, Toyoshi; Matsumoto, Shingo; Yasukawa, Keiji; Inuo, Mieko; Tsubouchi, Hirotaka; Sonoda, Noriyuki; Kobayashi, Kunihisa; Utsumi, Hideo; Nawata, Hajime

2005-01-01

This study was undertaken to evaluate oxidative stress in the kidney of diabetic mice by electron spin resonance (ESR) imaging technique. Oxidative stress in the kidney was evaluated as organ-specific reducing activity with the signal decay rates of carbamoyl-PROXYL probe using ESR imaging. The signal decay rates were significantly faster in corresponding image pixels of the kidneys of streptozotocin-induced diabetic mice than in those of controls. This technique further demonstrated that administration of angiotensin II type 1 receptor blocker (ARB), olmesartan (5 mg/kg), completely restored the signal decay rates in the diabetic kidneys to control values. In conclusion, this study provided for the first time the in vivo evidence for increased oxidative stress in the kidneys of diabetic mice and its normalization by ARB as evaluated by ESR imaging. This technique would be useful as a means of further elucidating the role of oxidative stress in diabetic nephropathy

A Randomized, Open-Label, Comparative Study of Efficacy and Safety of Tolterodine Combined with Tamsulosin or Doxazosin in Patients with Benign Prostatic Hyperplasia

Science.gov (United States)

Cao, Yanwei; Wang, Yonghua; Guo, Lei; Yang, Xuecheng; Chen, Tao; Niu, Haitao

2016-01-01

Background Benign prostatic hyperplasia (BPH), a common disease in men over age 50 years, often causes bladder outlet obstruction and lower urinary tract symptoms (LUTS). Alpha blockers in combination with muscarinic receptor antagonists may have the potential to improve symptoms. This study aimed to assess the efficacy and safety of doxazosin or tamsulosin combined with tolterodine extend release (ER) in patients with BPH and LUTS. Material/Methods In a prospective, randomized, open-label study (ChiCTR-IPR-15005763), 220 consecutive men with BPH and LUTS were allocated to receive doxazosin 4 mg and tolterodine ER 4 mg per day (doxazosin group) or tamsulosin 0.2 mg and tolterodine ER 4 mg per day (tamsulosin group). Treatment lasted 12 weeks. The primary endpoint was the international prostatic symptom score (IPSS). Secondary endpoints were quality of life (QoL) and maximum flow rate (Qmax), which were evaluated at 0, 6, and 12 weeks, and urodynamic parameters assessed at 0 and 12 weeks. Results A total of 192 patients completed the trial. Baseline measurements showed no differences between the groups. After 6 weeks, IPSS improved in both groups and QoL was significantly better in the doxazosin group (P=0.01). After 12 weeks, Qmax, IPSS, QoL, intravesical pressure (Pves), and bladder compliance (BC) in the doxazosin group were significantly better than in the tamsulosin group (P=0.03, P<0.001, P<0.001, P=0.027, and P=0.044, respectively). Conclusions Administration of alpha blockers combined with muscarinic receptor blocker for 12 weeks improved LUTS in men with BPH. PMID:27260129

Use of beta-blockers and risk of serious upper gastrointestinal bleeding

DEFF Research Database (Denmark)

Reilev, Mette; Damkier, Per; Rasmussen, Lotte

2017-01-01

Background: Some studies indicate a reduced risk of serious upper gastrointestinal bleeding (UGIB) for users of beta-blockers, but the association remains to be confirmed in larger studies and characterized with respect to differences among beta-blockers. We aimed to assess whether beta-blocker use...... and adjusted odds ratios (ORs) of the association between current beta-blocker use and the risk of UGIB by using conditional logistic regression and further stratified by selective and non-selective beta-blockers, respectively. Results: We identified 3571 UGIB cases and 35,582 controls. Use of beta-blockers...... was not found to be associated with a decreased risk of UGIB (adjusted OR 1.10; 95% CI: 1.00-1.21). The association remained neutral after stratification by selective and non-selective beta-blockers, and by single beta-blocker substances. Similarly, we found no association between current beta-blocker use...

Cognitive enhancing effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on learning and memory

Science.gov (United States)

Nade, V. S.; Kawale, L. A.; Valte, K. D.; Shendye, N. V.

2015-01-01

Objective: The present study was designed to investigate cognitive enhancing property of angiotensin-converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in rats. Materials and Methods: The elevated plus maze (EPM), passive avoidance test (PAT), and water maze test (WMT) were used to assess cognitive enhancing activity in young and aged rats. Ramipril (10 mg/kg, p.o.), perindopril (10 mg/kg, i.p), losartan (20 mg/kg, i.p), and valsartan (20 mg/kg, p.o) were administered to assess their effect on learning and memory. Scopolamine (1 mg/kg, i.p) was used to impair cognitive function. Piracetam (200 mg/kg, i.p) was used as reference drug. Results: All the treatments significantly attenuated amnesia induced by aging and scopolamine. In EPM, aged and scopolamine-treated rats showed an increase in transfer latency (TL) whereas, ACEI and ARBs showed a significant decrease in TL. Treatment with ACEI and ARBs significantly increased step down latencies and decreased latency to reach the platform in target quadrant in young, aged and scopolamine-treated animals in PAT and WMT, respectively. The treatments inhibited acetylcholinesterase (AChE) enzyme in the brain. Similarly, all the treatments attenuated scopolamine-induced lipid peroxidation and normalize antioxidant enzymes. Conclusion: The results suggest that the cognitive enhancing effect of ACEI and ARBs may be due to inhibition of AChE or by regulation of antioxidant system or increase in formation of angiotensin IV. PMID:26069362

β1-Adrenoceptor blocker aggravated ventricular arrhythmia.

Science.gov (United States)

Wang, Yan; Patel, Dimpi; Wang, Dao Wu; Yan, Jiang Tao; Hsia, Henry H; Liu, Hao; Zhao, Chun Xia; Zuo, Hou Juan; Wang, Dao Wen

2013-11-01

To assess the impact of β1 -adrenoceptor blockers (β1 -blocker) and isoprenaline on the incidence of idiopathic repetitive ventricular arrhythmia that apparently decreases with preprocedural anxiety. From January 2010 to July 2012, six patients were identified who had idiopathic ventricular arrhythmias that apparently decreased (by greater than 90%) with preprocedural anxiety. The number of ectopic ventricular beats per hour (VPH) was calculated from Holter or telemetry monitoring to assess the ectopic burden. The mean VPH of 24 hours from Holter before admission (VPH-m) was used as baseline (100%) for normalization. β1 -Blockers, isoprenaline, and/or aminophylline were administrated successively on the ward and catheter lab to evaluate their effects on the ventricular arrhythmias. Among 97 consecutive patients with idiopathic ventricular arrhythmias, six had reduction in normalized VPHs in the hour before the scheduled procedure time from (104.6 ± 4.6%) to (2.8 ± 1.6%) possibly due to preprocedural anxiety (P < 0.05), then increased to (97.9 ± 9.7%) during β1 -blocker administration (P < 0.05), then quickly reduced to (1.6 ± 1.0%) during subsequent isoprenaline infusion. Repeated β1 -blocker quickly counteracted the inhibitory effect of isoprenaline, and VPHs increased to (120.9 ± 2.4%) from (1.6 ± 1.0%; P < 0.05). Isoprenaline and β1 -blocker showed similar effects on the arrhythmias in catheter lab. In some patients with structurally normal heart and ventricular arrhythmias there is a marked reduction of arrhythmias associated with preprocedural anxiety. These patients exhibit a reproducible sequence of β1 -blocker aggravation and catecholamine inhibition of ventricular arrhythmias, including both repetitive ventricular premature beats and monomorphic ventricular tachycardia. ©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.

α1-Blockers in Men with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Obstruction: Is Silodosin Different?

Science.gov (United States)

Roehrborn, Claus G; Cruz, Francisco; Fusco, Ferdinando

2017-01-01

Available α1-blockers (ABs) have different profiles of receptor selectivity. Silodosin exhibits the highest selectivity for the α 1A adrenergic receptor. This pharmacological feature couples with a singular urodynamic and clinical profile. The magnitude of bladder outlet obstruction improvement in patients receiving silodosin is higher if compared to other ABs. From a clinical point of view, current evidence suggests an advantage in favor of silodosin in terms of nocturia improvement and cardiovascular safety. The incidence of ejaculatory dysfunction with silodosin is higher compared to other Abs.

The role of adrenergic receptors in nicotine-induced hyperglycemia ...

African Journals Online (AJOL)

The role of adrenergic receptors in nicotine-induced hyperglycaemia has not been well studied in amphibians. Thus, this study investigates the effects of alpha and beta adrenergic receptor blockers in nicotine-induced hyperglycaemia in the common African toad Bufo regularis. Toads fasted for 24 h were anaesthetized with ...

The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

DEFF Research Database (Denmark)

Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels

2011-01-01

The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...

Systematic review of use of β-blockers in sepsis

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Cyril Jacob Chacko

2015-01-01

Conclusion: There is insufficient evidence to justify the routine use of β-blockers in sepsis. A large adequately powered multi-centered randomized controlled clinical trial is required to address the question on the efficacy of β-blocker usage in sepsis. This trial should also consider a number of important questions including the choice of β-blocker used, optimal dosing, timing of intervention, duration of intervention and discontinuation of the drug. Until such time based on the available evidence, there is no place for the use of β-blockers in sepsis in current clinical practice.

Ramelteon combined with an ?1-blocker decreases nocturia in men with benign prostatic hyperplasia

OpenAIRE

Kawahara, Takashi; Morita, Satoshi; Ito, Hiroki; Terao, Hideyuki; Sakata, Ryoko; Ishiguro, Hitoshi; Tanaka, Katsuyuki; Miyamoto, Hiroshi; Matsuzaki, Junichi; Kubota, Yoshinobu; Uemura, Hiroji

2013-01-01

Background Nocturia is defined as waking one or more times during the night due to the urge to void. Recently, the effectiveness of several sedatives and analgesics for nocturia has been reported. We herein investigated the effects of ramelteon, an antioxidant and sleep inducer, on nocturia unresponsive to ?1-blocker monotherapy in males with lower urinary tract symptoms (LUTS) as a pilot study. Methods Subjects were 19 patients who had LUTS suggestive of benign prostate hyperplasia, received...

Three in one: safety, efficacy, and patient acceptability of triple fixed-dose combination medicine in the management of hypertension

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Taylor AA

2012-08-01

Full Text Available Addison A Taylor, Shawn RagbirDepartment of Medicine, Baylor College of Medicine, Houston, TX, USAAbstract: Hypertensive patients whose blood pressures are more than 20 mmHg above their goal will often require three or more medications. Careful selection of medications whose actions are complementary or have an improved adverse effect profile when combined can affect not only the blood pressure but also patient acceptance, thus improving persistence in taking the medications as prescribed. This review will highlight the three single-pill three-drug combinations currently available in the US and will address their efficacy, safety, and tolerability. All three include the dihydropyridine calcium-channel blocker, amlodipine, and the thiazide diuretic, hydrochlorothiazide. They each contain a different renin–angiotensin system blocker. One includes the angiotensin-receptor blocker, olmesartan, while another contains valsartan. The third combination includes the direct renin inhibitor, aliskiren. All three fixed-dose combinations (FDC at maximum doses of each component lowers the blood pressure of patients with stage II hypertension by 37 to 40 mmHg systolic and 21 to 25 mmHg diastolic, which is superior to any two of the components that comprise the three-drug FDC. These drugs are effective in males and females, the elderly, diabetics, minority populations, and patients with metabolic syndrome. Triple-drug FDCs are well tolerated with a low incidence of adverse effects, the most common being peripheral edema related to amlodipine. Extrapolation of data from two-drug FDC suggests that medication compliance (adherence and persistence should be better with these FDCs than with the individual components taken as separate medications, although additional studies are necessary to confirm this.Keywords: calcium-channel blockers, hypertension, patient tolerability, renin–angiotensin system antagonists, safety, triple-drug combinations

Systematic review of use of β-blockers in sepsis.

Science.gov (United States)

Chacko, Cyril Jacob; Gopal, Shameer

2015-01-01

We proposed a review of present literature and systematic analysis of present literature to summarize the evidence on the use of β-blockers on the outcome of a patient with severe sepsis and septic shock. Medline, EMBASE, Cochrane Library were searched from 1946 to December 2013. The bibliography of all relevant articles was hand searched. Full-text search of the grey literature was done through the medical institution database. The database search identified a total of 1241 possible studies. The citation list was hand searched by both the authors. A total of 9 studies were identified. Most studies found a benefit from β-blocker administration in sepsis. This included improved heart rate (HR) control, decreased mortality and improvement in acid-base parameters. Chronic β-blocker usage in sepsis was also associated with improved mortality. The administration of β-blockers during sepsis was associated with better control of HR. The methodological quality of all the included studies, however, was poor. There is insufficient evidence to justify the routine use of β-blockers in sepsis. A large adequately powered multi-centered randomized controlled clinical trial is required to address the question on the efficacy of β-blocker usage in sepsis. This trial should also consider a number of important questions including the choice of β-blocker used, optimal dosing, timing of intervention, duration of intervention and discontinuation of the drug. Until such time based on the available evidence, there is no place for the use of β-blockers in sepsis in current clinical practice.

Beta-Blockers for Exams Identify Students at High Risk of Psychiatric Morbidity.

Science.gov (United States)

Butt, Jawad H; Dalsgaard, Søren; Torp-Pedersen, Christian; Køber, Lars; Gislason, Gunnar H; Kruuse, Christina; Fosbøl, Emil L

2017-04-01

Beta-blockers relieve the autonomic symptoms of exam-related anxiety and may be beneficial in exam-related and performance anxiety, but knowledge on related psychiatric outcomes is unknown. We hypothesized that beta-blocker therapy for exam-related anxiety identifies young students at risk of later psychiatric events. Using Danish nationwide administrative registries, we studied healthy students aged 14-30 years (1996-2012) with a first-time claimed prescription for a beta-blocker during the exam period (May-June); students who were prescribed a beta-blocker for medical reasons were excluded. We matched these students on age, sex, and time of year to healthy and study active controls with no use of beta-blockers. Risk of incident use of antidepressants, incident use of other psychotropic medications, and suicide attempts was examined by cumulative incidence curves for unadjusted associations and multivariable cause-specific Cox proportional hazard analyses for adjusted hazard ratios (HRs). We identified 12,147 healthy students with exam-related beta-blocker use and 12,147 matched healthy students with no current or prior use of beta-blockers (median age, 19 years; 80.3% women). Among all healthy students, 0.14% had a first-time prescription for a beta-blocker during the exam period with the highest proportion among students aged 19 years (0.39%). Eighty-one percent of the students filled only that single prescription for a beta-blocker during follow-up. During follow-up, 2225 (18.3%) beta-blocker users and 1400 (11.5%) nonbeta-blocker users were prescribed an antidepressant (p beta-blocker users and 658 (5.4%) nonbeta-blocker users were prescribed a psychotropic drug (p beta-blocker users and 6 (0.05%) nonbeta-blocker users attempted suicide (p = 0.03). Exam-related beta-blocker use was associated with an increased risk of antidepressant use (adjusted HRs, 1.68 [95% confidence intervals (CIs), 1.57-1.79], p beta-blockers during the exam period was

The role of nitrates, beta blockers, and calcium antagonists in stable angina pectoris.

Science.gov (United States)

Chan, P K; Heo, J Y; Garibian, G; Askenase, A; Segal, B L; Iskandrian, A S

1988-09-01

Numerous controlled studies have shown that nitrates, beta blockers, and calcium antagonists are effective in the treatment of stable angina pectoris. The pharmacokinetics, pharmacodynamics, and hemodynamic effects of these agents are different, and thus combination therapy offers additive improvement and also counterbalancing of the undesirable side effects of each drug. The choice of therapy depends on the severity of symptoms, associated diseases, compliance, side effects, and status of left ventricular function. The main mechanism of improvement is a decrease in myocardial oxygen consumption, though an increase in coronary blood flow is another potential reason for the use of calcium blockers. This review considers the properties of these drugs, their mechanism of action, and the results of randomized studies.

Fixed-dose combination therapy of nebivolol and valsartan for the treatment of hypertension.

Science.gov (United States)

Sander, Gary E; Fernandez, Camilo; Giles, Thomas D

2016-01-01

Recent large clinical trials have refuted earlier suggestions from the Joint National Committee 8 committee that less aggressive targets for blood pressure control were all that could be justified in most hypertensive patients. It now does appear that in fact "lower is better," with blood pressure targets valsartan, an angiotensin II subtype 1 receptor blocker, were more effective in reducing blood pressure than the corresponding monotherapies, with comparable tolerability. In addition, an ABPM-biomarkers substudy from that trial (n=805) demonstrated that the FDC prevented a valsartan-induced increase in plasma renin activity, and that the nebivolol/valsartan 20/320 mg/day dose reduced plasma aldosterone concentration significantly more than valsartan 320 mg/day. This article will describe the properties of nebivolol that make it unique and separate it from other β-blockers, and will further support the pharmacological advantages of this particular combination.

Calcium channel blockers and Alzheimer's disease★

Science.gov (United States)

Tan, Yi; Deng, Yulin; Qing, Hong

2012-01-01

Alzheimer's disease is characterized by two pathological hallmarks: amyloid plaques and neurofibrillary tangles. In addition, calcium homeostasis is disrupted in the course of human aging. Recent research shows that dense plaques can cause functional alteration of calcium signals in mice with Alzheimer's disease. Calcium channel blockers are effective therapeutics for treating Alzheimer's disease. This review provides an overview of the current research of calcium channel blockers involved in Alzheimer's disease therapy. PMID:25767489

Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly

Directory of Open Access Journals (Sweden)

Bodh I Jugdutt

2010-12-01

Full Text Available Bodh I JugduttDivision of Cardiology, Department of Medicine, University of Alberta and Hospital, Edmonton, CanadaAbstract: Elderly patients (age≥65 years with hypertension are at high risk for vascular complications, especially when diabetes is present. Antihypertensive drugs that inhibit the renin-angiotensin system have been shown to be effective for controlling blood pressure in adult and elderly patients. Importantly, renin-angiotensin system inhibitors were shown to have benefits beyond their classic cardioprotective and vasculoprotective effects, including reducing the risk of new-onset diabetes and associated cardiovascular effects. The discovery that the renin-angiotensin system inhibitor and angiotensin II type 1 (AT1 receptor blocker (ARB, telmisartan, can selectively activate the peroxisome proliferator-activated receptor-γ (PPARγ, an established antidiabetic drug target provides the unique opportunity to prevent and treat cardiovascular complications in high-risk elderly patients with hypertension and new-onset diabetes. Two large clinical trials, ONTARGET (Ongoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular disease have assessed the cardioprotective and antidiabetic effects of telmisartan. The collective data suggest that telmisartan is a promising drug for controlling hypertension and reducing vascular risk in high-risk elderly patients with new-onset diabetes.Keywords: elderly, hypertension, telmisartan, angiotensin II type 1 receptor blocker, peroxisome proliferator-activated receptor-γ, diabetes, vascular risk

Non-selective beta-blockers decrease thrombotic events in patients with heart failure

NARCIS (Netherlands)

De Peuter, Olav R.; Souverein, Patrick C.; Klungel, Olaf H.; Lip, Gregory Y.; Buller, Harry R.; De Boer, Anthonius; Kamphuisen, Pieter W.

2010-01-01

Background: Beta-blockers are often prescribed to patients with heart failure (HF) without distinctions between types of beta-blockers. The 2002 COMET study showed superiority of carvedilol (a non-selective beta-blocker) over metoprolol (selective beta-blocker) on mortality and cardiovascular events

The Treatment Effect of an ACE-Inhibitor Based Regimen with Perindopril in Relation to Beta-Blocker use in 29,463 Patients with Vascular Disease: a Combined Analysis of Individual Data of ADVANCE, EUROPA and PROGRESS Trials

NARCIS (Netherlands)

J.J. Brugts (Jasper); M. Bertrand (Michel); W.J. Remme (Willem); R. Ferrari (Roberto); K.A.A. Fox (Keith); S. MacMahon (Stephen); J. Chalmers (John); M.L. Simoons (Maarten); H. Boersma (Eric)

2017-01-01

textabstractIntroduction: In everyday practice, angiotensin converting enzyme inhibitors and beta-blockers are cornerstone treatments in patients with (cardio-)vascular disease. Clear data that evaluate the effects of the combination of these agents on morbidity and mortality are lacking. Methods:

The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity

DEFF Research Database (Denmark)

Lund, Trine Meldgaard; Ploug, K.B.; Iversen, Anne

2015-01-01

-hydroxybutyrate might change neuronal function as there is a known coupling between metabolism and neurotransmission. The purpose of this study was to shed light on the effects of the ketone body β-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown...... an effect of β-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when β-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of β...... to a combination of glucose and R-β-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release....

[Focus on beta-blockers for vascular specialists in 2012].

Science.gov (United States)

Mairesse, S; Blacher, J; Safar, M-E

2011-12-01

Since they were launched on the market in 1964, cardiovascular indications for beta-blockers have been validated and accepted worldwide. Numerous studies and meta-analysis have confirmed their benefits. They reduce mortality in post infarction and acute coronary syndrome populations and also in people with stable coronary heart disease. Moreover, heart failure with systolic left ventricular dysfunction is a major indication for this therapeutic class, providing a 30% decrease in mortality. In patients with permanent atrial fibrillation, beta-blockers are recommended for rate control. In hypertension patients, first-line drug treatment with beta-blockers is currently discussed. Indeed, several studies have shown that patients randomized in the beta-blocker arms experienced more coronary heart and cerebrovascular diseases than comparators. Their lesser effect on central blood pressure decrease could partially explain those results. Nevertheless, beta-blockers are still considered as first-line drugs for hypertension in the French and European guidelines. Long-term comparative studies focusing on central blood pressure are needed. Concerning the other indications for beta-blockers in vascular diseases, their use perioperatively to reduce surgical cardiovascular risk raised much hope, but the most recent results are disappointed and even suggest possible higher mortality. Finally, except for patients with critical ischemia of the lower limbs, presence of peripheral artery disease should probably be considered as a condition favoring their prescription. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

A PROSPECTIVE STUDY OF EFFECT OF TELMISARTAN (ANGIOTENSIN II RECEPTOR BLOCKER ON METABOLIC PARAMETERS IN HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME

Directory of Open Access Journals (Sweden)

Somesekhar

2016-04-01

Full Text Available BACKGROUND The metabolic syndrome is currently a major worldwide epidemic. It strongly associates with obesity, insulin resistance, type 2 diabetes, and cardiovascular diseases, which are major pathologies contributing to mortality and morbidity worldwide. The effect of PPAR-y on metabolic syndrome is significant it is critical regulator of adipogenesis the gain in PPAR-y is resulted in obesity but loss of PPAR–y by mutation is associated with loss of weight and insulin resistance. Telmisartan is an orally active, long-acting, non-peptide angiotensin type 1 (ATI receptor blocker. In addition to this, it has been identified as partial agonist/selective modulator of the nuclear hormone receptor PPAR-y. MATERIAL AND METHOD This is a prospective, randomised and open labelled 16 weeks study conducted in the Dept. of General Medicine, Konaseema Institute of Medical Science, Amalapuram. Present study is designed to study the effect of telmisartan on various metabolic parameters in hypertensive patients who fulfilled the criteria of metabolic syndrome. RESULT There was statistically significant change in all parameters most important was lipid profile; LDL concentration was decreased from 139.2 mg/dL to 120.2 mg/dL. Baseline triglyceride concentration was 161.0 mg/dL which was changed 152.8 mg/dL Total cholesterol was decreased from 203.2 to 193.8 mg/dL. CONCLUSION In our study, we have also found that use of telmisartan is associated with decrease in lipid concentration in addition to its effect on blood pressure regulation. But a long term study with high dose required of this drug is required because safety profile of this drug is better than thiazolidinedione. Financial part of this study is our limitation.

Meta-analysis of randomized controlled trials on magnesium in addition to beta-blocker for prevention of postoperative atrial arrhythmias after coronary artery bypass grafting

Directory of Open Access Journals (Sweden)

Wu Xiaosan

2013-01-01

Full Text Available Abstract Background Atrial arrhythmia (AA is the most common complication after coronary artery bypass grafting (CABG. Only beta-blockers and amiodarone have been convincingly shown to decrease its incidence. The effectiveness of magnesium on this complication is still controversial. This meta-analysis was performed to evaluate the effect of magnesium as a sole or adjuvant agent in addition to beta-blocker on suppressing postoperative AA after CABG. Methods We searched the PubMed, Medline, ISI Web of Knowledge, Cochrane library databases and online clinical trial database up to May 2012. We used random effects model when there was significant heterogeneity between trials and fixed effects model when heterogeneity was negligible. Results Five randomized controlled trials were identified, enrolling a total of 1251 patients. The combination of magnesium and beta-blocker did not significantly decrease the incidence of postoperative AA after CABG versus beta-blocker alone (odds ratio (OR 1.12, 95% confidence interval (CI 0.86-1.47, P = 0.40. Magnesium in addition to beta-blocker did not significantly affect LOS (weighted mean difference −0.14 days of stay, 95% CI −0.58 to 0.29, P = 0.24 or the overall mortality (OR 0.59, 95% CI 0.08-4.56, P = 0.62. However the risk of postoperative adverse events was higher in the combination of magnesium and beta-blocker group than beta-blocker alone (OR 2.80, 95% CI 1.66-4.71, P = 0.0001. Conclusions This meta-analysis offers the more definitive evidence against the prophylactic administration of intravenous magnesium for prevention of AA after CABG when beta-blockers are routinely administered, and shows an association with more adverse events in those people who received magnesium.

Hypoxia increases exercise heart rate despite combined inhibition of β-adrenergic and muscarinic receptors

DEFF Research Database (Denmark)

Siebenmann, Christoph; Rasmussen, Peter; Sørensen, Henrik

2015-01-01

Hypoxia increases the heart rate (HR) response to exercise but the mechanism(s) remain unclear. We tested the hypothesis that the tachycardic effect of hypoxia persists during separate but not combined inhibition of β-adrenergic and muscarinic receptors. Nine subjects performed incremental exercise...... combined β-adrenergic and muscarinic receptor inhibition....

EphA4 blockers promote axonal regeneration and functional recovery following spinal cord injury in mice.

Directory of Open Access Journals (Sweden)

Yona Goldshmit

Full Text Available Upregulation and activation of developmental axon guidance molecules, such as semaphorins and members of the Eph receptor tyrosine kinase family and their ligands, the ephrins, play a role in the inhibition of axonal regeneration following injury to the central nervous system. Previously we have demonstrated in a knockout model that axonal regeneration following spinal cord injury is promoted in the absence of the axon guidance protein EphA4. Antagonism of EphA4 was therefore proposed as a potential therapy to promote recovery from spinal cord injury. To further assess this potential, two soluble recombinant blockers of EphA4, unclustered ephrin-A5-Fc and EphA4-Fc, were examined for their ability to promote axonal regeneration and to improve functional outcome following spinal cord hemisection in wildtype mice. A 2-week administration of either of these blockers following spinal cord injury was sufficient to promote substantial axonal regeneration and functional recovery by 5 weeks following injury. Both inhibitors produced a moderate reduction in astrocytic gliosis, indicating that much of the effect of the blockers may be due to promotion of axon growth. These studies provide definitive evidence that soluble inhibitors of EphA4 function offer considerable therapeutic potential for the treatment of spinal cord injury and may have broader potential for the treatment of other central nervous system injuries.

Photochemical fate of beta-blockers in NOM enriched waters

International Nuclear Information System (INIS)

Wang, Ling; Xu, Haomin; Cooper, William J.; Song, Weihua

2012-01-01

Beta-blockers, prescribed for the treatment of high blood pressure and for long-term use after a heart attack, have been detected in surface and ground waters. This study examines the photochemical fate of three beta-blockers, atenolol, metoprolol, and nadolol. Hydrolysis accounted for minor losses of these beta-blockers in the pH range 4–10. The rate of direct photolysis at pH 7 in a solar simulator varied from 6.1 to 8.9 h −1 at pH 7. However, the addition of a natural organic matter (NOM) isolate enhanced the photochemical loss of all three compounds. Indirect photochemical fate, generally described by reactions with hydroxyl radical (·OH) and singlet oxygen ( 1 ΔO 2 ), and, the direct reaction with the triplet excited state, 3 NOM ⁎ , also varied but collectively appeared to be the major loss factor. Bimolecular reaction rate constants of the three beta-blockers with 1 ΔO 2 and ·OH were measured and accounted for 0.02–0.04% and 7.2–38.9% of their loss, respectively. These data suggest that the 3 NOM ⁎ contributed 50.6–85.4%. Experiments with various 3 NOM ⁎ quenchers supported the hypothesis that it was singly the most important reaction. Atenolol was chosen for more detailed investigation, with the photoproducts identified by LC–MS analysis. The results suggested that electron-transfer could be an important mechanism in photochemical fate of beta-blockers in the presence of NOM. - Highlights: ► Photochemical degradation of beta-blockers in the simulated natural waters. ► Reactive Oxygen Species play a minor role in the indirect photodegradation. ► The loss of beta-blockers results from direct reaction with 3 DOM ⁎ .

Beta-blockers and depression in elderly hypertension patients in primary care

DEFF Research Database (Denmark)

Ringoir, Lianne; Pedersen, Susanne S.; Widdershoven, Jos W M G

2014-01-01

BACKGROUND AND OBJECTIVES: Previous findings regarding a possible association between beta-blocker use and depression are mixed. To our knowledge there have been no studies investigating the association of beta-blockers with depression in primary care hypertension patients without previous...... myocardial infarction. The aim of this study was to determine the relation between lipophilic beta-blocker use and depression in elderly primary care patients with hypertension. METHODS: This was a cross-sectional study in primary care practices located in the South of The Netherlands. Primary care...... for potential confounders. CONCLUSIONS: Our findings show that primary care hypertension patients who use a lipophilic beta-blocker are more likely to have higher depression scores than those who do not use a lipophilic beta-blocker....

Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

Science.gov (United States)

Han, Xiao-Feng; He, Xing; Wang, Miao; Xu, Di; Hao, Li-Ping; Liang, Ai-Hua; Zhang, Jun; Zhou, Zhi-Ming

2015-10-20

Novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I] Sar(1) Ile(8)-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC₅₀ = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC₅₀ = 7.3 nM), 14R (IC₅₀ = 6.3 nM), and 14S (IC₅₀ = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC₅₀ = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

Science.gov (United States)

Thiele, Maja; Wiest, Reiner; Gluud, Lise Lotte; Albillos, Agustín; Krag, Aleksander

2013-11-01

Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular carcinoma via a reduction of the inflammatory load from the gut to the liver and inhibition of angiogenesis. Due to their effect on the portal pressure, non-selective beta-blockers are used for prevention of esophageal variceal bleeding. Recently, non-hemodynamic effects of beta-blockers have received increasing attention. Blockage of β-adrenoceptors in the intestinal mucosa and gut lymphatic tissue together with changes in type and virulence of the intestinal microbiota lead to reduced bacterial translocation and a subsequent decrease in the portal load of pathogen-associated molecular patterns. This may reduce hepatic inflammation. Blockage of β-adrenoceptors also decrease angiogenesis by inhibition of vascular endothelial growth factors. Because gut-derived inflammation and neo-angiogenesis are important in hepatic carcinogenesis, non-selective beta-blockers can potentially reduce the development and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mechanical stress activates NMDA receptors in the absence of agonists

OpenAIRE

Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K.; Sachs, Frederick; Hua, Susan Z.

2017-01-01

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor i...

Poor tolerance of beta-blockers by elderly patients with heart failure

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Satoshi Yanagisawa

2010-11-01

Full Text Available Satoshi Yanagisawa, Noriyuki Suzuki, Toshikazu TanakaDepartment of Cardiology, Okazaki City Hospital, Aichi, JapanAbstract: Despite the well-understood importance of beta-blocker therapy in heart failure, it is sometimes not possible to use beta-blockers in elderly patients due to poor tolerance. In this report, we describe the case of an 83-year-old patient with severe systolic heart failure complicated by aortic valve stenosis and atrial fibrillation. A simple therapeutic approach involving discontinuation of beta-blockers remarkably alleviated the symptoms such as left ventricular ejection fraction, and improved the chest radiography and laboratory findings; further, atrial fibrillation converted to sinus rhythm. It is important to carefully administer beta-blocker therapy to elderly patients with heart failure, especially after considering cardiac output.Keywords: elderly, octogenarians, beta-blockers, heart failure

Beta-blocker use and fall risk in older individuals

NARCIS (Netherlands)

Ham, Annelies C.; Dijk, van S.C.; Swart, Karin M.A.; Enneman, Anke W.; Zwaluw, van der Nikita L.; Brouwer-Brolsma, Elske M.; Schoor, van Natasja M.; Zillikens, M.C.; Lips, Paul; Groot, de Lisette C.P.G.M.; Hofman, Albert; Witkamp, Renger F.; Uitterlinden, André G.; Stricker, Bruno H.; Velde, van der Nathalie

2017-01-01

Aims: To investigate the association between use of β-blockers and β-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Methods: Data from two prospective studies were used, including community-dwelling

[Combination drug therapy in patients with BPH].

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Kuzmenko, A V; Kuzmenko, V V; Gyaurgiev, T A

2018-03-01

Introuction. One of the risk factors for LUTS is an infravesical obstruction, which is most often caused by benign prostatic hyperplasia (BPH). BPH symptoms are formed due to three components: static (mechanical), dynamic, and impaired functional capacity of the bladder. Medical treatment with 1-blockers decreases the outflow obstruction. 5-alpha reductase inhibitors are used to inhibit the static component of BPH. To investigate the effectiveness of various modifications of medical therapy of BPH using -blockers and 5-reductase inhibitors and combinations thereof. The study comprised 90 BPH patients who were divided into three groups, with each group containing 30 people. Patients of group I, II and III received monotherapy with -blockers, a combination of 5-reductase and -blockers, and fixed-dose combination drug Duodart, respectively. Evaluation of the treatment effectiveness included filling out voiding diaries, completing the I-PSS and QL questionnaires, uroflowmetry, transrectal ultrasonography of the prostate and estimation of the incidence of adverse effects. Also, compliance with the treatment was evaluated, and the number of patients who had episodes of acute urinary retention and required surgical treatment during the 12 month treatment course was registered. Compared to monotherapy, combination therapy with -blockers and 5-reductase inhibitors more effectively reduces the LUTS, increases Qmax and prevents the disease progression, which manifests in a lower incidence of AUR and fewer surgical interventions in groups II and III. However, the combination therapy can be associated with some side effects. Patients who received fixed-dose combination drug Duodart had a greater compliance rate than patients on the combination of drugs, which, in our opinion, is associated with fewer cases of AUR and surgical interventions. The use of Duodart in patients with BPH effectively alleviates LUTS and reduces the risk of the disease progression, which manifests itself

COMPARATIVE EFFECTS OF MONOTHERAPY WITH MAGNESIUM AND COMBINED THERAPY WITH MAGNESIUM AND Β-BLOCKER ON PRIMARY MITRAL VALVE PROLAPSE WITH HEART RHYTHM DISORDERS

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E. G. Nurtdinova

2007-01-01

Full Text Available Aim. To compare effects of monotherapy with magnesium and combined therapy with magnesium and β-blocker on primary mitral valve prolapse (MVP with heart rhythm disorders.Material and methods. 71 patients with primary MVP 1-2 degree and heart rhythm disorders were involved in the study. The patients were split into three groups. Group I (25 persons received monotherapy with magnesium orotate at a dose of 1-3 g per day; group II (28 persons received combined therapy with magnesium orotate and betaxolol. The control group (18 persons received no therapy. Initially and after 12 weeks of observation all the patients underwent electrocardiography (ECG, ECG-Holter monitoring, echocardiography and autonomic balance assessment by A.M. Vein’s questionnaire.Results. In 12 weeks of treatment groups I and II showed positive dynamics in the MVP manifestations, including significant reduction in severity of the autonomic dysfunction syndrome, ECG positive dynamics, antiarrhythmic effect, decrease in the degree of prolapse, diminution of mitral regurgitation and left auricle volumes. More substantial hemodynamic effects were found in the group of patients who received combination therapy.Conclusion. Combined therapy has proven advantages in comparison with magnesium monotherapy in terms of daily quantity of extrasystoles, reduction in heart rate, decrease in autonomic disfunction and normalization of intracardiac hemodynamics.

COMPARATIVE EFFECTS OF MONOTHERAPY WITH MAGNESIUM AND COMBINED THERAPY WITH MAGNESIUM AND Β-BLOCKER ON PRIMARY MITRAL VALVE PROLAPSE WITH HEART RHYTHM DISORDERS

Directory of Open Access Journals (Sweden)

E. G. Nurtdinova

2015-12-01

Full Text Available Aim. To compare effects of monotherapy with magnesium and combined therapy with magnesium and β-blocker on primary mitral valve prolapse (MVP with heart rhythm disorders.Material and methods. 71 patients with primary MVP 1-2 degree and heart rhythm disorders were involved in the study. The patients were split into three groups. Group I (25 persons received monotherapy with magnesium orotate at a dose of 1-3 g per day; group II (28 persons received combined therapy with magnesium orotate and betaxolol. The control group (18 persons received no therapy. Initially and after 12 weeks of observation all the patients underwent electrocardiography (ECG, ECG-Holter monitoring, echocardiography and autonomic balance assessment by A.M. Vein’s questionnaire.Results. In 12 weeks of treatment groups I and II showed positive dynamics in the MVP manifestations, including significant reduction in severity of the autonomic dysfunction syndrome, ECG positive dynamics, antiarrhythmic effect, decrease in the degree of prolapse, diminution of mitral regurgitation and left auricle volumes. More substantial hemodynamic effects were found in the group of patients who received combination therapy.Conclusion. Combined therapy has proven advantages in comparison with magnesium monotherapy in terms of daily quantity of extrasystoles, reduction in heart rate, decrease in autonomic disfunction and normalization of intracardiac hemodynamics.

The anti-proliferative effect of cation channel blockers in T lymphocytes depends on the strength of mitogenic stimulation.

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Petho, Zoltan; Balajthy, Andras; Bartok, Adam; Bene, Krisztian; Somodi, Sandor; Szilagyi, Orsolya; Rajnavolgyi, Eva; Panyi, Gyorgy; Varga, Zoltan

2016-03-01

Ion channels are crucially important for the activation and proliferation of T lymphocytes, and thus, for the function of the immune system. Previous studies on the effects of channel blockers on T cell proliferation reported variable effectiveness due to differing experimental systems. Therefore our aim was to investigate how the strength of the mitogenic stimulation influences the efficiency of cation channel blockers in inhibiting activation, cytokine secretion and proliferation of T cells under standardized conditions. Human peripheral blood lymphocytes were activated via monoclonal antibodies targeting the TCR-CD3 complex and the co-stimulator CD28. We applied the blockers of Kv1.3 (Anuroctoxin), KCa3.1 (TRAM-34) and CRAC (2-Apb) channels of T cells either alone or in combination with rapamycin, the inhibitor of the mammalian target of rapamycin (mTOR). Five days after the stimulation ELISA and flow cytometric measurements were performed to determine IL-10 and IFN-γ secretion, cellular viability and proliferation. Our results showed that ion channel blockers and rapamycin inhibit IL-10 and IFN-γ secretion and cell division in a dose-dependent manner. Simultaneous application of the blockers for each channel along with rapamycin was the most effective, indicating synergy among the various activation pathways. Upon increasing the extent of mitogenic stimulation the anti-proliferative effect of the ion channel blockers diminished. This phenomenon may be important in understanding the fine-tuning of T cell activation. Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

Absent Lung Deflation Because of Blockade Using an Endobronchial Blocker.

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Garg, Rakesh; Pandit, Anuja

2017-06-01

One-lung ventilation is required for various thoracic procedures. In addition, various strategies such as the use of double-lumen tube, uninvent tubes, and endobronchial blocker have been used for performing one-lung ventilation. Each of these techniques has its advantages and limitations. Certain factors for failure of endobronchial blocker to provide lung deflation has been described in literature. We report a different aetiology of failure of lung deflation, although the endobronchial blocker was appropriately placed.

Local anesthetic inhibition of G protein-coupled receptor signaling by interference with Galpha(q) protein function

NARCIS (Netherlands)

Hollmann, M. W.; Wieczorek, K. S.; Berger, A.; Durieux, M. E.

2001-01-01

Although local anesthetics are considered primarily Na(+) channel blockers, previous studies suggest a common intracellular site of action on different G protein-coupled receptors. In the present study, we characterized this site for the LPA, m1 muscarinic, and trypsin receptor. Xenopus laevis

Brain penetration of telmisartan, a unique centrally acting angiotensin II type 1 receptor blocker, studied by PET in conscious rhesus macaques

International Nuclear Information System (INIS)

Noda, Akihiro; Fushiki, Hiroshi; Murakami, Yoshihiro; Sasaki, Hiroshi; Miyoshi, Sosuke; Kakuta, Hirotoshi; Nishimura, Shintaro

2012-01-01

Introduction: Telmisartan is a widely used, long-acting antihypertensive agent. Known to be a selective angiotensin II type 1 (AT 1 ) receptor (AT 1 R) blocker (ARB), telmisartan acts as a partial agonist of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and inhibits centrally mediated effects of angiotensin II in rats following peripheral administration, although the brain penetration of telmisartan remains unclear. We investigated the brain concentration and localization of telmisartan using 11 C-labeled telmisartan and positron emission tomography (PET) in conscious rhesus macaques. Methods: Three male rhesus macaques were bolus intravenously administered [ 11 C]telmisartan either alone or as a mixture with unlabeled telmisartan (1 mg/kg). Dynamic PET images were acquired for 95 min following administration. Blood samples were collected for the analysis of plasma concentration and metabolites, and brain and plasma concentrations were calculated from detected radioactivity using the specific activity of the administered drug preparation, in which whole blood radioactivity was used for the correction of intravascular blood radioactivity in brain. Results: Telmisartan penetrated into the brain little but enough to block AT 1 R and showed a consistently increasing brain/plasma ratio within the PET scanning period, suggesting slow clearance of the compound from the brain compared to the plasma clearance. Brain/plasma ratios at 30, 60, and 90 min were 0.06, 0.13, and 0.18, respectively. No marked localization according to the AT 1 R distribution was noted over the entire brain, even on tracer alone dosing. Conclusions: Telmisartan penetrated into the brain enough to block AT 1 R and showed a slow clearance from the brain in conscious rhesus macaques, supporting the long-acting and central responses of telmisartan as a unique property among ARBs.

Quantifying the effects of diuretics and β-adrenoceptor blockers on glycaemic control in diabetes mellitus - a systematic review and meta-analysis.

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Hirst, Jennifer A; Farmer, Andrew J; Feakins, Benjamin G; Aronson, Jeffrey K; Stevens, Richard J

2015-05-01

Although there are reports that β-adrenoceptor antagonists (beta-blockers) and diuretics can affect glycaemic control in people with diabetes mellitus, there is no clear information on how blood glucose concentrations may change and by how much. We report results from a systematic review to quantify the effects of these antihypertensive drugs on glycaemic control in adults with established diabetes. We systematically reviewed the literature to identify randomized controlled trials in which glycaemic control was studied in adults with diabetes taking either beta-blockers or diuretics. We combined data on HbA1c and fasting blood glucose using fixed effects meta-analysis. From 3864 papers retrieved, we found 10 studies of beta-blockers and 12 studies of diuretics to include in the meta-analysis. One study included both comparisons, totalling 21 included reports. Beta-blockers increased fasting blood glucose concentrations by 0.64 mmol l(-1) (95% CI 0.24, 1.03) and diuretics by 0.77 mmol l(-1) (95% CI 0.14, 1.39) compared with placebo. Effect sizes were largest in trials of non-selective beta-blockers (1.33, 95% CI 0.72, 1.95) and thiazide diuretics (1.69, 95% CI 0.60, 2.69). Beta-blockers increased HbA1c concentrations by 0.75% (95% CI 0.30, 1.20) and diuretics by 0.24% (95% CI -0.17, 0.65) compared with placebo. There was no significant difference in the number of hypoglycaemic events between beta-blockers and placebo in three trials. Randomized trials suggest that thiazide diuretics and non-selective beta-blockers increase fasting blood glucose and HbA1c concentrations in patients with diabetes by moderate amounts. These data will inform prescribing and monitoring of beta-blockers and diuretics in patients with diabetes. © 2014 The British Pharmacological Society.

Blocking mineralocorticoid receptors impairs, blocking glucocorticoid receptors enhances memory retrieval in humans.

Science.gov (United States)

Rimmele, Ulrike; Besedovsky, Luciana; Lange, Tanja; Born, Jan

2013-04-01

Memory retrieval is impaired at very low as well as very high cortisol levels, but not at intermediate levels. This inverted-U-shaped relationship between cortisol levels and memory retrieval may originate from different roles of the mineralocorticoid (MR) and glucocorticoid receptor (GR) that bind cortisol with distinctly different affinity. Here, we examined the role of MRs and GRs in human memory retrieval using specific receptor antagonists. In two double-blind within-subject, cross-over designed studies, young healthy men were asked to retrieve emotional and neutral texts and pictures (learnt 3 days earlier) between 0745 and 0915 hours in the morning, either after administration of 400 mg of the MR blocker spironolactone vs placebo (200 mg at 2300 hours and 200 mg at 0400 hours, Study I) or after administration of the GR blocker mifepristone vs placebo (200 mg at 2300 hours, Study II). Blockade of MRs impaired free recall of both texts and pictures particularly for emotional material. In contrast, blockade of GRs resulted in better memory retrieval for pictures, with the effect being more pronounced for neutral than emotional materials. These findings indicate indeed opposing roles of MRs and GRs in memory retrieval, with optimal retrieval at intermediate cortisol levels likely mediated by high MR but concurrently low GR activation.

Beta-blockers influence the short-term and long-term prognostic information of natriuretic peptides and catecholamines in chronic heart failure independent from specific agents.

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Frankenstein, Lutz; Nelles, Manfred; Slavutsky, Maxim; Schellberg, Dieter; Doesch, Andreas; Katus, Hugo; Remppis, Andrew; Zugck, Christian

2007-10-01

In chronic heart failure (CHF), the physiologic effects of natriuretic peptides and catecholamines are interdependent. Furthermore, reports state an agent-dependent effect of individual beta-blockers on biomarkers. Data on the short-term and long-term predictive power comparing these biomarkers as well as accounting for the influence of beta-blocker treatment both on the marker or the resultant prognostic information are scarce. We included 513 consecutive patients with systolic CHF, measured atrial natriuretic peptide (ANP), N-terminal prohormone brain natriuretic peptide (NTproBNP), noradrenaline, and adrenaline, and monitored them for 90 +/- 25 months. Death or the combination of death and cardiac transplantation at 1 year, 5 years, and overall follow-up were considered end points. Compared with patients not taking beta-blockers, patients taking beta-blockers had significantly lower levels of catecholamines but not natriuretic peptides. Only for adrenaline was the amount of this effect related to the specific beta-blocker chosen. Receiver operating characteristic curves demonstrated superior prognostic accuracy for NTproBNP both at the 1- and 5-year follow-up compared with ANP, noradrenaline, and adrenaline. In multivariate analysis including established risk markers (New York Heart Association functional class, left ventricular ejection fraction, peak oxygen uptake, and 6-minute walk test), of all neurohumoral parameters, only NTproBNP remained an independent predictor for both end points. Long-term beta-blocker therapy is associated with decreased levels of plasma catecholamines but not natriuretic peptides. This effect is independent from the actual beta-blocker chosen for natriuretic peptides and noradrenaline. In multivariate analysis, both for short-term and long-term prediction of mortality or the combined end point of death and cardiac transplantation, only NTproBNP remained independent from established clinical risk markers.

Gold nanoparticle–choline complexes can block nicotinic acetylcholine receptors

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Chur Chin

2010-04-01

Full Text Available Chur Chin1, In Kyeom Kim2, Dong Yoon Lim3, Ki Suk Kim4, Hyang Ae Lee4, Eun Joo Kim41Department of Pediatrics, Fatima Hospital, Daegu, Korea; 2Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Korea; 3Department of Pharmacology, School of Medicine, Chosun University, Gwangju, Korea; 4Korea Institute of Toxicology, Daejeon, KoreaAbstract: We identified a novel class of direct ion-channel blockers of ligand-gated ion channels called the gold nanoparticle–choline complex. Negatively charged gold nanoparticles (1.4 nm block ion pores by binding to the sulfur group of the cysteine loop of nicotinic acetylcholine receptors (nAChRs, and currents evoked by acetylcholine (Ach can break these bonds. The current evoked by ACh in nAChRs was blocked directly in ion pores by the gold nanoparticle–choline complex. In adrenal-gland perfusion studies, the complex also blocked nAChRs by diminishing catecholamine release by about 75%. An in vivo study showed muscle relaxation in rats after injection of the complex. These results will foster the application of gold nanoparticles as a direct ion-channel blocker. Keywords: negatively charged gold nanoparticle, choline, gold–sulfur bond, nicotinic acetylcholine receptor, direct ion-channel blocker

L-Carnitine for the treatment of a calcium channel blocker and metformin poisoning.

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St-Onge, Maude; Ajmo, Ian; Poirier, Diane; Laliberté, Martin

2013-09-01

The object of the current communication is to discuss the theory and the evidence for the use of L-carnitine in calcium channel blocker and metformin poisonings. A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of L-carnitine was administered as a last resort. One hour after L-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days. L-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning.

Photochemical fate of beta-blockers in NOM enriched waters

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Wang, Ling; Xu, Haomin; Cooper, William J. [Urban Water Research Center, Department of Civil and Environmental Engineering, University of California, Irvine, Irvine, CA 92697-2175 (United States); Song, Weihua, E-mail: wsong@fudan.edu.cn [Department of Environmental Science and Engineering, Fudan University, Shanghai 200433 (China)

2012-06-01

Beta-blockers, prescribed for the treatment of high blood pressure and for long-term use after a heart attack, have been detected in surface and ground waters. This study examines the photochemical fate of three beta-blockers, atenolol, metoprolol, and nadolol. Hydrolysis accounted for minor losses of these beta-blockers in the pH range 4-10. The rate of direct photolysis at pH 7 in a solar simulator varied from 6.1 to 8.9 h{sup -1} at pH 7. However, the addition of a natural organic matter (NOM) isolate enhanced the photochemical loss of all three compounds. Indirect photochemical fate, generally described by reactions with hydroxyl radical ({center_dot}OH) and singlet oxygen ({sup 1}{Delta}O{sub 2}), and, the direct reaction with the triplet excited state, {sup 3}NOM{sup Low-Asterisk }, also varied but collectively appeared to be the major loss factor. Bimolecular reaction rate constants of the three beta-blockers with {sup 1}{Delta}O{sub 2} and {center_dot}OH were measured and accounted for 0.02-0.04% and 7.2-38.9% of their loss, respectively. These data suggest that the {sup 3}NOM{sup Low-Asterisk} contributed 50.6-85.4%. Experiments with various {sup 3}NOM{sup Low-Asterisk} quenchers supported the hypothesis that it was singly the most important reaction. Atenolol was chosen for more detailed investigation, with the photoproducts identified by LC-MS analysis. The results suggested that electron-transfer could be an important mechanism in photochemical fate of beta-blockers in the presence of NOM. - Highlights: Black-Right-Pointing-Pointer Photochemical degradation of beta-blockers in the simulated natural waters. Black-Right-Pointing-Pointer Reactive Oxygen Species play a minor role in the indirect photodegradation. Black-Right-Pointing-Pointer The loss of beta-blockers results from direct reaction with {sup 3}DOM{sup Low-Asterisk }.

Tolerability to beta-blocker therapy among heart failure patients in clinical practice.

Science.gov (United States)

Butler, Javed; Khadim, Ghazanfar; Belue, Rhonda; Chomsky, Don; Dittus, Robert S; Griffin, Marie; Wilson, John R

2003-06-01

Although beta-blockers were well-tolerated by heart failure (HF) patients in clinical trials, tolerability of these drugs in a general population of HF patients is not well-described. We studied a total of 308 encounters with beta-blockers therapy in 268 ambulatory HF patients. Side effects and frequency and predictors of discontinuation of therapy were studied. Independent predictors of discontinuation were assessed. Weight gain (59%), fatigue (56%), dizziness (41%), and dyspnea (29%) were the most common side effects. Fifty-one patients (19%) were discontinued on therapy with any 1 particular beta-blocker. Fatigue (30%) and hypotension (28%) were the most common reasons for discontinuation. Forty (78%) of these were given a trial with a different beta-blocker. Of these, 22 (55%) attempts with a different beta-blocker were tolerated. Thus the overall absolute discontinuation rate was only 7% for patients who were given a trial with different beta-blockers or 11% for the entire study population. Independent predictors of discontinuation of therapy included advanced symptoms, nonischemic etiology, history of pulmonary disease, and higher diuretic doses. Side effects with beta-blockers in a general population of HF patients are common; however, with changes in medical management, most patients can tolerate them eventually. In case of intolerance to one kind, a trial with a different beta-blocker is indicated.

Beta-blocker withdrawal among patients presenting for surgery from home

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Schonberger, Robert B.; Lukens, Carrie L.; Turkoglu, O. Dicle; Feinleib, Jessica L.; Haspel, Kenneth L.; Burg, Matthew M.

2012-01-01

Structured Abstract Objective This study sought to measure the incidence of perioperative beta-blocker non-compliance by patients who were prescribed chronic beta blocker therapy and presented for surgery from home. The effect of patient non-compliance on day of surgery presenting heart rate was also examined. Design Prospective observational study with outcome data obtained from review of the medical record. Setting The preoperative clinic and operating rooms of a Veterans Administration hospital. Participants Patients on chronic beta blocker therapy who presented from home for surgery. Interventions None. Measurements and Main Results Demographic and comorbidity data as well as data on self-reported compliance to beta-blocker therapy, initial day of surgery vital signs, and recent ambulatory vital signs were collected. Ten out of fifty subjects (20%; 95% CI = 9-31%) reported not taking their day of surgery beta-blocker. These self-reported non-adherers demonstrated a higher presenting heart rate on the day of surgery vs. adherent subjects (median of 78 beats per minute vs. 65 beats per minute, p=0.02 by Wilcoxon Rank-Sum Test). The difference-in-difference between baseline primary care and day of surgery heart rate was also statistically significant between compliant and non-compliant subjects (-7 beats per minute vs. +12.5 beats per minute, p<0.00001). Conclusions Patient self-report and physiologic data documented failure to take beta-blockers and possible beta-blocker withdrawal in 20% of patients who presented for surgery from home. If these findings are confirmed in larger studies, improved patient understanding of and compliance with medication instructions during preoperative visits should be a focus of future quality improvement initiatives. PMID:22418043

Transdermal delivery of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) and others for management of hypertension.

Science.gov (United States)

Ahad, Abdul; Al-Mohizea, Abdullah Mohammed; Al-Jenoobi, Fahad Ibrahim; Aqil, Mohd

2016-01-01

Angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs) are some of the most commonly prescribed medications for hypertension. Most of all conventional dosage forms of ARBs and ACEIs undergo extensive first-pass metabolism, which significantly reduces bioavailability. Majority of ARBs and ACEIs are inherently short acting due to a rapid elimination half-life. In addition, oral dosage forms of ARBs and ACEIs have many high incidences of adverse effects due to variable absorption profiles, higher frequency of administration and poor patient compliance. Many attempts have been made globally at the laboratory level to investigate the skin permeation and to develop transdermal therapeutic systems of various ARBs, ACEIs and other anti-hypertensives, to circumvent the drawbacks associated with their conventional dosage form. This manuscript presents an outline of the transdermal research specifically in the area of ARBs, ACEIs and other anti-hypertensives reported in various pharmaceutical journals. The transdermal delivery has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. As we can experience from this review article that transdermal delivery of different ARBs and ACEIs improves bioavailability as well as patient compliance by many folds. In fact, the rationale development of some newer ARBs, ACEIs and other anti-hypertensives transdermal systems will provide new ways of treatment, circumventing current limitations for conventional dosage forms.

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

Energy Technology Data Exchange (ETDEWEB)

Choi, Yoon Jung [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Lee, Jue Yeon [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Lee, Seung Jin [Department of Industrial Pharmacy, College of Pharmacy, Ewha Womans University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Chung, Chong-Pyoung [Department of Periodontology, School of Dentistry, Seoul National University, Seoul (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of); Park, Yoon Jeong, E-mail: parkyj@snu.ac.kr [Craniomaxillofacial Reconstructive Sciences Major, College of Dentistry, Seoul National University, Seoul 110-749 (Korea, Republic of); Research Center, Nano Intelligent Biomedical Engineering Corporation (NIBEC), Seoul (Korea, Republic of)

2011-12-16

Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and

Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

International Nuclear Information System (INIS)

Choi, Yoon Jung; Lee, Jue Yeon; Lee, Seung Jin; Chung, Chong-Pyoung; Park, Yoon Jeong

2011-01-01

Highlights: ► Doxazocin directly up-regulated bone metabolism at a low dose. ► Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. ► This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor γ, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and according to our data doxazosin might be useful for application in the field of bone

Ligand-based design and synthesis of novel sodium channel blockers from a combined phenytoin–lidocaine pharmacophore

OpenAIRE

Wang, Yuesheng; Jones, Paulianda J.; Batts, Timothy W.; Landry, Victoria; Patel, Manoj K.; Brown, Milton L.

2008-01-01

The voltage-gated sodium channel remains a rich area for the development of novel blockers. In this study we used comparative molecular field analysis (CoMFA), a ligand-based design strategy, to generate a 3D model based upon local anesthetics, hydantoins, and α-hydroxyphenylamides to elucidate a SAR for their binding site in the neuronal sodium channel. Correlation by partial least squares (PLS) analysis of in vitro sodium channel binding activity (expressed as pIC50) and the CoMFA descripto...

Memory is preserved in older adults taking AT1 receptor blockers.

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Ho, Jean K; Nation, Daniel A

2017-04-26

Prior work suggests that some but not all antihypertensive treatments may benefit cognition and risk for Alzheimer's disease, independent of stroke. Angiotensin II receptor blockers (ARBs) have been highlighted as one antihypertensive drug class that may confer greatest benefit. The participants comprised 1626 nondemented adults, aged 55-91 years, recruited from Alzheimer's Disease Neuroimaging Initiative sites. Three groups were compared: ARB users (HTN-ARBs), other antihypertensive drug users (HTN-Other), and normotensives. In post hoc analyses, we also examined (1) users of ARBs and angiotensin-converting enzyme inhibitors (ACEIs), (2) users of blood-brain barrier (BBB)-crossing ARBs and users of non-BBB-crossing ARBs, and (3) users of BBB-crossing ARBs and ACEIs (BBB crossers) and users of non-BBB-crossing ARBs and ACEIs (BBB noncrossers). Groups were compared regarding cognition and magnetic resonance imaging measures of brain volume and white matter hyperintensities (WMH), using analysis of covariance and multilevel models. At baseline, the HTN-Other group performed worse than normotensives on Rey Auditory Verbal Learning Test (RAVLT) Immediate Recall (p = 0.002), Delayed Recall (p Memory (p = 0.001), and Trails A (p Memory (p = 0.04) and worse than normotensives on Trails A (p = 0.04). The HTN-Other group performed worse than normotensives on Logical Memory Immediate (p = 0.02) and Delayed Recall over the 3-year follow-up (p = 0.007). Over the follow-up period, those taking BBB-crossing ARBs performed better than the HTN-Other group on AVLT Delayed Recall (p = 0.04), Logical Memory Immediate (p = 0.02), and Delayed Recall (p = 0.05). They also had fewer WMH than the HTN-Other group (p = 0.008) and those taking non-BBB-crossing ARBs (p = 0.05). There were no group differences in brain volume. Users of BBB-crossing medications (ARBs or ACEIs) showed better performance on AVLT Delayed Recall over time than all

A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

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2015-12-01

AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor (GR), which may compensate for diminished AR activity. The

Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on the risk of pneumonia and severe exacerbations in patients with COPD

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Lai CC

2018-03-01

Full Text Available Chih-Cheng Lai,1 Ya-Hui Wang,2 Cheng-Yi Wang,3 Hao-Chien Wang,4 Chong-Jen Yu,4 Likwang Chen5 On behalf of the Taiwan Clinical Trial Consortium for Respiratory Diseases (TCORE 1Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Taiwan; 2Medical Research Center, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 3Department of Internal Medicine, Cardinal Tien Hospital and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; 4Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; 5Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan Objectives: This study aimed to compare the effects of angiotensin-converting-enzyme inhibitors (ACEis and angiotensin receptor blockers (ARBs on the risk of pneumonia and severe exacerbations in patients with COPD.Patients and methods: All patients with COPD who used ACEis and ARBs for >90 days between 2000 and 2005 were recruited. Pairwise matching (1:1 of the ACEi and ARB groups resulted in two similar subgroups, with 6,226 patients in each. The primary outcomes were pneumonia and COPD exacerbations, and the secondary outcome was death.Results: During the follow-up period, the incidence of pneumonia was 7.20 per 100 person-years in the ACEi group and 5.89 per 100 person-years in the ARB group. The ACEi group had a higher risk of pneumonia (adjusted hazard ratio [aHR], 1.22; 95% CI, 1.15–1.29 than the ARB group. The incidence of severe exacerbations was 0.65 per person-year for the patients receiving ACEis and 0.52 per person-year for those receiving ARBs. The patients receiving ACEis had a higher risk of severe exacerbations (aHR, 1.19; 95% CI, 1.16–1.21 than those receiving ARBs. Similar trends were noted in terms of severe exacerbations requiring

A novel hypothesis for the binding mode of HERG channel blockers

International Nuclear Information System (INIS)

Choe, Han; Nah, Kwang Hoon; Lee, Soo Nam; Lee, Han Sam; Lee, Hui Sun; Jo, Su Hyun; Leem, Chae Hun; Jang, Yeon Jin

2006-01-01

We present a new docking model for HERG channel blockade. Our new model suggests three key interactions such that (1) a protonated nitrogen of the channel blocker forms a hydrogen bond with the carbonyl oxygen of HERG residue T623; (2) an aromatic moiety of the channel blocker makes a π-π interaction with the aromatic ring of HERG residue Y652; and (3) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. The previous model assumes two interactions such that (1) a protonated nitrogen of the channel blocker forms a cation-π interaction with the aromatic ring of HERG residue Y652; and (2) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. To test these models, we classified 69 known HERG channel blockers into eight binding types based on their plausible binding modes, and further categorized them into two groups based on the number of interactions our model would predict with the HERG channel (two or three). We then compared the pIC 5 value distributions between these two groups. If the old hypothesis is correct, the distributions should not differ between the two groups (i.e., both groups show only two binding interactions). If our novel hypothesis is correct, the distributions should differ between Groups 1 and 2. Consistent with our hypothesis, the two groups differed with regard to pIC 5 , and the group having more predicted interactions with the HERG channel had a higher mean pIC 5 value. Although additional work will be required to further validate our hypothesis, this improved understanding of the HERG channel blocker binding mode may help promote the development of in silico predictions methods for identifying potential HERG channel blockers

Quantifying the effects of diuretics and β-adrenoceptor blockers on glycaemic control in diabetes mellitus – a systematic review and meta-analysis

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Hirst, Jennifer A; Farmer, Andrew J; Feakins, Benjamin G; Aronson, Jeffrey K; Stevens, Richard J

2015-01-01

Aims Although there are reports that β-adrenoceptor antagonists (beta-blockers) and diuretics can affect glycaemic control in people with diabetes mellitus, there is no clear information on how blood glucose concentrations may change and by how much. We report results from a systematic review to quantify the effects of these antihypertensive drugs on glycaemic control in adults with established diabetes. Methods We systematically reviewed the literature to identify randomized controlled trials in which glycaemic control was studied in adults with diabetes taking either beta-blockers or diuretics. We combined data on HbA1c and fasting blood glucose using fixed effects meta-analysis. Results From 3864 papers retrieved, we found 10 studies of beta-blockers and 12 studies of diuretics to include in the meta-analysis. One study included both comparisons, totalling 21 included reports. Beta-blockers increased fasting blood glucose concentrations by 0.64 mmol l−1 (95% CI 0.24, 1.03) and diuretics by 0.77 mmol l−1 (95% CI 0.14, 1.39) compared with placebo. Effect sizes were largest in trials of non-selective beta-blockers (1.33, 95% CI 0.72, 1.95) and thiazide diuretics (1.69, 95% CI 0.60, 2.69). Beta-blockers increased HbA1c concentrations by 0.75% (95% CI 0.30, 1.20) and diuretics by 0.24% (95% CI −0.17, 0.65) compared with placebo. There was no significant difference in the number of hypoglycaemic events between beta-blockers and placebo in three trials. Conclusions Randomized trials suggest that thiazide diuretics and non-selective beta-blockers increase fasting blood glucose and HbA1c concentrations in patients with diabetes by moderate amounts. These data will inform prescribing and monitoring of beta-blockers and diuretics in patients with diabetes. PMID:25377481

Perioperative beta blockers in patients having non-cardiac surgery

DEFF Research Database (Denmark)

Bangalore, Sripal; Wetterslev, Jørn; Pranesh, Shruthi

2008-01-01

American College of Cardiology and American Heart Association (ACC/AHA) guidelines on perioperative assessment recommend perioperative beta blockers for non-cardiac surgery, although results of some clinical trials seem not to support this recommendation. We aimed to critically review the evidence...... to assess the use of perioperative beta blockers in patients having non-cardiac surgery....

TNFα blockers and infectious risk in rheumatoid arthritis

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S. Todesco

2011-06-01

Full Text Available Patients suffering from rheumatoid arthritis have increased risk of infections when compared with general population. The risk depends directly from disease activity and severity. Furthermore, risk increases with aging, immunosuppressive agents and comorbidities such as diabetes, pulmonary and cardiac diseases. In particular corticosteroids, even at low doses, are a major risk factor. Due to disease related risk it is difficult to separate the risk deriving from the use of TNF alpha blockers. Data from clinical trials, meta-analysis and national registers are somewhat contradictory. In patients with rheumatoid arthritis on routine follow-up, treatment with TNF alpha blockers seems to carry an increased risk of infections compared to traditional DMARDs but not associated with increased risk of overall serious infection. Physicians should carefully monitor for signs of infection when using TNF alpha blockers, particularly shortly after treatment initiation.

Beta blockers, norepinephrine, and cancer: an epidemiological viewpoint

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Fitzgerald PJ

2012-06-01

Full Text Available Paul J FitzgeraldThe Zanvyl Krieger Mind/Brain Institute, Solomon H Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USAAbstract: There is growing evidence that the neurotransmitter norepinephrine (NE and its sister molecule epinephrine (EPI (adrenaline affect some types of cancer. Several recent epidemiological studies have shown that chronic use of beta blocking drugs (which antagonize NE/EPI receptors results in lower recurrence, progression, or mortality of breast cancer and malignant melanoma. Preclinical studies have shown that manipulation of the levels or receptors of NE and EPI with drugs affects experimentally induced cancers. Psychological stress may play an etiological role in some cases of cancer (which has been shown epidemiologically, and this could be partly mediated by NE and EPI released by the sympathetic nervous system as part of the body’s “fight or flight” response. A less well-appreciated phenomenon is that the genetic tone of NE/EPI may play a role in cancer. NE and EPI may affect cancer by interacting with molecular pathways already implicated in abnormal cellular replication, such as the P38/MAPK pathway, or via oxidative stress. NE/EPI-based drugs other than beta blockers also may prevent or treat various types of cancer, as may cholinesterase inhibitors that inhibit the sympathetic nervous system, which could be tested epidemiologically.Keywords: clonidine, guanfacine, aspirin, acetylcholine, epinephrine, adrenaline, sympathetic nervous system, parasympathetic nervous system, inflammation

NMDA receptors are important regulators of pancreatic cancer and are potential targets for treatment

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North WG

2017-07-01

Full Text Available William G North,1,2 Fuli Liu,1 Liz Z Lin,1 Ruiyang Tian,2 Bonnie Akerman1 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, 2Woomera Therapeutics Inc, Lebanon, NH, USA Abstract: Pancreatic cancer, particularly adenocarcinoma of the pancreas, is a common disease with a poor prognosis. In this study, the importance of N-methyl-D-aspartate (NMDA receptors for the growth and survival of pancreatic cancer was investigated. Immunohistochemistry performed with antibodies against GluN1 and GluN2B revealed that all invasive adenocarcinoma and neuroendocrine pancreatic tumors likely express these two NMDA receptor proteins. These proteins were found to be membrane components of pancreatic cancer cell lines, and both channel-blocker antagonist and GluN2B antagonist significantly reduced cell viability in vitro. Both types of antagonists caused an internalization of the receptors. Dizocilpine maleate (MK-801 and ifenprodil hemitartrate both significantly inhibited the growth of pancreatic tumor xenografts in nu/nu mice. These findings predict that, as for other solid tumors investigated by us, pancreatic cancer could be successfully treated, alone or in combination, with NMDA receptor antagonists or other receptor-inhibiting blocking agents. Keywords: pancreatic cancer, NMDA receptors, inhibitors, potential therapy

Beta-blockers for exams identify students at high risk of psychiatric morbidity

DEFF Research Database (Denmark)

Butt, Jawad H.; Dalsgaard, Søren; Torp-Pedersen, Christian

2017-01-01

Objectives: Beta-blockers relieve the autonomic symptoms of exam-related anxiety and may be beneficial in exam-related and performance anxiety, but knowledge on related psychiatric outcomes is unknown. We hypothesized that beta-blocker therapy for exam-related anxiety identifies young students...... at risk of later psychiatric events. Methods: Using Danish nationwide administrative registries, we studied healthy students aged 14-30 years (1996-2012) with a first-time claimed prescription for a beta-blocker during the exam period (May-June); students who were prescribed a beta-blocker for medical...... reasons were excluded. We matched these students on age, sex, and time of year to healthy and study active controls with no use of beta-blockers. Risk of incident use of antidepressants, incident use of other psychotropic medications, and suicide attempts was examined by cumulative incidence curves...

β-Blocker treatment during pregnancy and adverse pregnancy outcomes

DEFF Research Database (Denmark)

Petersen, Kasper Meidahl; Jimenez-Solem, Espen; Andersen, Jon Traerup

2012-01-01

To investigate the association between exposure to β-blockers during pregnancy and the risk of being born small for gestational age (SGA), preterm birth and perinatal mortality in a nationwide cohort.......To investigate the association between exposure to β-blockers during pregnancy and the risk of being born small for gestational age (SGA), preterm birth and perinatal mortality in a nationwide cohort....

Identifying plant cell-surface receptors: combining 'classical' techniques with novel methods.

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Uebler, Susanne; Dresselhaus, Thomas

2014-04-01

Cell-cell communication during development and reproduction in plants depends largely on a few phytohormones and many diverse classes of polymorphic secreted peptides. The peptide ligands are bound at the cell surface of target cells by their membranous interaction partners representing, in most cases, either receptor-like kinases or ion channels. Although knowledge of both the extracellular ligand and its corresponding receptor(s) is necessary to describe the downstream signalling pathway(s), to date only a few ligand-receptor pairs have been identified. Several methods, such as affinity purification and yeast two-hybrid screens, have been used very successfully to elucidate interactions between soluble proteins, but most of these methods cannot be applied to membranous proteins. Experimental obstacles such as low concentration and poor solubility of membrane receptors, as well as instable transient interactions, often hamper the use of these 'classical' approaches. However, over the last few years, a lot of progress has been made to overcome these problems by combining classical techniques with new methodologies. In the present article, we review the most promising recent methods in identifying cell-surface receptor interactions, with an emphasis on success stories outside the field of plant research.

Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists.

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Jaeger, Mariane; Ghisleni, Eduarda C; Fratini, Lívia; Brunetto, Algemir L; Gregianin, Lauro José; Brunetto, André T; Schwartsmann, Gilberto; de Farias, Caroline B; Roesler, Rafael

2016-01-01

Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists. D283 MB cells were treated with different doses of the HDACi sodium butyrate (NaB), the neuromedin B receptor (NMBR) antagonist BIM-23127, the gastrin releasing peptide receptor (GRPR) antagonist RC-3095, or combinations of NaB with each receptor antagonist. Cell viability was examined by cell counting. NaB alone or combined with receptor antagonists reduced cell viability at all doses tested. BIM-23127 alone did not affect cell viability, whereas RC-3095 at an intermediate dose significantly increased cell number. Although HDACi are promising agents to inhibit MB growth, the present results provide preliminary evidence that combining HDACi with bombesin receptor antagonists is not an effective strategy to improve the effects of HDACi against MB cells.

Colonic vascular conductance increased by Daikenchuto via calcitonin gene-related peptide and receptor-activity modifying protein 1.

Science.gov (United States)

Kono, Toru; Koseki, Takashi; Chiba, Shinichi; Ebisawa, Yoshiaki; Chisato, Naoyuki; Iwamoto, Jun; Kasai, Shinichi

2008-11-01

Daikencyuto (DKT) is a traditional Japanese medicine (Kampo) and is a mixture of extract powders from dried Japanese pepper, processed ginger, ginseng radix, and maltose powder and has been used as the treatment of paralytic ileus. DKT may increase gastrointestinal motility by an up-regulation of the calcitonin gene-related peptide (CGRP). CGRP is also the most powerful vasoactive substance. In the present study, we investigated whether DKT has any effect on the colonic blood flow in rats. Experiments were performed on fasted anesthetized and artificially ventilated Wistar rats. Systemic mean arterial blood pressure and heart rate were recorded. Red blood cell flux in colonic blood flow was measured using noncontact laser tissue blood flowmetry, and colonic vascular conductance (CVC) was calculated as the ratio of flux to mean arterial blood pressure. We examined four key physiological mechanisms underlying the response using blocker drugs: CGRP1 receptor blocker (CGRP(8-37)), nitric oxide synthase inhibitor, vasoactive intestinal polypeptide (VIP) receptor blocker ([4-Cl-DPhe6, Leu17]-VIP), and substance P receptor blocker (spantide). Reverse transcription-polymerase chain reaction was used for the detection of mRNA of calcitonin receptor-like receptor, receptor-activity modifying protein 1, the component of CGRP 1 receptor and CGRP. After laparotomy, a cannula was inserted into the proximal colon to administer the DKT and to measure CVC at the distal colon. Intracolonal administration of DKT (10, 100, and 300 mg/kg) increased CVC (basal CVC, 0.10 mL/mmHg) from the first 15-min observation period (0.14, 0.17, and 0.17 mL/mmHg, respectively) and with peak response at either 45 min (0.17 mL/mmHg by 10 mg/kg), or 75 and 60 min (0.23 and 0.21 mL/mmHg by 100 and 300 mg/kg, respectively). CGRP(8-37) completely abolished the DKT-induced hyperemia, whereas nitric oxide synthase inhibitor partially attenuated the DKT-induced hyperemia. [4-Cl-DPhe6, Leu17]-VIP and spantide

Topical beta-Blockers and Mortality

NARCIS (Netherlands)

Muskens, Rogier P. H. M.; Wolfs, Roger C. W.; Wittenian, Jacqueline C. M.; Hofman, Albert; de Jong, Paulus T. V. M.; Stricker, Bruno H. C.; Jansonius, Nomdo M.

Purpose: To study the associations between long-term and short-term use of topical beta-blockers and mortality. Design: Prospective population-based cohort study. Participants: To examine long-term effects, 3842 participants aged 55 years and older were recruited. To examine short-term effects, 484

Tumour necrosis factor-alpha blockers: potential limitations in the management of advanced endometriosis? A case report.

Science.gov (United States)

Shakiba, Khashayar; Falcone, Tommaso

2006-09-01

Several studies have shown that tumour necrosis factor (TNF)-alpha levels are increased in the peritoneal fluid of women with endometriosis, with correlation between TNF-alpha concentrations and the degree of disease. It is also likely that elevation of peritoneal fluids' TNF-alpha levels may play a role in the pathogenesis of infertility associated with endometriosis. Use of drugs such as etanercept, a TNF-alpha receptor immunoglobulin fusion protein which inhibits TNF-alpha activity, showed in an animal study to reduce the severity of the disease, and the size of endometriotic foci. TNF-alpha blockers were recommended as a possible new line of therapy for endometriosis. Our case involved a 35-year-old Para 0, with rheumatic arthritis and stage 4 endometriosis. After 6 years of constant use of etanercept, she showed no improvement of endometriosis as demonstrated at laparoscopy. However, she underwent a successful IVF after the first attempt. TNF-alpha-blocker medications might not be beneficial for patients with advanced endometriosis. However, we cannot exclude the possible effect of these medications on early-stage endometriosis, and further study is required. Some of the immunologic abnormalities in the pelvis of patients with endometriosis could be the consequence of the disease and not the cause, and possibly suppression of immune cells and their products may not have a major effect on endometriotic lesions at an advanced stage. This also could explain why suppression of TNF-alpha showed no effect on infertility. However, use of TNF-alpha-blockers before IVF might increase the success rate in advanced endometriosis.

Valsartan: the past, present and future

DEFF Research Database (Denmark)

Køber, Lars; Torp-Pedersen, Christian

2005-01-01

Valsartan (Diovan((R))) is a widely use angiotensin receptor blocker that prevents angiotensin II from binding to the subtype 1 receptor. Stimulation of the subtype 1 receptor is believed to mediate many of the deleterious effects accompanied by increased angiotensin II levels. Valsartan...... is effective in the treatment of hypertension, alone and in combination with hydrochlorothiazide. Valsartan is similarly as effective as angiotensin-converting enzyme (ACE) blockers following myocardial infarction accompanied with left ventricular dysfunction, and/or heart failure. For the treatment...... of congestive heart failure with left ventricular dysfunction, valsartan offers a reduction in mortality in patients not able to tolerate an ACE inhibitor and in combination with an ACE inhibitor, valsartan reduces morbidity (hospitalization for heart failure)....

The role of GluN2B-containing NMDA receptors in short- and long-term fear recall.

Science.gov (United States)

Mikics, Eva; Toth, Mate; Biro, Laszlo; Bruzsik, Biborka; Nagy, Boglarka; Haller, Jozsef

2017-08-01

N-methyl-d-aspartate (NMDA) receptors are crucial synaptic elements in long-term memory formation, including the associative learning of fearful events. Although NMDA blockers were consistently shown to inhibit fear memory acquisition and recall, the clinical use of general NMDA blockers is hampered by their side effects. Recent studies revealed significant heterogeneity in the distribution and neurophysiological characteristics of NMDA receptors with different GluN2 (NR2) subunit composition, which may have differential role in fear learning and recall. To investigate the specific role of NMDA receptor subpopulations with different GluN2 subunit compositions in the formation of lasting traumatic memories, we contrasted the effects of general NMDA receptor blockade with GluN2A-, GluN2B-, and GluN2C/D subunit selective antagonists (MK-801, PEAQX, Ro25-6981, PPDA, respectively). To investigate acute and lasting consequences, behavioral responses were investigated 1 and 28days after fear conditioning. We found that MK-801 (0.05 and 0.1mg/kg) decreased fear recall at both time points. GluN2B receptor subunit blockade produced highly similar effects, albeit efficacy was somewhat smaller 28days after fear conditioning. Unlike MK-801, Ro25-6981 (3 and 10mg/kg) did not affect locomotor activity in the open-field. In contrast, GluN2A and GluN2C/D blockers (6 and 20mg/kg PEAQX; 3 and 10mg/kg PPDA, respectively) had no effect on conditioned fear recall at any time point and dose. This sharp contrast between GluN2B- and other subunit-containing NMDA receptor function indicates that GluN2B receptor subunits are intimately involved in fear memory formation, and may provide a novel pharmacological target in post-traumatic stress disorder or other fear-related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

The metabolic impact of β-hydroxybutyrate on neurotransmission: Reduced glycolysis mediates changes in calcium responses and KATP channel receptor sensitivity.

Science.gov (United States)

Lund, Trine M; Ploug, Kenneth B; Iversen, Anne; Jensen, Anders A; Jansen-Olesen, Inger

2015-03-01

Glucose is the main energy substrate for neurons, and ketone bodies are known to be alternative substrates. However, the capacity of ketone bodies to support different neuronal functions is still unknown. Thus, a change in energy substrate from glucose alone to a combination of glucose and β-hydroxybutyrate might change neuronal function as there is a known coupling between metabolism and neurotransmission. The purpose of this study was to shed light on the effects of the ketone body β-hydroxybutyrate on glycolysis and neurotransmission in cultured murine glutamatergic neurons. Previous studies have shown an effect of β-hydroxybutyrate on glucose metabolism, and the present study further specified this by showing attenuation of glycolysis when β-hydroxybutyrate was present in these neurons. In addition, the NMDA receptor-induced calcium responses in the neurons were diminished in the presence of β-hydroxybutyrate, whereas a direct effect of the ketone body on transmitter release was absent. However, the presence of β-hydroxybutyrate augmented transmitter release induced by the KATP channel blocker glibenclamide, thus giving an indirect indication of the involvement of KATP channels in the effects of ketone bodies on transmitter release. Energy metabolism and neurotransmission are linked and involve ATP-sensitive potassium (KATP ) channels. However, it is still unclear how and to what degree available energy substrate affects this link. We investigated the effect of changing energy substrate from only glucose to a combination of glucose and R-β-hydroxybutyrate in cultured neurons. Using the latter combination, glycolysis was diminished, NMDA receptor-induced calcium responses were lower, and the KATP channel blocker glibenclamide caused a higher transmitter release. © 2014 International Society for Neurochemistry.

Combating Combination of Hypertension and Diabetes in Different Rat Models

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Talma Rosenthal

2010-03-01

Full Text Available Rat experimental models are used extensively for studying physiological mechanisms and treatments of hypertension and diabetes co-existence. Each one of these conditions is a major risk factor for cardiovascular disease (CVD, and the combination of the two conditions is a potent enhancer of CVD. Five major animal models that advanced our understanding of the mechanisms and therapeutic approaches in humans are discussed in this review: Zucker, Goto-Kakizaki, SHROB, SHR/NDmcr-cp and Cohen Rosenthal diabetic hypertensive (CRDH rats. The use of various drugs, such as angiotensin-converting enzyme (ACE inhibitors (ACEIs, various angiotensin receptor blockers (ARBs, and calcium channel blockers (CCBs, to combat the effects of concomitant pathologies on the combination of diabetes and hypertension, as well as the non-pharmacological approach are reviewed in detail for each rat model. Results from experiments on these models indicate that classical factors contributing to the pathology of hypertension and diabetes combination—Including hypertension, hyperglycemia, hyperinsulinemia and hyperlipidemia—can now be treated, although these treatments do not completely prevent renal complications. Animal studies have focused on several mechanisms involved in hypertension/diabetes that remain to be translated into clinical medicine, including hypoxia, oxidative stress, and advanced glycation. Several target molecules have been identified that need to be incorporated into a treatment modality. The challenge continues to be the identification and interpretation of the clinical evidence from the animal models and their application to human treatment.

Prevalence of major depressive disorder in patients receiving beta-blocker therapy versus other medications.

Science.gov (United States)

Carney, R M; Rich, M W; teVelde, A; Saini, J; Clark, K; Freedland, K E

1987-08-01

Depression is believed to be a common side effect in patients receiving beta-blocker therapy. However, diagnoses of depression defined by current diagnostic criteria may not be more common in patients receiving beta-blockers than in patients with the same medical disorder receiving other medications. Seventy-seven patients undergoing elective cardiac catheterization for evaluation of chest pain received a semi-structured diagnostic psychiatric interview. Twenty-one percent of the patients receiving beta-blockers and 33 percent of the patients receiving medications other than beta-blockers met the current American Psychiatric Association criteria for major depressive disorder (DSM-III) (p = NS). The mean heart rate and state anxiety scores for patients taking beta-blockers were significantly lower than those measured in patients taking medications other than beta-blockers. No other medical or demographic differences were observed between the two groups. Despite the methodologic limitations of the study, there does not appear to be a difference in the point prevalence of depression between patients receiving beta-blockers and those receiving other medications.

Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices

DEFF Research Database (Denmark)

Gluud, Lise L; Klingenberg, Sarah; Nikolova, Dimitrinka

2007-01-01

To compare banding ligation versus beta-blockers as primary prophylaxis in patients with esophageal varices and no previous bleeding.......To compare banding ligation versus beta-blockers as primary prophylaxis in patients with esophageal varices and no previous bleeding....

[MODERN PROKINETICS AND THEIR ROLE IN THE TREATMENT OF GASTROENTEROLOGICAL PATHOLOGY].

Science.gov (United States)

Sheptulin, A A; Belousova, I B

2016-01-01

The importance of prokinetics (drugs stimulating motor function of the gastrointestinal tract) arises from the high prevalence of gastroenterological pathology associated with primary or secondary disturbances of this function in esophagus, stomach, and intestines. The main groups of prokinetics are beta-blockers of dopamine receptors, inhibitors of acetylcholine esterase (or their combination with dopamine receptor blockers), 5-HT4-receptor agonists. They find wide application for the treatment of gastroesophgeal reflux disease, functional dyspepsia and constipation, obstipational form of irritable bowel syndrome, and other conditions accompanied by motor function disorders of the gastrointestinal tract.

Beta-blocker use and COPD mortality: a systematic review and meta-analysis

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Etminan Mahyar

2012-09-01

Full Text Available Abstract Background Despite the benefits of beta-blockers in patients with established or sub-clinical coronary artery disease, their use in patients with chronic obstructive pulmonary disease (COPD has been controversial. Currently, no systematic review has examined the impact of beta-blockers on mortality in COPD. Methods We systematically searched electronic bibliographic databases including MEDLINE, EMBASE and Cochrane Library for clinical studies that examine the association between beta-blocker use and all cause mortality in patients with COPD. Risk ratios across studies were pooled using random effects models to estimate a pooled relative risk across studies. Publication bias was assessed using a funnel plot. Results Our search identified nine retrospective cohort studies that met the study inclusion criteria. The pooled relative risk of COPD related mortality secondary to beta-blocker use was 0.69 (95% CI: 0.62-0.78; I2=82%. Conclusion The results of this review are consistent with a protective effect of beta-blockers with respect to all cause mortality. Due to the observational nature of the included studies, the possibility of confounding that may have affected these results cannot be excluded. The hypothesis that beta blocker therapy might be of benefit in COPD needs to be evaluated in randomised controlled trials.

Risk of Cardiovascular Events in Patients With Diabetes Mellitus on β-Blockers.

Science.gov (United States)

Tsujimoto, Tetsuro; Sugiyama, Takehiro; Shapiro, Martin F; Noda, Mitsuhiko; Kajio, Hiroshi

2017-07-01

Although the use of β-blockers may help in achieving maximum effects of intensive glycemic control because of a decrease in the adverse effects after severe hypoglycemia, they pose a potential risk for the occurrence of severe hypoglycemia. This study aimed to evaluate whether the use of β-blockers is effective in patients with diabetes mellitus and whether its use is associated with the occurrence of severe hypoglycemia. Using the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) data, we performed Cox proportional hazards analyses with a propensity score adjustment. The primary outcome was the first occurrence of a cardiovascular event during the study period, which included nonfatal myocardial infarction, unstable angina, nonfatal stroke, and cardiovascular death. The mean follow-up periods (±SD) were 4.6±1.6 years in patients on β-blockers (n=2527) and 4.7±1.6 years in those not on β-blockers (n=2527). The cardiovascular event rate was significantly higher in patients on β-blockers than in those not on β-blockers (hazard ratio, 1.46; 95% confidence interval, 1.24-1.72; P diabetes mellitus was associated with an increased risk for cardiovascular events. © 2017 The Authors.

Effect of beta-blockers on exacerbation rate and lung function in chronic obstructive pulmonary disease (COPD).

Science.gov (United States)

Duffy, Sean; Marron, Robert; Voelker, Helen; Albert, Richard; Connett, John; Bailey, William; Casaburi, Richard; Cooper, J Allen; Curtis, Jeffrey L; Dransfield, Mark; Han, MeiLan K; Make, Barry; Marchetti, Nathaniel; Martinez, Fernando; Lazarus, Stephen; Niewoehner, Dennis; Scanlon, Paul D; Sciurba, Frank; Scharf, Steven; Reed, Robert M; Washko, George; Woodruff, Prescott; McEvoy, Charlene; Aaron, Shawn; Sin, Don; Criner, Gerard J

2017-06-19

Beta-blockers are commonly prescribed for patients with cardiovascular disease. Providers have been wary of treating chronic obstructive pulmonary disease (COPD) patients with beta-blockers due to concern for bronchospasm, but retrospective studies have shown that cardio-selective beta-blockers are safe in COPD and possibly beneficial. However, these benefits may reflect symptom improvements due to the cardiac effects of the medication. The purpose of this study is to evaluate associations between beta-blocker use and both exacerbation rates and longitudinal measures of lung function in two well-characterized COPD cohorts. We retrospectively analyzed 1219 participants with over 180 days of follow up from the STATCOPE trial, which excluded most cardiac comorbidities, and from the placebo arm of the MACRO trial. Primary endpoints were exacerbation rates per person-year and change in spirometry over time in association with beta blocker use. Overall 13.9% (170/1219) of participants reported taking beta-blockers at enrollment. We found no statistically significant differences in exacerbation rates with respect to beta-blocker use regardless of the prevalence of cardiac comorbidities. In the MACRO cohort, patients taking beta-blockers had an exacerbation rate of 1.72/person-year versus a rate of 1.71/person-year in patients not taking beta-blockers. In the STATCOPE cohort, patients taking beta-blockers had an exacerbation rate of 1.14/person-year. Patients without beta-blockers had an exacerbation rate of 1.34/person-year. We found no detrimental effect of beta blockers with respect to change in lung function over time. We found no evidence that beta-blocker use was unsafe or associated with worse pulmonary outcomes in study participants with moderate to severe COPD.

Beta-blockers and depression in elderly hypertension patients in primary care

NARCIS (Netherlands)

Ringoir, Lianne; Pedersen, Susanne S.; Widdershoven, Jos W. M. G.; Pouwer, Francois; Keyzer, Josephine M. L.; Romeijnders, Arnold C.; Pop, Victor J. M.

2014-01-01

Background and Objectives: Previous findings regarding a possible association between beta-blocker use and depression are mixed. To our knowledge there have been no studies investigating the association of beta-blockers with depression in primary care hypertension patients without previous

Point correlation dimension can reveal functional changes caused by gap junction blockers in the 4-aminopyridine in vivo rat epilepsy model

Energy Technology Data Exchange (ETDEWEB)

Jardanhazy, Anett [Department of Neurology, University of Szeged, Semmelweis u. 6, Szeged H-6725 (Hungary); Molnar, Mark [Department of Psychophysiology, Institute for Psychology of the Hungarian Academy of Sciences, P.O. Box 398, Budapest H-1394 (Hungary)], E-mail: molnar@cogpsyphy.hu; Jardanhazy, Tamas [Department of Neurology, University of Szeged, Semmelweis u. 6, Szeged H-6725 (Hungary)], E-mail: jt@nepsy.szote.u-szeged.hu

2009-04-15

The contribution of gap junction (GJ) blockers to seizure initiation was reexamined by means of an analysis on nonlinear dynamics with point correlation dimension (PD2i) at as well as around the primary focus, and mirror focus in an already active 4-aminopyridine-induced in vivo epilepsy model. From the data base of the ECoGs of anesthetized adult rats treated with quinine, a selective blocker of Cx36, and in combination with an additional broad-spectrum GJ blocker, carbenoxolone, 14 cases of each condition were reexamined with a stationarity insensitive nonlinear PD2i method. The blockade of the Cx36 channels decreased the usual drop of the point correlation dimension at the beginning of the seizures, and this was enhanced by the additional use of the global blocker carbenoxolone. The so-called characteristic DC shift just prior to seizure onset denotes a low dimensional seizure event and the recognizable seizures display very variable, rapidly changing dynamics, as revealed by the PD2i analysis. This nonlinear PD2i analysis demonstrated that the different GJ blockers in the already active epileptic model helped seizure initiation, but exerted inhibitory effects on the seizure onset itself, acting differently on the local components of the network organization generating seizure discharges, possibly changing the coupling strengths and time delays in the GJ-s.

Point correlation dimension can reveal functional changes caused by gap junction blockers in the 4-aminopyridine in vivo rat epilepsy model

International Nuclear Information System (INIS)

Jardanhazy, Anett; Molnar, Mark; Jardanhazy, Tamas

2009-01-01

The contribution of gap junction (GJ) blockers to seizure initiation was reexamined by means of an analysis on nonlinear dynamics with point correlation dimension (PD2i) at as well as around the primary focus, and mirror focus in an already active 4-aminopyridine-induced in vivo epilepsy model. From the data base of the ECoGs of anesthetized adult rats treated with quinine, a selective blocker of Cx36, and in combination with an additional broad-spectrum GJ blocker, carbenoxolone, 14 cases of each condition were reexamined with a stationarity insensitive nonlinear PD2i method. The blockade of the Cx36 channels decreased the usual drop of the point correlation dimension at the beginning of the seizures, and this was enhanced by the additional use of the global blocker carbenoxolone. The so-called characteristic DC shift just prior to seizure onset denotes a low dimensional seizure event and the recognizable seizures display very variable, rapidly changing dynamics, as revealed by the PD2i analysis. This nonlinear PD2i analysis demonstrated that the different GJ blockers in the already active epileptic model helped seizure initiation, but exerted inhibitory effects on the seizure onset itself, acting differently on the local components of the network organization generating seizure discharges, possibly changing the coupling strengths and time delays in the GJ-s.

Beta-blockers and depression after myocardial infarction - A multicenter prospective study

NARCIS (Netherlands)

van Melle, Joost P.; Verbeek, Danielle E. P.; van den Berg, Maarten P.; Ormel, Johan; van der Linde, Marcel R.; de Jonge, Peter

2006-01-01

OBJECTIVES The purpose of this research was to explore the prospective relationship between the use of beta-blockers and depression in myocardial infarction (MI) patients. BACKGROUND Beta-blocker use has been reported to be associated with the development of depression, but the methodological

β-Blocker-Associated Risks in Patients With Uncomplicated Hypertension Undergoing Noncardiac Surgery

DEFF Research Database (Denmark)

Jørgensen, Mads E; Hlatky, Mark A; Køber, Lars Valeur

2015-01-01

IMPORTANCE: Perioperative β-blocker strategies are important to reduce risks of adverse events. Effectiveness and safety may differ according to patients' baseline risk. OBJECTIVE: To determine the risk of major adverse cardiovascular events (MACEs) associated with long-term β-blocker therapy...... antihypertensive drugs (β-blockers, thiazides, calcium antagonists, or renin-angiotensin system [RAS] inhibitors) undergoing noncardiac surgery between 2005 and 2011. INTERVENTIONS: Various antihypertensive treatment regimens, chosen as part of usual care. MAIN OUTCOMES AND MEASURES: Thirty-day risk of MACEs...... (cardiovascular death, nonfatal ischemic stroke, nonfatal myocardial infarction) and all-cause mortality, assessed using multivariable logistic regression models and adjusted numbers needed to harm (NNH). RESULTS: The baseline characteristics of the 14,644 patients who received β-blockers (65% female, mean [SD...

Beta-blocker use and clinical outcomes after primary vascular surgery

DEFF Research Database (Denmark)

Høgh, A.; Lindholt, J.S.; Nielsen, Henrik

2013-01-01

To explore the associations between beta-blocker use and clinical outcomes (death, hospitalisation with myocardial infarction (MI) or stroke, major amputation and recurrent vascular surgery) after primary vascular reconstruction.......To explore the associations between beta-blocker use and clinical outcomes (death, hospitalisation with myocardial infarction (MI) or stroke, major amputation and recurrent vascular surgery) after primary vascular reconstruction....

A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

Science.gov (United States)

2017-12-01

Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER... receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor , the glucocorticoid receptor (GR...trial. 15. SUBJECT TERMS Castration resistant prostate cancer (CRPC); Androgen Receptor (AR); Glucocorticoid receptor (GR); Enzalutamide;

Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial

DEFF Research Database (Denmark)

Sandset, Else Charlotte; Murray, Gordon; Boysen, Gudrun

2010-01-01

BACKGROUND: Elevated blood pressure following acute stroke is common, and yet early antihypertensive treatment is controversial. ACCESS suggested a beneficial effect of the angiotensin receptor blocker candesartan in the acute phase of stroke, but these findings need to be confirmed in new, large...

Pre-stroke use of beta-blockers does not affect ischaemic stroke severity and outcome

NARCIS (Netherlands)

De Raedt, S.; Haentjens, P.; De Smedt, A.; Brouns, R.; Uyttenboogaart, Maarten; Luijckx, G. J.; De Keyser, J.

Background and purpose: It is unclear whether pre-stroke beta-blockers use may influence stroke outcome. This study evaluates the independent effect of pre-stroke use of beta-blockers on ischaemic stroke severity and 3 months functional outcome. Methods: Pre-stroke use of beta-blockers was

Beta-Blocker Use in Pregnancy and Risk of Specific Congenital Anomalies

DEFF Research Database (Denmark)

Bergman, Jorieke E H; Lutke, L Renée; Gans, Rijk O B

2018-01-01

INTRODUCTION: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy. OBJECTIVE: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the r...

Effects of beta-blockers and nicardipine on oxotremorine-induced tremor in common marmosets.

Science.gov (United States)

Mitsuda, M; Nomoto, M; Iwata, S

1999-10-01

Effects of beta-blockers (propranolol, arotinolol and nipradilol) and a Ca2+ channel blocker (nicardipine) on oxotremorine-induced tremor were studied in common marmosets. Generalized tremor was elicited by an intraperitoneal administration of 0.25 mg/kg oxotremorine. Intensity of the tremor was classified into 7 degrees, and it was evaluated every 10 min. The total intensity of oxotremorine-induced tremor for each drug was expressed as "points", which were the sum of tremor intensity scores evaluated every 10 min up to 190 min following the administration of oxotremorine. Beta-blockers significantly suppressed the tremor. On the other hand, the Ca2+ channel blocker exacerbated the tremor.

[Elderly heart failure patients and the role of beta-blocker therapy

NARCIS (Netherlands)

Middeljans-Tijssen, C.W.; Jansen, R.W.M.M.

2006-01-01

In this article different aspects of chronic heart failure in old age are described. We mainly focus on the place of beta-blocker therapy in chronic heart failure. Beta-blockers are recommended for the treatment of stable chronic heart failure with left ventricular systolic dysfunction. There is

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduced dementia risk in patients with diabetes mellitus and hypertension.

Science.gov (United States)

Kuan, Yi-Chun; Huang, Kuang-Wei; Yen, Der-Jen; Hu, Chaur-Jong; Lin, Cheng-Li; Kao, Chia-Hung

2016-10-01

The effects of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) on dementia risk in patients with type 2 diabetes mellitus (DM) and hypertension remain unknown. We investigated the effects of ACEIs and ARBs on dementia risk in patients with type 2 DM and hypertension. We conducted a cohort study by using the Taiwan National Health Insurance Research Database. We included 2377 patients receiving ACEIs and 1780 patients receiving ARBs in the ACEI and ARB cohorts, respectively. We included a comparable number of patients not receiving ACEIs and ARBs as controls in the non-ACEI and non-ARB cohorts through propensity score matching. The effect of ACEIs and ARBs on dementia risk was estimated through multivariate Cox proportional hazard regression after adjustment for several confounding factors. During the 12-year follow-up period, compared with the non-ACEI cohort, all-cause dementia risk decreased by 26% in the ACEI cohort [hazard ratio (HR)=0.74, 95% confidence interval (CI)=0.56-0.96]. The all-cause dementia risk was nearly 40% lower in the ARB cohort than in the non-ARB cohort (HR=0.60, 95% CI=0.37-0.97). These drugs prevented the occurrence of vascular dementia (VD), however, this effect was nonsignificant for Alzheimer's dementia (AD). Treatment duration- and dosage-related protection effects on dementia occurrence were observed. ACEIs and ARBs may effectively prevent all-cause dementia, particularly VD, in patients with type 2 DM and hypertension. Moreover, compared with ACEIs, ARBs appear to be more advantageous in dementia prevention. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats.

Science.gov (United States)

Jenkins, Tiffany L; Coleman, Amanda E; Schmiedt, Chad W; Brown, Scott A

2015-09-01

To compare the attenuation of the angiotensin I-induced blood pressure response by once-daily oral administration of various doses of angiotensin receptor blockers (irbesartan, telmisartan, and losartan), benazepril hydrochloride, or lactose monohydrate (placebo) for 8 days in clinically normal cats. 6 healthy cats (approx 17 months old) with surgically implanted arterial telemetric blood pressure-measuring catheters. Cats were administered orally the placebo or each of the drug treatments (benazepril [2.5 mg/cat], irbesartan [6 and 10 mg/kg], telmisartan [0.5, 1, and 3 mg/kg], and losartan [2.5 mg/kg]) once daily for 8 days in a crossover study. Approximately 90 minutes after capsule administration on day 8, each cat was anesthetized and arterial blood pressure measurements were recorded before and after IV administration of each of 4 boluses of angiotensin I (20, 100, 500, and 1,000 ng/kg). This protocol was repeated 24 hours after benazepril treatment and telmisartan (3 mg/kg) treatment. Differences in the angiotensin I-induced change in systolic arterial blood pressure (ΔSBP) among treatments were determined. At 90 minutes after capsule administration, only losartan did not significantly reduce ΔSBP in response to the 3 higher angiotensin doses, compared with placebo. Among drug treatments, telmisartan (3 mg/kg dosage) attenuated ΔSBP to a significantly greater degree than benazepril and all other treatments. At 24 hours, telmisartan was more effective than benazepril (mean ± SEM ΔSBP, 15.7 ± 1.9 mm Hg vs 55.9 ± 12.42 mm Hg, respectively). Results indicated that telmisartan administration may have advantages over benazepril administration for cats with renal or cardiovascular disease.

Crambescidin 816 induces calcium influx though glutamate receptors in primary cultures of cortical neurons

Directory of Open Access Journals (Sweden)

Víctor Martín Vázquez

2014-06-01

In summary, our data suggest that the cytotoxic effect of 10 μM Cramb816 in cortical neurons may be related to an increase in the cytosolic calcium concentration elicited by the toxin, which is shown to be mediated by glutamate receptor activation. Further studies analyzing the effect of glutamate receptor blockers on the cytotoxic effect of Cramb816 are needed to confirm this hypothesis.

Association between exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers prior to septic shock and acute kidney injury.

Science.gov (United States)

Suberviola, B; Rodrigo, E; González-Castro, A; Serrano, M; Heras, M; Castellanos-Ortega, Á

To evaluate the association between angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) use prior to a septic shock episode and the development, prognosis and long-term recovery from acute kidney injury (AKI). A single-centre, prospective observational study was carried out between September 2005 and August 2010. Patients admitted to the ICU of a third level hospital. A total of 386 septic shock patients were studied. None. Use of ACEIs/ARBs, AKI development, recovery of previous creatinine levels and time to recovery. A total of 386 patients were included, of which 312 (80.8%) developed AKI during ICU stay and 23% were receiving ACEIs/ARBs. The percentage of patients on ACEIs/ARBs increased significantly in relation to more severe stages of AKI irrespective of the kind of AKI score. After adjusting for confounders, the development of AKI was independently associated to the use of ACEIs/ARBs (OR 2.19; 95%CI 1.21-3.84; p=.04). With respect to the recovery of kidney function, the group of patients on ACEIs/ARBs had significantly higher creatinine levels at ICU discharge and needed hemodialysis more frequently thereafter. However, use of ACEIs/ARBs affected neither recovery of previous creatinine levels nor significantly delayed recovery. The use of ACEIs/ARBs before septic shock episodes was correlated to AKI development and severity, but did not affect the recovery of kidney function after sepsis resolution. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention.

Science.gov (United States)

Battes, Linda C; Pedersen, Susanne S; Oemrawsingh, Rohit M; van Geuns, Robert J; Al Amri, Ibtihal; Regar, Evelyn; de Jaegere, Peter P T; Serruys, Patrick; van Domburg, Ron T

2012-02-01

Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between beta blocker dose and depressive symptoms. Patients treated with PCI (N=685) completed the depression scale of the Hospital Anxiety and Depression Scale 1 and 12 months post PCI. Information about type and dose of beta blocker use was extracted from medical records. Of all patients, 68% (466/685) were on beta blocker therapy at baseline. In adjusted analysis, beta blocker use at 1 month post PCI (OR: 0.82; 95% CI: 0.53-1.26) was not significantly associated with depressive symptoms. At 12 months post PCI, there was a significant relationship between beta blocker use and depressive symptoms (OR: 0.51; 95% CI: 0.31-0.84), with beta blocker therapy associated with a 49% risk reduction in depressive symptoms. There was a dose-response relationship between beta blocker dose and depressive symptoms 12 months post PCI, with the risk reduction in depressive symptoms in relation to a low dose being 36% (OR: 0.64; 95% CI: 0.37-1.10) and 58% (OR: 0.42; 95% CI: 0.24-0.76) in relation to a high dose. Patients treated with beta blocker therapy were less likely to experience depressive symptoms 12 months post PCI, with there being a dose-response relationship with a higher dose providing a more pronounced protective effect. Copyright © 2011 Elsevier B.V. All rights reserved.

Impact of beta-blockers on cardiopulmonary exercise testing in patients with advanced liver disease.

Science.gov (United States)

Wallen, M P; Hall, A; Dias, K A; Ramos, J S; Keating, S E; Woodward, A J; Skinner, T L; Macdonald, G A; Arena, R; Coombes, J S

2017-10-01

Patients with advanced liver disease may develop portal hypertension that can result in variceal haemorrhage. Beta-blockers reduce portal pressure and minimise haemorrhage risk. These medications may attenuate measures of cardiopulmonary performance, such as the ventilatory threshold and peak oxygen uptake measured via cardiopulmonary exercise testing. To determine the effect of beta-blockers on cardiopulmonary exercise testing variables in patients with advanced liver disease. This was a cross-sectional analysis of 72 participants who completed a cardiopulmonary exercise test before liver transplantation. All participants remained on their usual beta-blocker dose and timing prior to the test. Variables measured during cardiopulmonary exercise testing included the ventilatory threshold, peak oxygen uptake, heart rate, oxygen pulse, the oxygen uptake efficiency slope and the ventilatory equivalents for carbon dioxide slope. Participants taking beta-blockers (n = 28) had a lower ventilatory threshold (P advanced liver disease taking beta-blockers compared to those not taking the medication. This may incorrectly risk stratify patients on beta-blockers and has implications for patient management before and after liver transplantation. The oxygen uptake efficiency slope was not influenced by beta-blockers and may therefore be a better measure of cardiopulmonary performance in this patient population. © 2017 John Wiley & Sons Ltd.

Role of adrenergic receptors in the caffeine-induced increase in ...

African Journals Online (AJOL)

The present study was designed to investigate the effects of alpha and beta adrenergic receptor blockers on caffeine-induced increase in canine hindlimb glucose uptake. The study was carried out on fasted male anaesthetized dogs divided into five groups (5dogs per group). Each dog was given a bolus injection of normal ...

An Analysis of Forensic Imaging in the Absence of Write-Blockers

Directory of Open Access Journals (Sweden)

Gary C Kessler

2014-09-01

Full Text Available Best practices in digital forensics demand use of write-blockers when creating forensic copies of digital media and this has been a core of computer forensics training for decades. The practice is so in-grained that images created without a write-blocker are immediate suspect for integrity. This paper describes a research framework to examine what occurs when a forensic image is acquired without benefit of a write-blocker in order to understand the true impact of such an eventuality. The initial tests document the changes made to a hard drive and flash drive when imaged and examined with a Windows-based forensics workstation.

Synthesis and characterization of a series of diarylguanidines that are noncompetitive N-methyl-D-aspartate receptor antagonists with neuroprotective properties

International Nuclear Information System (INIS)

Keana, J.F.W.; McBurney, R.N.; Scherz, M.W.

1989-01-01

Four diarylguanidine derivatives were synthesized. These compounds were found to displace, at submicromolar concentrations, 3 H-labeled 1-[1-(2-thienyl)cyclohexyl]piperidine and (+)-[ 3 H]MK-801 from phencyclidine receptors in brain membrane preparations. In electrophysiological experiments the diarylguanidines blocked N-methyl-D-aspartate (NMDA)-activated ion channels. These dairylguanidines also protected rat hippocampal neurons in vitro from glutamate-induced cell death. The results show that some diarylguanidines are noncompetitive antagonists of NMDA receptor-mediated responses and have the neuroprotective property that is commonly associated with blockers of the NMDA receptor-gated cation channel. Diarylguanidines are structurally unrelated to known blockers of NMDA channels and, therefore, represent a new compound series for the development of neuroprotective agents with therapeutic value in patients suffering from stroke, from brain or spinal cord trauma, from hypoglycemia, and possibly from brain ischemia due to heart attack

β-Blockers, Cocaine, and the Unopposed α-Stimulation Phenomenon.

Science.gov (United States)

Richards, John R; Hollander, Judd E; Ramoska, Edward A; Fareed, Fareed N; Sand, I Charles; Izquierdo Gómez, María Manuela; Lange, Richard A

2017-05-01

Cocaine abuse remains a significant worldwide health problem. Patients with cardiovascular toxicity from cocaine abuse frequently present to the emergency department for treatment. These patients may be tachycardic, hypertensive, agitated, and have chest pain. Several pharmacological options exist for treatment of cocaine-induced cardiovascular toxicity. For the past 3 decades, the phenomenon of unopposed α-stimulation after β-blocker use in cocaine-positive patients has been cited as an absolute contraindication, despite limited and inconsistent clinical evidence. In this review, the authors of the original studies, case reports, and systematic review in which unopposed α-stimulation was believed to be a factor investigate the pathophysiology, pharmacology, and published evidence behind the unopposed α-stimulation phenomenon. We also investigate other potential explanations for unopposed α-stimulation, including the unique and deleterious pharmacologic properties of cocaine in the absence of β-blockers. The safety and efficacy of the mixed β-/α-blockers labetalol and carvedilol are also discussed in relation to unopposed α-stimulation.

Determination of beta-adrenergic receptor blocking pharmaceuticals in united states wastewater effluent

Energy Technology Data Exchange (ETDEWEB)

Huggett, D.B.; Khan, I.A.; Foran, C.M.; Schlenk, D

2003-02-01

This is the first report of beta-adrenergic receptor antagonist pharmaceuticals in United States wastewater effluent. - Beta adrenergic receptor antagonists ({beta}-Blockers) are frequently prescribed medications in the United States and have been identified in European municipal wastewater effluent, however no studies to date have investigated these compounds in United States wastewater effluent. Municipal wastewater effluent was collected from treatment facilities in Mississippi, Texas, and New York to investigate the occurrence of metoprolol, nadolol, and propranolol. Propranolol was identified in all wastewater samples analyzed (n=34) at concentrations {<=}1.9 {mu}g/l. Metoprolol and nadolol were identified in {>=}71% of the samples with concentrations of metoprolol {<=}1.2 {mu}g/l and nadolol {<=}0.36 {mu}g/l. Time course studies at both Mississippi plants and the Texas plant indicate that concentrations of propranolol, metoprolol, and nadolol remain relatively constant at each sampling period. This study indicates that {beta}-Blockers are present in United States wastewater effluent in the ng/l to {mu}g/l range.

Curcumin: an orally bioavailable blocker of TNF and other pro-inflammatory biomarkers

Science.gov (United States)

Aggarwal, Bharat B; Gupta, Subash C; Sung, Bokyung

2013-01-01

TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-α, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis. These drugs include the chimeric TNF antibody (infliximab), humanized TNF-α antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year. As well as being expensive ($15 000–20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-α action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin's activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23425071

Can Beta Blockers Cause Weight Gain?

Science.gov (United States)

... cause weight gain? Can beta blockers cause weight gain? Answers from Sheldon G. Sheps, M.D. Yes. Weight gain can occur as a side effect of some ... and metoprolol (Lopressor, Toprol-XL). The average weight gain is about 2.6 pounds (about 1.2 ...

Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention

DEFF Research Database (Denmark)

Battes, Linda C; Pedersen, Susanne S.; Oemrawsingh, Rohit M

2012-01-01

Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between...... beta blocker dose and depressive symptoms....

Beta-blocker subtype and risks of perioperative adverse events following non-cardiac surgery

DEFF Research Database (Denmark)

Jørgensen, Mads E.; Sanders, Robert D.; Køber, Lars

2017-01-01

Aims Beta-blockers vary in pharmacodynamics and pharmacokinetic properties. It is unknown whether specific types are associated with increased perioperative risks. We evaluated perioperative risks associated with beta-blocker subtypes, overall and in patient subgroups. Methods and results We...... performed a Danish Nationwide cohort study, 2005-2011, of patients treated chronically with beta blocker (atenolol, bisoprolol, carvedilol, metoprolol, propranolol, or other) prior to non-cardiac surgery. Risks of 30-day all-cause mortality (ACM) and 30-day major adverse cardiovascular events (MACE) were...... in analyses stratified by age, surgery priority, duration of anaesthesia or surgery risk (all P for interaction >0.05). Conclusion Risks of ACM and MACE did not systematically differ by beta-blocker subtype. Findings may guide clinical practice and future trials....

Role of triple fixed combination valsartan, amlodipine and hydrochlorothiazide in controlling blood pressure

Directory of Open Access Journals (Sweden)

Monica Doménech

2010-04-01

Full Text Available Monica Doménech, Antonio CocaHypertension Unit, Department of Internal Medicine, Institute of Internal Medicine and Dermatology, Hospital Clinic (IDIBAPS, University of Barcelona, SpainAbstract: Hypertension is one of the main risk factors for the development of cardiovascular diseases and the search for new therapeutic strategies aimed at optimizing its control remains an ongoing research and clinical challenge. In recent years, there has been a marked increase in the use of combinations of antihypertensive drugs with complementary mechanisms of action, with the aims of reducing blood pressure levels more rapidly and vigorously than strategies employing monotherapy and improving treatment compliance and adhesion. Therefore, as recommended by the 2009 reappraisal of the European Society of Hypertension/European Society of Cardiology Guidelines, the use of a triple combination that combines a calcium channel blocker, an angiotensin II receptor blocker and a thiazide diuretic seems a reasonable and efficacious combination for the management of hypertensive patients with moderate, high or very high risk. This article reviews the clinical trials carried out with the fixed combination of amlodipine/valsartan/hydrochlorothiazide at the doses recommended for each drug in monotherapy. The data show that this combination achieved greater reductions in mean sitting diastolic and systolic blood pressure than amlodipine, valsartan or hydrochlorothiazide in monotherapy, with favorable pharmacodynamic and pharmacokinetic profiles. The triple combination at high single doses should be used with caution in elderly patients and those with renal or liver failure. Although the tolerability and safety of the triple combination are good, the mostfrequently reported adverse effects were peripheral edema, headache and dizziness. Analytical alterations were consistent with the already-known biochemical effects of amlodipine, valsartan or hydrochlorothiazide in

Angiotensin II receptor one (AT1) mediates dextrose induced endoplasmic reticulum stress and superoxide production in human coronary artery endothelial cells.

Science.gov (United States)

Haas, Michael J; Onstead-Haas, Luisa; Lee, Tracey; Torfah, Maisoon; Mooradian, Arshag D

2016-10-01

Renin-angiotensin-aldosterone system (RAAS) has been implicated in diabetes-related vascular complications partly through oxidative stress. To determine the role of angiotensin II receptor subtype one (AT1) in dextrose induced endoplasmic reticulum (ER) stress, another cellular stress implicated in vascular disease. Human coronary artery endothelial cells with or without AT1 receptor knock down were treated with 27.5mM dextrose for 24h in the presence of various pharmacologic blockers of RAAS and ER stress and superoxide (SO) production were measured. Transfection of cells with AT1 antisense RNA knocked down cellular AT1 by approximately 80%. The ER stress was measured using the placental alkaline phosphatase (ES-TRAP) assay and western blot analysis of glucose regulated protein 78 (GRP78), c-jun-N-terminal kinase 1 (JNK1), phospho-JNK1, eukaryotic translation initiation factor 2α (eIF2α) and phospho-eIF2α measurements. Superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride (MCLA) chemiluminescence. In cells with AT1 knock down, dextrose induced ER stress was significantly blunted and treatment with 27.5mM dextrose resulted in significantly smaller increase in SO production compared to 27.5mM dextrose treated and sham transfected cells. Dextrose induced ER stress was reduced with pharmacologic blockers of AT1 (losartan and candesartan) and mineralocorticoid receptor blocker (spironolactone) but not with angiotensin converting enzyme inhibitors (captopril and lisinopril). The dextrose induced SO generation was inhibited by all pharmacologic blockers of RAAS tested. The results indicate that dextrose induced ER stress and SO production in endothelial cells are mediated at least partly through AT1 receptor activation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Late Pregnancy β Blocker Exposure and Risks of Neonatal Hypoglycemia and Bradycardia.

Science.gov (United States)

Bateman, Brian T; Patorno, Elisabetta; Desai, Rishi J; Seely, Ellen W; Mogun, Helen; Maeda, Ayumi; Fischer, Michael A; Hernandez-Diaz, Sonia; Huybrechts, Krista F

2016-09-01

β blockers are widely used in the treatment of hypertensive disorders during pregnancy. These medications cross the placenta and may cause physiologic changes in neonates exposed in utero. We sought to define the risks of neonatal hypoglycemia and bradycardia associated with maternal exposure to β blockers at the time of delivery in a large, nationwide cohort of Medicaid beneficiaries. We used a cohort of 2 292 116 completed pregnancies linked to liveborn infants of Medicaid-enrolled women from 2003 to 2007. We examined the risks of neonatal hypoglycemia and neonatal bradycardia associated with maternal exposure to β blockers at the time of delivery. Propensity score matching was used to control for potential confounders including maternal demographics, obstetric and medical conditions, and exposure to other medications. There were 10 585 (0.5%) pregnancies exposed to β blockers at the time of delivery. The risk of neonatal hypoglycemia was 4.3% in the β blocker-exposed neonates versus 1.2% in the unexposed; the risk of neonatal bradycardia was 1.6% in the exposed versus 0.5% in the unexposed. After controlling for confounders, risk remained elevated for both neonatal hypoglycemia and bradycardia among exposed pregnancies versus unexposed (adjusted odds ratio, 1.68, 95% confidence interval, 1.50-1.89 and adjusted odds ratio, 1.29, 95% confidence interval, 1.07-1.55, respectively). Our findings suggest that neonates born to mothers exposed to β blockers in late pregnancy, including labetalol, are at elevated risk for neonatal hypoglycemia and bradycardia. Copyright © 2016 by the American Academy of Pediatrics.

Polymer membrane electrodes for sensitive potentiometric determination of beta-blockers.

Science.gov (United States)

Wassil, Anwar A; Farag, Abd El-Ftaah Bastawy; Moukdad, Fatma A

2007-01-01

The construction of PVC matrix-type beta-blockers (sotalol, carvedilol, and betaxolol) ion selective electrodes and their use for direct potentiometry of their respective species are described. The proposed sensors are based on the complex ion associates of beta-blockers with tungstophosphate (TP) and Ammonium Reineckate (Rein) ionophoris in poly vinyl chloride membrane (PVC) with Dioctylphthalate (DOP) plasticizer. The four electrodes (Beta-TP), (Sota-TP), (Carve-TP), and (Cave-Rein) show stable potential response with near Nernstian slope of 50.8, 33.7, 32.35, and 33 mv per decade, range of concentration 10-2-10-7 M beta-blockers. Selectivity coefficients data obtained for 11 different organic and inorganic ions are presented. The electrodes have fast response time (30 and 40 s) and were used over wide range of pH 4.5-8.5. Validation of the method according to the quality assurance standers shows suitability of proposed sensors for use in the quality control assessment of these drugs. The results obtained for the determination of beta-blockers with the proposed electrodes show average recoveries of 100.78% and a mean standard deviation of +/-1.2. The nominal are obtained. The data agree well with those obtained by standard methods.

Comparison of the clinical outcome of different beta-blockers in heart failure patients

DEFF Research Database (Denmark)

Bølling, Rasmus; Scheller, Nikolai Madrid; Køber, Lars

2014-01-01

AIM: To compare survival on different beta-blockers in heart failure. METHODS AND RESULTS: We identified all Danish patients ≥35 years of age who were hospitalized with a first admission for heart failure and who initiated treatment with a beta-blocker within 60 days of discharge. The study period....... In an unadjusted model carvedilol was associated with a lower mortality [hazard ratio (HR) 0.737, 0.714-0.761] compared with metoprolol (reference) while bisoprolol was not associated with an increased mortality (HR 1.020, 0.973-1.069). In a model adjusted for possible confounders and stratified according to beta-blocker...... receiving high-dose carvedilol (≥50 mg daily) showed significantly lower all-cause mortality risk and hospitalization risk, compared with other beta-blockers....

In Vivo Phosphoproteomics Analysis Reveals the Cardiac Targets of β-Adrenergic Receptor Signaling

DEFF Research Database (Denmark)

Lundby, Alicia; Andersen, Martin N; Steffensen, Annette B

2013-01-01

β-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting β-adrenergic receptors (βARs) and thus decreasing contractility and heart rate. βARs initiate phosphorylation-dependent signaling cascades, but only a small number of the target proteins are known. We...

The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels.

Science.gov (United States)

Ozoe, Yoshihisa; Asahi, Miho; Ozoe, Fumiyo; Nakahira, Kunimitsu; Mita, Takeshi

2010-01-01

A structurally unique isoxazoline class compound, A1443, exhibits antiparasitic activity against cat fleas and dog ticks comparable to that of the commercial ectoparasiticide fipronil. This isoxazoline compound inhibits specific binding of the gamma-aminobutyric acid (GABA) receptor channel blocker [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) to housefly-head membranes, with an IC(50) value of 455pM. In contrast, the IC(50) value in rat-brain membranes is>10muM. To study the mode of action of this isoxazoline, we utilized MdGBCl and MdGluCl cDNAs, which encode the subunits of housefly GABA- and glutamate-gated chloride channels, respectively. Two-electrode voltage clamp electrophysiology was used to confirm that A1443 blocks GABA- and glutamate-induced chloride currents in Xenopus oocytes expressing MdGBCl or MdGluCl channels, with IC(50) values of 5.32 and 79.9 nM, respectively. Blockade by A1443 was observed in A2'S-MdGBCl and S2'A-MdGluCl mutant channels at levels similar to those of the respective wild-types, and houseflies expressing A2'S-MdGBCl channels were as susceptible to A1443 as standard houseflies. These findings indicate that A1443 is a novel and specific blocker of insect ligand-gated chloride channels. Copyright 2009 Elsevier Inc. All rights reserved.

Pilot-Reported Beta-Blockers Identified by Forensic Toxicology Analysis of Postmortem Specimens.

Science.gov (United States)

Canfield, Dennis V; Dubowski, Kurt M; Whinnery, James M; Forster, Estrella M

2018-01-01

This study compared beta-blockers reported by pilots with the medications found by postmortem toxicology analysis of specimens received from fatal aviation accidents between 1999 and 2015. Several studies have compared drugs using the standard approach: Compare the drug found by toxicology analysis with the drug reported by the pilot. This study uniquely examined first the pilot-reported medication and then compared it to that detected by toxicology analysis. This study will serve two purposes: (i) to determine the capability of a toxicology laboratory to detect reported medications, and (ii) to identify pilots with medications below detectable limits. All information required for this study was extracted from the Toxicology Data Base system and was searched using ToxFlo or SQL Server Management Studio. The following information was collected and analyzed: pilot-reported trade and/or generic drug, date specimens received, time of accident, type of aviation operations (CFR), state, pilot level, age, class of medical, specimen type, specimen concentration, dose reported, frequency reported associated with the accident, quantity reported, National Transportation Safety Board (NTSB) accident event number, and all NTSB reports. There were 319 pilots that either reported taking a beta-blocker or were found to be taking a beta-blocker by postmortem toxicology analysis. Time of death, therapeutic concentration and specimen type were found to be factors in the ability of the laboratory to detect beta-blockers. Beta-blockers taken by pilots will, in most cases, be found by a competent postmortem forensic toxicology laboratory at therapeutic concentrations. The dose taken by the pilot was not found to be a factor in the ability of the laboratory to identify beta-blockers. Time of dose, route of administration, specimen tested and therapeutic concentration of the drug were found to be factors in the ability of the laboratory to identify beta-blockers in postmortem specimens

Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs.

Science.gov (United States)

Michael, G; Kane, K A; Coker, S J

2008-08-01

Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

Directory of Open Access Journals (Sweden)

Garrido-Gil Pablo

2012-02-01

Full Text Available Abstract Background Several recent studies have shown that angiotensin type 1 receptor (AT1 antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ. PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions. Methods We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662. Results We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co

Occurrence and fate of the angiotensin II receptor antagonist transformation product valsartan acid in the water cycle--a comparative study with selected β-blockers and the persistent anthropogenic wastewater indicators carbamazepine and acesulfame.

Science.gov (United States)

Nödler, Karsten; Hillebrand, Olav; Idzik, Krzysztof; Strathmann, Martin; Schiperski, Ferry; Zirlewagen, Johannes; Licha, Tobias

2013-11-01

The substantial transformation of the angiotensin II receptor antagonist valsartan to the transformation product 2'-(2H-tetrazol-5-yl)-[1,1'-biphenyl]-4-carboxylic acid (referred to as valsartan acid) during the activated sludge process was demonstrated in the literature and confirmed in the here presented study. However, there was a severe lack of knowledge regarding the occurrence and fate of this compound in surface water and its behavior during drinking water treatment. In this work a comparative study on the occurrence and persistency of valsartan acid, three frequently used β-blockers (metoprolol, atenolol, and sotalol), atenolol acid (one significant transformation product of atenolol and metoprolol), and the two widely distributed persistent anthropogenic wastewater indicators carbamazepine and acesulfame in raw sewage, treated wastewater, surface water, groundwater, and tap water is presented. Median concentrations of valsartan acid in the analyzed matrices were 101, 1,310, 69, waters valsartan acid was found just as relevant as the analyzed β-blockers and the anticonvulsant carbamazepine. Regarding its persistency in surface waters it was comparable to carbamazepine and acesulfame. Furthermore, removal of valsartan acid during bank filtration was poor, which demonstrated the relevance of this compound for drinking water suppliers. Regarding drinking water treatment (Muelheim Process) the compound was resistant to ozonation but effectively eliminated (≥90%) by subsequent activated carbon filtration. However, without applying activated carbon filtration the compound may enter the drinking water distribution system as it was demonstrated for Berlin tap water. Copyright © 2013 Elsevier Ltd. All rights reserved.

How Do Beta Blocker Drugs Affect Exercise?

Science.gov (United States)

... in lieu of exercise. Exercise has many other benefits and is important to maintain your health. Read how physical activity improves the quality of life . Concerns About Exercising While on Beta Blockers “It’s important to remember ...

The role of the central histaminergic receptors in the exercise-induced improvements of the spatial learning and memory in rats.

Science.gov (United States)

Taati, Majid; Moghaddasi, Mehrnoush; Esmaeili, Masoumeh; Pourkhodadad, Soheila; Nayebzadeh, Hassan

2014-10-31

While it is well known that exercise can improve cognitive performance, the underlying mechanisms are not fully understood. There is now evidence that histamine can modulate learning and memory in different types of behavioral tasks. The present study was designed to examine the possible role of central histamine H1 and H2 receptors in forced treadmill running-induced enhancement of learning and memory in rats. For this purpose the animals received intracerebroventricularly chlorpheniramine (H1 receptor blocker) and cimetidine (H2 receptor blocker) before each day of fifteen consecutive days of exercise. Then their learning and memory were tested on the water maze task using a four-trial-per-day for 4 consecutive days. A probe trial was performed after the last training day. Our data showed that cimetidine reversed the exercise-induced improvement in learning and memory in rats; however, this was not the case regarding chlorpheniramine. Our findings indicate that central histamine H2 receptors play an important role in mediating the beneficial effects of forced exercise on learning and memory. Copyright © 2014 Elsevier B.V. All rights reserved.

Development of a population pharmacokinetic model to predict brain distribution and dopamine D2 receptor occupancy of raclopride in nonanesthetized rat

NARCIS (Netherlands)

Wong, Y.C.; Ilkova, T.I.; Wijk, van R.C.; Hartman, R.J.; Lange, de E.C.M.

2018-01-01

BACKGROUND: Raclopride is a selective antagonist of the dopamine D2 receptor. It is one of the most frequently used in vivo D2 tracers (at low doses) for assessing drug-induced receptor occupancy (RO) in animals and humans. It is also commonly used as a pharmacological blocker (at high doses) to

Systemic delivery of β-blockers via transdermal route for hypertension

Science.gov (United States)

Ahad, Abdul; Al-Jenoobi, Fahad I.; Al-Mohizea, Abdullah M.; Akhtar, Naseem; Raish, Mohammad; Aqil, Mohd.

2014-01-01

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later. PMID:26702253

Clinical utility of fixed-dose combinations in hypertension: evidence for the potential of nebivolol/valsartan

Directory of Open Access Journals (Sweden)

Varagic J

2014-11-01

Full Text Available Jasmina Varagic,1–3 Henry Punzi,4,5 Carlos M Ferrario2,3,61Hypertension and Vascular Research Center, 2Division of Surgical Sciences, 3Department of Physiology and Pharmacology, Wake Forest University, Winston-Salem, NC USA; 4Trinity Hypertension and Diagnostic Research Center, Carrollton, TX, USA; 5Department of Family and Community Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; 6Department of Internal Medicine and Nephrology, Wake Forest University, Winston-Salem, NC, USAAbstract: Despite significant advances in pharmacologic approaches to treat hypertension during the last decades, hypertension- and hypertension-related organ damage are still a high health and economic burden because a large proportion of patients with hypertension do not achieve optimal blood pressure control. There is now general agreement that combination therapy with two or more antihypertensive drugs is required for targeted blood pressure accomplishment and reduction of global cardiovascular risk. The goals of combination therapies are to reduce long-term cardiovascular events by targeting different mechanism underlying hypertension and target organ disease, to block the counterregulatory pathways activated by monotherapies, to improve tolerability and decrease the adverse effects of up-titrated single agents, and to increase persistence and adherence with antihypertensive therapy. Multiple clinical trials provide evidence that fixed-dose combinations in a single pill offer several advantages when compared with loose-dose combinations. This review discusses the advances in hypertension control and associated cardiovascular disease as they relate to the prospect of combination therapy targeting a third-generation beta (β 1-adrenergic receptor (nebivolol and an angiotensin II receptor blocker (valsartan in fixed-dose single-pill formulations.Keywords: blood pressure control, hypertension, β1-adrenergic receptor, renin angiotensin system

Discontinuation of beta-blockers and the risk of myocardial infarction in the elderly.

NARCIS (Netherlands)

Teichert, M.; Smet, P.A.G.M. de; Hofman, A.; Witteman, J.C.; Stricker, B.H.C.

2007-01-01

BACKGROUND: It has been shown that the abrupt cessation of treatment with beta-adrenoceptor antagonists (beta-blockers) increases the risk of myocardial infarction in patients with hypertension. As beta-blockers differ in their pharmacokinetic and pharmacodynamic properties, this risk of

Discontinuation of β-blockers and the risk of myocardial infarction in the elderly

NARCIS (Netherlands)

M. Teichert (Martina); P.A. de Smet (Peter); A. Hofman (Albert); J.C.M. Witteman (Jacqueline); B.H.Ch. Stricker (Bruno)

2007-01-01

textabstractBackground: It has been shown that the abrupt cessation of treatment with β-adrenoceptor antagonists (β-blockers) increases the risk of myocardial infarction in patients with hypertension. As β-blockers differ in their pharmacokinetic and pharmacodynamic properties, this risk of

Safe browsing - is an ad-blocker enough?

CERN Multimedia

CERN. Geneva

2015-01-01

An ad-blocker plugin in your browser stops advertisements and maybe some malware. But is it enough? Are you feeling secure while surfing the Web? If your answer is yes, think twice! What else can you do to protect yourself?

Addition of Aliskiren to Angiotensin Receptor Blocker Improves Ambulatory Blood Pressure Profile and Cardiorenal Function Better than Addition of Benazepril in Chronic Kidney Disease

Directory of Open Access Journals (Sweden)

Satoshi Umemura

2013-07-01

Full Text Available An altered ambulatory blood pressure (BP and heart rate (HR profile is related to chronic kidney disease (CKD and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18 or the benazepril add-on group (n = 18. Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

Addition of aliskiren to Angiotensin receptor blocker improves ambulatory blood pressure profile and cardiorenal function better than addition of benazepril in chronic kidney disease.

Science.gov (United States)

Ohsawa, Masato; Tamura, Kouichi; Kanaoka, Tomohiko; Wakui, Hiromichi; Maeda, Akinobu; Dejima, Toru; Azushima, Kengo; Uneda, Kazushi; Kobayashi, Ryu; Tsurumi-Ikeya, Yuko; Toya, Yoshiyuki; Fujikawa, Tetsuya; Umemura, Satoshi

2013-07-24

An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

DMPD: Lipopolysaccharide-binding molecules: transporters, blockers and sensors. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 15241548 Lipopolysaccharide-binding molecules: transporters, blockers and sensors. ...binding molecules: transporters, blockers and sensors. PubmedID 15241548 Title Lipopolysaccharide-binding molecules: transport...Chaby R. Cell Mol Life Sci. 2004 Jul;61(14):1697-713. (.png) (.svg) (.html) (.csml) Show Lipopolysaccharide-

A novel method to generate T-cell receptor-deficient chimeric antigen receptor T cells.

Science.gov (United States)

Kamiya, Takahiro; Wong, Desmond; Png, Yi Tian; Campana, Dario

2018-03-13

Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRαβ, we combined an antibody-derived single-chain variable fragment specific for CD3ε with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3ε, blocking surface CD3 and TCRαβ expression. In 25 experiments, median TCRαβ expression in T lymphocytes was reduced from 95.7% to 25.0%; CD3/TCRαβ cell depletion yielded virtually pure TCRαβ-negative T cells. Anti-CD3ε PEBLs abrogated TCRαβ-mediated signaling, without affecting immunophenotype or proliferation. In anti-CD3ε PEBL-T cells, expression of an anti-CD19-41BB-CD3ζ CAR induced cytokine secretion, long-term proliferation, and CD19 + leukemia cell killing, at rates meeting or exceeding those of CAR-T cells with normal CD3/TCRαβ expression. In immunodeficient mice, anti-CD3ε PEBL-T cells had markedly reduced GVHD potential; when transduced with anti-CD19 CAR, these T cells killed engrafted leukemic cells. PEBL blockade of surface CD3/TCRαβ expression is an effective tool to prepare allogeneic CAR-T cells. Combined PEBL and CAR expression can be achieved in a single-step procedure, is easily adaptable to current cell manufacturing protocols, and can be used to target other T-cell molecules to further enhance CAR-T-cell therapies. © 2018 by The American Society of Hematology.

Excitatory amino acid neurotoxicity and modulation of glutamate receptor expression in organotypic brain slice cultures

DEFF Research Database (Denmark)

Zimmer, J; Kristensen, Bjarne Winther; Jakobsen, B

2000-01-01

Using organotypic slice cultures of hippocampus and cortex-striatum from newborn to 7 day old rats, we are currently studying the excitotoxic effects of kainic acid (KA), AMPA and NMDA and the neuroprotective effects of glutamate receptor blockers, like NBQX. For detection and quantitation...

Recent Clinical Drug Trials Evidence in Marfan Syndrome and Clinical Implications.

Science.gov (United States)

Singh, Michael N; Lacro, Ronald V

2016-01-01

Marfan syndrome is a genetic disorder of connective tissue with principal manifestations in the cardiovascular, ocular, and skeletal systems. Cardiovascular disease, mainly progressive aortic root dilation and aortic dissection, is the leading cause of morbidity and mortality. The primary aims of this report were to examine the evidence related to medical therapy for Marfan syndrome, including recently completed randomized clinical trials on the efficacy of β-blockers and angiotensin II receptor blockers for the prophylactic treatment of aortic enlargement in Marfan syndrome, and to provide recommendations for medical therapy on the basis of available evidence. Medical therapy for Marfan syndrome should be individualized according to patient tolerance and risk factors such as age, aortic size, and family history of aortic dissection. The Pediatric Heart Network trial showed that atenolol and losartan each reduced the rate of aortic dilation. All patients with known or suspected Marfan syndrome and aortic root dilation should receive medical therapy with adequate doses of either β-blocker or angiotensin receptor blocker. The Pediatric Heart Network trial also showed that atenolol and losartan are more effective at reduction of aortic root z score in younger subjects, which suggests that medical therapy should be prescribed even in the youngest children with aortic dilation. For patients with Marfan syndrome without aortic dilation, the available evidence is less clear. If aortic dilation is severe and/or progressive, therapy with a combination of β-blocker and angiotensin receptor blocker should be considered, although trial results are mixed with respect to the efficacy of combination therapy vs monotherapy. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis.

Science.gov (United States)

Tokuda, Kazuhiro; O'Dell, Kazuko A; Izumi, Yukitoshi; Zorumski, Charles F

2010-12-15

Benzodiazepines (BDZs) enhance GABA(A) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors [translocator protein (18 kDa) (TSPO)] and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ, with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectively. Midazolam, but not clonazepam, increased neurosteroid levels in CA1 pyramidal neurons without changing TSPO immunostaining. Midazolam, but not clonazepam, also augmented a form of spike inhibition after stimulation adjacent to the pyramidal cell layer and inhibited induction of long-term potentiation. These effects were prevented by finasteride, an inhibitor of neurosteroid synthesis, or 17PA [17-phenyl-(3α,5α)-androst-16-en-3-ol], a blocker of neurosteroid effects on GABA(A) receptors. Moreover, the synaptic effects were mimicked by a combination of clonazepam with FGIN (2-[2-(4-fluorophenyl)-1H-indol-3-yl]-N,N-dihexylacetamide), a selective TSPO agonist, or a combination of clonazepam with exogenous allopregnanolone. Consistent with these in vitro results, finasteride abolished the effects of midazolam on contextual fear learning when administrated 1 d before midazolam injection. Thus, dual activation of CBRs and TSPO appears to result in unique actions of clinically important BDZs. Furthermore, endogenous neurosteroids are shown to be important regulators of pyramidal neuron function and synaptic plasticity.

Use of β-Blockers in Pulmonary Hypertension.

Science.gov (United States)

Perros, Frédéric; de Man, Frances S; Bogaard, Harm J; Antigny, Fabrice; Simonneau, Gérald; Bonnet, Sébastien; Provencher, Steeve; Galiè, Nazzareno; Humbert, Marc

2017-04-01

Contrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postcapillary pulmonary hypertension because of left heart disease. In pulmonary hypertension, the status of the right ventricle is one of the most important predictors of both morbidity and mortality. Paradoxically, there are currently no approved therapies targeting the right ventricle in pulmonary hypertension. By analogy with the key role of β-blockers in the management of left heart failure, some authors have proposed to use these agents to support the right ventricle function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of β-blockers in pulmonary hypertension. © 2017 American Heart Association, Inc.

Effects of Calcium Channel Blockers on Antidepressant Action of Alprazolam and Imipramine

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Gorash ZM

2007-01-01

Full Text Available Alprazolam is effective as an anxiolytic and in the adjunct treatment of depression. In this study, the effects of calcium channel antagonists on the antidepressant action of alprazolam and imipramine were investigated. A forced swimming maze was used to study behavioral despair in albino mice. Mice were divided into nine groups (n = 7 per group. One group received a single dose of 1% Tween 80; two groups each received a single dose of the antidepressant alone (alprazolam or imipramine; two groups each received a single dose of the calcium channel blocker (nifedipine or verapamil; four groups each received a single dose of the calcium channel blocker followed by a single dose of the antidepressant (with same doses used for either in the previous four groups. Drug administration was performed concurrently on the nine groups. Our data confirmed the antidepressant action of alprazolam and imipramine. Both nifedipine and verapamil produced a significant antidepressant effect (delay the onset of immobility when administered separately. Verapamil augmented the antidepressant effects of alprazolam and imipramine (additive antidepressant effect. This may be due to the possibility that verapamil might have antidepressant-like effect through different mechanism. Nifedipine and imipramine combined led to a delay in the onset of immobility greater than their single use but less than the sum of their independent administration. This may be due to the fact that nifedipine on its own might act as an antidepressant but blocks one imipramine mechanism that depends on L-type calcium channel activation. Combining nifedipine with alprazolam produced additional antidepressant effects, which indicates that they exert antidepressant effects through different mechanisms.

Determination of beta-adrenergic receptor blocking pharmaceuticals in united states wastewater effluent

International Nuclear Information System (INIS)

Huggett, D.B.; Khan, I.A.; Foran, C.M.; Schlenk, D.

2003-01-01

This is the first report of beta-adrenergic receptor antagonist pharmaceuticals in United States wastewater effluent. - Beta adrenergic receptor antagonists (β-Blockers) are frequently prescribed medications in the United States and have been identified in European municipal wastewater effluent, however no studies to date have investigated these compounds in United States wastewater effluent. Municipal wastewater effluent was collected from treatment facilities in Mississippi, Texas, and New York to investigate the occurrence of metoprolol, nadolol, and propranolol. Propranolol was identified in all wastewater samples analyzed (n=34) at concentrations ≤1.9 μg/l. Metoprolol and nadolol were identified in ≥71% of the samples with concentrations of metoprolol ≤1.2 μg/l and nadolol ≤0.36 μg/l. Time course studies at both Mississippi plants and the Texas plant indicate that concentrations of propranolol, metoprolol, and nadolol remain relatively constant at each sampling period. This study indicates that β-Blockers are present in United States wastewater effluent in the ng/l to μg/l range

Banding ligation versus beta-blockers for primary prevention in oesophageal varices in adults

DEFF Research Database (Denmark)

Gluud, Lise Lotte; Krag, Aleksander

2012-01-01

Non-selective beta-blockers are used as a first-line treatment for primary prevention in patients with medium- to high-risk oesophageal varices. The effect of non-selective beta-blockers on mortality is debated and many patients experience adverse events. Trials on banding ligation versus non...

Cellular Responses to Beta Blocker Exposures in Marine ...

Science.gov (United States)

β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent activation of adenylate cyclase and increases in blood pressure by limiting cAMP production and protein kinase A activation. After being taken therapeutically, β blockers may make their way to coastal habitats via discharge from waste water treatment plants, posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular biomarkers of β blocker exposure using two drugs, propranolol and metoprolol, in three commercially important marine bivalves -Crassostrea virginica, Mytilus edulis and Mercenaria mercenaria. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug for 24 hours. Samples were preserved for cellular biomarker assays. Elevated cellular damage and changes in enzymatic activities were noted at environmentally relevant concentrations, and M. mercenaria was found to be the most sensitive bivalve out of the three species tested. These studies enhance our understanding of the potential impacts of commonly used prescription medication on organisms in coastal ecosystems, and demonstrate that filter feeders such as marine bivalves may serve as good model organisms to examine the effects of water soluble drugs. Evaluating a suite of biomarkers

Adição de Bloqueador do receptor de angiotensina II na insuficiência cardíaca descompensada Adición de bloqueante del receptor de angiotensina II en la insuficiencia cardiaca descompensada Angiotensin II receptor blocker add-on therapy for low cardiac output in decompensated heart failure

Directory of Open Access Journals (Sweden)

Marcelo E. Ochiai

2010-02-01

pacientes internados por descompensación de la insuficiencia cardiaca y con empleo por más de 15 días de dobutamina, o una o más intentos sin éxito de retirada; dosis optimizada de IECA; y FEVI BACKGROUND: During heart failure (HF decompensation, an intense activation of the renin-angiotensin-aldosterone system occurs; however, the use of angiotensin-converting enzyme inhibitor (ACEI cannot block it completely. Otherwise, the addition of angiotensin II receptor blocker (ARB can be useful when the inotropic dependence occurs. We evaluated the efficacy of the ARB-ACEI association on dobutamine withdrawal in advanced decompensated HF. OBJECTIVE: To assess the efficacy of association angiotensin receptor blocker - angiotensin converting enzyme inhibitor to withdraw the intravenous inotropic support in decompensated severe heart failure. METHODS: In a case-control study (N = 24, we selected patients admitted at the hospital due to HF that had been using dobutamine for more than 15 days, with one or more unsuccessful drug withdrawal attempts; optimized dose of ACEI and ejection fraction (EF < 0.45. Then, the patients additionally received ARB (n=12 or not (control, n=12. The outcome was the successful dobutamine withdrawal, evaluated by logistic regression, with a p < 0.05. RESULTS: The EF was 0.25 and the age was 53 years, with a dobutamine dose of 10.7 μg/kg.min. The successful drug withdrawal was observed in 8 patients from the ARB group (67.7% and in 2 patients from the control group (16.7%. The odds ratio (OR was 10.0 (95%CI: 1.4 to 69.3; p = 0.02. The worsening in renal function was similar (ARB group: 42% vs. control group: 67%; p=0.129. CONCLUSION: In this pilot study, the ARB-ACEI association was associated with successful dobutamine withdrawal in advanced decompensated heart failure. The worsening in renal function was similar in both groups. Further studies are necessary to clarify the issue.

MK-801, but not drugs acting at strychnine-insensitive glycine receptors, attenuate methamphetamine nigrostriatal toxicity.

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Layer, R T; Bland, L R; Skolnick, P

1993-10-15

Repeated administration of methamphetamine (METH) results in damage to nigrostriatal dopaminergic neurons. Both competitive N-methyl-D-aspartate (NMDA) receptor antagonists and use-dependent cation channel blockers attenuate METH-induced damage. The objectives of the present study were to examine whether comparable reductions in METH-induced damage could be obtained by compounds acting at strychnine-insensitive glycine receptors on the NMDA receptor complex. Four injections of METH (5 mg/kg i.p.) resulted in a approximately 70.9% depletion of striatal dopamine (DA) and approximately 62.7% depletion of dihydroxyphenylacetic acid (DOPAC) content, respectively. A significant protection against METH-induced DA and DOPAC depletion was afforded by the use-dependent channel blocker, MK-801. The competitive glycine antagonist 7-chlorokynurenic acid (7-Cl-KA), the low efficacy glycine partial agonist (+)-3-amino-1-hydroxy-2-pyrrolidone ((+)-HA-966), and the high efficacy partial glycine agonist 1-aminocyclopropane-carboxylic acid (ACPC) were ineffective against METH-induced toxicity despite their abilities to attenuate glutamate-induced neurotoxicity under both in vivo and in vitro conditions. These results indicate that glycinergic ligands do not possess the same broad neuroprotective spectrum as other classes of NMDA antagonists.

THE EFFICACY OF COMBINED PHARMACOLOGICAL BLOCKING OF RAAS IN CHILDREN WITH CHRONIC RENAL DISEASE

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E.S. Otroshchenko

2010-01-01

Full Text Available 14 children with various clinical forms of steroid-resistant nephrotic syndrome have been examined to assess the efficacy of pharmacological blocking of RAAS using inhibitors of angiotensin-converting enzyme and Angiotensin II receptor blockers. While assessing the efficacy of the nephroprotective therapy, the following was found in all the children: a reliably meaningful 1,5 times reduction ((р = 0,013 in the daily proteinuria level in 3 to 6 months, and by the end of the study — a 2,5 times reduction (р = 0,001 and improvement in the renal filtration function metrics in 3 to 6 months (р = 0,001, in 1 year (р = 0,013 and by the end of the study (p = 0,002 in comparison with the metrics prior to the launch of the nephroprotective therapy. Key words: chronic renal disease, proteinuria, RAAS, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers. (Pediatric Pharmacology. – 2010; 7(2:105-109

Are lipophilic beta-blockers preferable for peri-operative ...

African Journals Online (AJOL)

Adele

management of hypertension and post myocardial infarction.4-6. Are lipophilic ... studies in hypertensive medical patients showed no difference in cardiovascular ... atenolol and bendroflumethiazide arm.7 In meta-analyses of beta-blocker ...

[Usefullness of Beta-blocker for Hemodynamic Changes Induced by Uterotonic Drug in a Patient with Hypertrophic Obstructive Cardiomyopathy Undergoing Elective Cesarean Section].

Science.gov (United States)

Tsukano, Yuri; Sugita, Michiko; Ikuta, Yoshihiro; Yamamoto, Tatsuo

2015-06-01

Combined spinal-epidural anesthesia (CSEA) was given to a 27-year-old woman with hypertrophic obstructive cardiomyopathy (HOCM) for a selective cesarean section. After the injection of uterotonic drug via uterine muscle and a vein after delivery, the patient developed dyspnea, tachycardia, ST-change on elecrocardiogram and hypotension. It is important in HOCM patients to control heart rate and left ventricular contractile force. We started to infuse beta-blocker (landiolol, 10 μg x kg(-1) x min(-1)) and improved these symptoms of the patient. This case demonstrates that CSEA is safe for HOCM patients and beta-blocker is effective to improve hemodynamic changes induced by uterotonic drug in these patients.

Combining GLP-1 receptor agonists with insulin

DEFF Research Database (Denmark)

Holst, Jens Juul; Vilsbøll, T

2013-01-01

Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among...... physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase insulin release and suppress glucagon secretion in a glucose......, compared with insulin, the antihyperglycaemic efficacy of GLP-1RAs is limited. The combination of a GLP-1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic...

Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

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Blessberger, Hermann; Kammler, Juergen; Domanovits, Hans; Schlager, Oliver; Wildner, Brigitte; Azar, Danyel; Schillinger, Martin; Wiesbauer, Franz; Steinwender, Clemens

2018-03-13

Randomized controlled trials have yielded conflicting results regarding the ability of beta-blockers to influence perioperative cardiovascular morbidity and mortality. Thus routine prescription of these drugs in unselected patients remains a controversial issue. The objective of this review was to systematically analyse the effects of perioperatively administered beta-blockers for prevention of surgery-related mortality and morbidity in patients undergoing any type of surgery while under general anaesthesia. We identified trials by searching the following databases from the date of their inception until June 2013: MEDLINE, Embase , the Cochrane Central Register of Controlled Trials (CENTRAL), Biosis Previews, CAB Abstracts, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Derwent Drug File, Science Citation Index Expanded, Life Sciences Collection, Global Health and PASCAL. In addition, we searched online resources to identify grey literature. We included randomized controlled trials if participants were randomly assigned to a beta-blocker group or a control group (standard care or placebo). Surgery (any type) had to be performed with all or at least a significant proportion of participants under general anaesthesia. Two review authors independently extracted data from all studies. In cases of disagreement, we reassessed the respective studies to reach consensus. We computed summary estimates in the absence of significant clinical heterogeneity. Risk ratios (RRs) were used for dichotomous outcomes, and mean differences (MDs) were used for continuous outcomes. We performed subgroup analyses for various potential effect modifiers. We included 88 randomized controlled trials with 19,161 participants. Six studies (7%) met the highest methodological quality criteria (studies with overall low risk of bias: adequate sequence generation, adequate allocation concealment, double/triple-blinded design with a placebo group, intention-to-treat analysis

Effects of beta-blockers on heart failure with preserved ejection fraction: a meta-analysis.

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Feng Liu

Full Text Available BACKGROUND: Effects of beta-blockers on the prognosis of the heart failure patients with preserved ejection fraction (HFpEF remain controversial. The aim of this meta-analysis was to determine the impact of beta-blockers on mortality and hospitalization in the patients with HFpEF. METHODS: A search of MEDLINE, EMBASE, and the Cochrane Library databases from 2005 to June 2013 was conducted. Clinical studies reporting outcomes of mortality and/or hospitalization for patients with HFpEF (EF ≥ 40%, being assigned to beta-blockers treatment and non-beta-blockers control group were included. RESULTS: A total of 12 clinical studies (2 randomized controlled trials and 10 observational studies involving 21,206 HFpEF patients were included for this meta-analysis. The pooled analysis demonstrated that beta-blocker exposure was associated with a 9% reduction in relative risk for all-cause mortality in patients with HFpEF (95% CI: 0.87 - 0.95; P < 0.001. Whereas, the all-cause hospitalization, HF hospitalization and composite outcomes (mortality and hospitalization were not affected by this treatment (P=0.26, P=0.97, and P=0.88 respectively. CONCLUSIONS: The beta-blockers treatment for the patients with HFpEF was associated with a lower risk of all-cause mortality, but not with a lower risk of hospitalization. These finding were mainly obtained from observational studies, and further investigations are needed to make an assertion.

Impact of beta-blocker treatment on the prognostic value of currently used risk predictors in congestive heart failure.

Science.gov (United States)

Zugck, Christian; Haunstetter, Armin; Krüger, Carsten; Kell, Robert; Schellberg, Dieter; Kübler, Wolfgang; Haass, Markus

2002-05-15

This prospective study tested the impact of beta-blocker treatment on currently used risk predictors in congestive heart failure (CHF). Given the survival benefit obtained by beta-blockade, risk stratification by factors established in the "pre-beta-blocker era" may be questioned. The study included 408 patients who had CHF with left ventricular ejection fraction (LVEF) 2.24 nmol/l (18% vs. 40%) and NT-proBNP >364 pmol/l (27% vs. 45%), although patients with beta-blocker treatment received only 37 +/- 21% of the maximal recommended beta-blocker dosages. The prognostic value of variables used for risk stratification of patients with CHF is markedly influenced by beta-blocker treatment. Therefore, in the beta-blocker era, a re-evaluation of the selection criteria for heart transplantation is warranted.

Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease

DEFF Research Database (Denmark)

Andersson, Charlotte; Shilane, David; Go, Alan S

2014-01-01

BACKGROUND: The effectiveness of beta-blockers for preventing cardiac events has been questioned for patients who have coronary heart disease (CHD) without a prior myocardial infarction (MI). OBJECTIVES: The purpose of this study was to assess the association of beta-blockers with outcomes among...... patients with new-onset CHD. METHODS: We studied consecutive patients discharged after the first CHD event (acute coronary syndrome or coronary revascularization) between 2000 and 2008 in an integrated healthcare delivery system who did not use beta-blockers in the year before entry. We used time......-varying Cox regression models to determine the hazard ratio (HR) associated with beta-blocker treatment and used treatment-by-covariate interaction tests (pint) to determine whether the association differed for patients with or without a recent MI. RESULTS: A total of 26,793 patients were included, 19...

C4d-negative antibody-mediated rejection with high anti-angiotensin II type I receptor antibodies in absence of donor-specific antibodies.

Science.gov (United States)

Fuss, Alexander; Hope, Christopher M; Deayton, Susan; Bennett, Greg Donald; Holdsworth, Rhonda; Carroll, Robert P; Coates, P Toby H

2015-07-01

Acute antibody-mediated rejection can occur in absence of circulating donor-specific antibodies. Agonistic antibodies targeting the anti-angiotensin II type 1 receptor (anti-AT1 R) are emerging as important non-human leucocyte antigen (HLA) antibodies. Elevated levels of anti-angiotensin II receptor antibodies were first observed in kidney transplant recipients with malignant hypertension and allograft rejection. They have now been studied in three separate kidney transplant populations and associate to frequency of rejection, severity of rejection and graft failure. We report 11 cases of biopsy-proven, Complement 4 fragment d (C4d)-negative, acute rejection occurring without circulating donor-specific anti-HLA antibodies. In eight cases, anti-angiotensin receptor antibodies were retrospectively examined. The remaining three subjects were identified from our centre's newly instituted routine anti-angiotensin receptor antibody screening. All subjects fulfilled Banff 2013 criteria for antibody-mediated rejection and all responded to anti-rejection therapy, which included plasma exchange and angiotensin receptor blocker therapy. These cases support the routine assessment of anti-AT1 R antibodies in kidney transplant recipients to identify subjects at risk. Further studies will need to determine optimal assessment protocol and the effectiveness of pre-emptive treatment with angiotensin receptor blockers. © 2015 Asian Pacific Society of Nephrology.

Synthesis of [18F]-labelled nebivolol as a β1-adrenergic receptor antagonist for PET imaging agent

International Nuclear Information System (INIS)

Kim, Taek Soo; Park, Jeong Hoon; Lee, Jun Young; Yang, Seung Dae; Chang, Dong Jo

2017-01-01

Selective β 1 -agonist and antagonists are used for the treatment of cardiac diseases including congestive heart failure, angina pectoris and arrhythmia. Selective β 1 -antagonists including nebivolol have high binding affinity on β 1 -adrenergic receptor, not β 2 -receptor mainly expressed in smooth muscle. Nebivolol is one of most selective β 1 -blockers in clinically used β 1 - blockers including atenolol and bisoprolol. We tried to develop clinically useful cardiac PET tracers using a selective β 1 -blocker. Nebivolol is C 2 -symmetric and has two chromane moiety with a secondary amino alcohol and aromatic fluorine. We adopted the general synthetic strategy using epoxide ring opening reaction. Unlike formal synthesis of nebivolol, we prepared two chromane building blocks with fluorine and iodine which was transformed to diaryliodonium salt for labelling of 18 F. Two epoxide building blocks were readily prepared from commercially available chromene carboxylic acids (1, 8). Then, the amino alcohol building block (15) was prepared by ammonolysis of epoxide (14) followed by coupling reaction with the other building block, epoxide (7). Diaryliodonium salt, a precursor for 18 F-aromatic substitution, was synthesized in moderate yield which was readily subjected to 18 F-aromatic substitution to give 18 F-labelled nebivolol

Tyrosine kinase receptor inhibitor-targeted combined chemotherapy for metastatic bladder cancer

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Chia-Lun Wu

2012-04-01

Full Text Available Overexpression of hypoxia-inducible factor-1 alpha is noted during the invasive and metastatic process of transitional cell carcinoma. It will upregulate vascular endothelial growth factor (VEGF and drive proliferation, invasiveness, metastasis, and antiapoptotic ability of cancer cells. We proposed that tyrosine kinase receptor inhibitor, sunitinib malate—(Sutent; Pfizer Inc., Taiwan, combined with chemotherapeutic drug may present synergistic cytotoxic enhancement to transitional cell carcinoma cells with subsequent inhibition of their cellular behaviors, including proliferation, invasiveness, and metastatic activity. The contents of VEGF-A in mouse bladder tumor cells (MBT-2 and culture medium were detected by quantification-polymerase chain reaction and Western blot individually. The inhibitory concentrations of various chemotherapeutic drugs, sunitinib, and their combination treatment in MBT-2 were determined by 3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT assay. Microchamber transmembrane migration assay was applied in evaluation of the inhibitory effects of different dosages of sunitinib and combination treatment on tumor cells. The cell cycle and apoptosis were analyzed after combination therapy by flow cytometry. Variation in apoptotic pathway was elucidated by Western blot using specific antibodies with cleaved PARP and caspase-3. Metastatic animal model mimicked by tail vein injection of MBT-2 cells was used to evaluate the treatment efficiency in tumor weight and survival rate. The mRNA and protein level of VEGF-A in MBT-2 cells increased by 70% at 48 hours interval under hypoxia stress condition. In MTT assay, MBT-2 cells had shown the highest sensitivity to epirubicin. Sunitinib combined with epirubicin had shown a synergistic cytotoxic effect to MBT-2 cells. Sunitinib and its combination with epirubicin showed significant inhibition on MBT-2 cells migration in microchambers. G2/M phase arrest and

Discovery and Development of Calcium Channel Blockers

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Théophile Godfraind

2017-05-01

Full Text Available In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan and Heibrunn (USA experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are

Clinical Outcomes with β-blockers for Myocardial Infarction A Meta-Analysis of Randomized Trials

DEFF Research Database (Denmark)

Bangalore, Sripal; Makani, Harikrishna; Radford, Martha

2014-01-01

BACKGROUND: Debate exists regarding the efficacy of â-blockers in myocardial infarction and their required duration of usage in contemporary practice. METHODS: We conducted a MEDLINE/EMBASE/CENTRAL search for randomized trials evaluating â-blockers in myocardial infarction enrolling at least 100 ...

Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review

Science.gov (United States)

2013-01-01

Background Clinicians are encouraged to take an individualized approach when treating hypertension in patients of African ancestry, but little is known about why the individual patient may respond well to calcium blockers and diuretics, but generally has an attenuated response to drugs inhibiting the renin-angiotensin system and to β-adrenergic blockers. Therefore, we systematically reviewed the factors associated with the differential drug response of patients of African ancestry to antihypertensive drug therapy. Methods Using the methodology of the systematic reviews narrative synthesis approach, we sought for published or unpublished studies that could explain the differential clinical efficacy of antihypertensive drugs in patients of African ancestry. PUBMED, EMBASE, LILACS, African Index Medicus and the Food and Drug Administration and European Medicines Agency databases were searched without language restriction from their inception through June 2012. Results We retrieved 3,763 papers, and included 72 reports that mainly considered the 4 major classes of antihypertensive drugs, calcium blockers, diuretics, drugs that interfere with the renin-angiotensin system and β-adrenergic blockers. Pharmacokinetics, plasma renin and genetic polymorphisms did not well predict the response of patients of African ancestry to antihypertensive drugs. An emerging view that low nitric oxide and high creatine kinase may explain individual responses to antihypertensive drugs unites previous observations, but currently clinical data are very limited. Conclusion Available data are inconclusive regarding why patients of African ancestry display the typical response to antihypertensive drugs. In lieu of biochemical or pharmacogenomic parameters, self-defined African ancestry seems the best available predictor of individual responses to antihypertensive drugs. PMID:23721258

Prevalence and prognostic significance of adrenergic escape during chronic β-blocker therapy in chronic heart failure

Science.gov (United States)

Frankenstein, Lutz; Zugck, Christian; Schellberg, Dieter; Nelles, Manfred; Froehlich, Hanna; Katus, Hugo; Remppis, Andrew

2009-01-01

Aims Like aldosterone escape to ACE-inhibitors, adrenergic escape (AE) to β-blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different β-blocker agents and doses. Methods and results This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable β-blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual β-blocker agents used and the dose equivalent taken, the prevalence of AE was 31–39%. Norepinephrine levels neither correlated with heart rate (r = 0.02; 95% CI: −0.08–0.11; P = 0.74) nor were they related to underlying rhythm (P = 0.09) or the individual β-blocker agent used (P = 0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387–2.645; χ2: 15.60). Conclusion We verified the presence of AE in CHF patients on chronic stable β-blocker therapy, irrespective of the individual β-blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape. PMID:19168516

Prevalence and prognostic significance of adrenergic escape during chronic beta-blocker therapy in chronic heart failure.

Science.gov (United States)

Frankenstein, Lutz; Zugck, Christian; Schellberg, Dieter; Nelles, Manfred; Froehlich, Hanna; Katus, Hugo; Remppis, Andrew

2009-02-01

Like aldosterone escape to ACE-inhibitors, adrenergic escape (AE) to beta-blockers appears conceivable in chronic heart failure (CHF), as generalized systemic neurohumoral activation has been described as the pathophysiological basis of this syndrome. The aim of this study was to examine the prevalence and prognostic value of AE with respect to different beta-blocker agents and doses. This was a prospective, observational study of 415 patients with systolic CHF receiving chronic stable beta-blocker therapy. AE was defined by norepinephrine levels above the upper limit of normal. Irrespective of the individual beta-blocker agents used and the dose equivalent taken, the prevalence of AE was 31-39%. Norepinephrine levels neither correlated with heart rate (r=0.02; 95% CI: -0.08-0.11; P=0.74) nor were they related to underlying rhythm (P=0.09) or the individual beta-blocker agent used (P=0.87). The presence of AE was a strong and independent indicator of mortality (adjusted HR: 1.915; 95% CI: 1.387-2.645; chi2: 15.60). We verified the presence of AE in CHF patients on chronic stable beta-blocker therapy, irrespective of the individual beta-blocker agent and the dose equivalent. As AE might indicate therapeutic failure, the determination of AE could help to identify those patients with CHF that might benefit from more aggressive treatment modalities. Heart rate, however, is not a surrogate for adrenergic escape.

P2Y receptor-mediated transient relaxation of rat longitudinal ileum preparations involves phospholipase C activation, intracellular Ca(2+) release and SK channel activation.

Science.gov (United States)

Mader, Felix; Krause, Ludwig; Tokay, Tursonjan; Hakenberg, Oliver W; Köhling, Rüdiger; Kirschstein, Timo

2016-05-01

Purinergic signaling plays a major role in the enteric nervous system, where it governs gut motility through a number of P2X and P2Y receptors. The aim of this study was to investigate the P2Y receptor-mediated motility in rat longitudinal ileum preparations. Ileum smooth muscle strips were prepared from rats, and fixed in an organ bath. Isometric contraction and relaxation responses of the muscle strips were measured with force transducers. Drugs were applied by adding of stock solutions to the organ bath to yield the individual final concentrations. Application of the non-hydrolyzable P2 receptor agonists α,β-Me-ATP or 2-Me-S-ADP (10, 100 μmol/L) dose-dependently elicited a transient relaxation response followed by a sustained contraction. The relaxation response was largely blocked by SK channel blockers apamin (500 nmol/L) and UCL1684 (10 μmol/L), PLC inhibitor U73122 (100 μmol/L), IP3 receptor blocker 2-APB (100 μmol/L) or sarcoendoplasmic Ca(2+) ATPase inhibitor thapsigargin (1 μmol/L), but not affected by atropine, NO synthase blocker L-NAME or tetrodotoxin. Furthermore, α,β-Me-ATP-induced relaxation was suppressed by P2Y1 receptor antagonist MRS2179 (50 μmol/L) or P2Y13 receptor antagonist MRS2211 (100 μmol/L), and was abolished by co-application of the two antagonists, whereas 2-Me-S-ADP-induced relaxation was abolished by P2Y6 receptor antagonist MRS2578 (50 μmol/L). In addition, P2Y1 receptor antagonist MRS2500 (1 μmol/L) not only abolished α,β-Me-ATP-induced relaxation, but also suppressed 2-Me-S-ADP-induced relaxation. P2Y receptor agonist-induced transient relaxation of rat ileum smooth muscle strips is mediated predominantly by P2Y1 receptor, but also by P2Y6 and P2Y13 receptors, and involves PLC, IP3, Ca(2+) release and SK channel activation, but is independent of acetylcholine and NO release.

Turbo Charge CPU Utilization in Fork/Join Using the ManagedBlocker

CERN Multimedia

CERN. Geneva

2017-01-01

Fork/Join is a framework for parallelizing calculations using recursive decomposition, also called divide and conquer. These algorithms occasionally end up duplicating work, especially at the beginning of the run. We can reduce wasted CPU cycles by implementing a reserved caching scheme. Before a task starts its calculation, it tries to reserve an entry in the shared map. If it is successful, it immediately begins. If not, it blocks until the other thread has finished its calculation. Unfortunately this might result in a significant number of blocked threads, decreasing CPU utilization. In this talk we will demonstrate this issue and offer a solution in the form of the ManagedBlocker. Combined with the Fork/Join, it can keep parallelism at the desired level.

Skin cancer associated with commonly prescribed drugs: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and statins -weighing the evidence.

Science.gov (United States)

Nardone, Beatrice; Orrell, Kelsey A; Vakharia, Paras P; West, Dennis P

2018-02-01

Skin cancers, including both malignant melanoma (MM) and nonmelanoma skin cancer (NMSC), are the most commonly diagnosed cancers in the US. The incidence of both MM and NMSC continues to rise. Areas covered: Current evidence for an association between four of the most commonly prescribed classes of drugs in the U.S. and risk for MM and NMSC is reported. Medline was searched (January 2000 to May 2017) for each drug in the classes and for 'basal cell carcinoma', 'squamous cell carcinoma', 'non-melanoma skin cancer', 'skin cancer' and 'melanoma'. Skin cancer risk information was reported for: tumor necrosis factor alpha inhibitors (TNF-αIs), angiotensin-receptor blockers (ARBs), phosphodiesterase type 5 inhibitors (PDE5Is) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase inhibitors (statins). Expert opinion: Since skin cancer risk is associated with all four classes of these commonly prescribed drugs that represent nearly 20% of the Top 100 drugs in the U.S., these important findings warrant enhanced education, especially for prescribers and those patients at high risk for skin cancer.

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

Science.gov (United States)

Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C

2015-10-27

Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

Beta-blocker therapy is not associated with symptoms of depression and anxiety in patients receiving an implantable cardioverter-defibrillator

DEFF Research Database (Denmark)

Hoogwegt, Madelein T; Kupper, Nina; Theuns, Dominic A M J

2012-01-01

Beta-blockers are frequently prescribed to implantable cardioverter-defibrillator (ICD) patients. Beta-blocker therapy has been proposed to induce emotional distress such as depression and anxiety, but a paucity of studies has examined the relationship between beta-blockers and distress. We...... investigated the association between beta-blocker therapy, including type and dosage, and symptoms of anxiety and depression in a consecutive cohort of patients receiving an ICD....

Combined sodium ion sensitivity in agonist binding and internalization of vasopressin V1b receptors.

Science.gov (United States)

Koshimizu, Taka-Aki; Kashiwazaki, Aki; Taniguchi, Junichi

2016-05-03

Reducing Na(+) in the extracellular environment may lead to two beneficial effects for increasing agonist binding to cell surface G-protein coupled receptors (GPCRs): reduction of Na(+)-mediated binding block and reduce of receptor internalization. However, such combined effects have not been explored. We used Chinese Hamster Ovary cells expressing vasopressin V1b receptors as a model to explore Na(+) sensitivity in agonist binding and receptor internalization. Under basal conditions, a large fraction of V1b receptors is located intracellularly, and a small fraction is in the plasma membrane. Decreases in external Na(+) increased cell surface [(3)H]AVP binding and decreased receptor internalization. Substitution of Na(+) by Cs(+) or NH4(+) inhibited agonist binding. To suppress receptor internalization, the concentration of NaCl, but not of CsCl, had to be less than 50 mM, due to the high sensitivity of the internalization machinery to Na(+) over Cs(+). Iso-osmotic supplementation of glucose or NH4Cl maintained internalization of the V1b receptor, even in a low-NaCl environment. Moreover, iodide ions, which acted as a counter anion, inhibited V1b agonist binding. In summary, we found external ionic conditions that could increase the presence of high-affinity state receptors at the cell surface with minimum internalization during agonist stimulations.

Abiraterone acetate, exemestane or the combination in postmenopausal patients with estrogen receptor-positive metastatic breast cancer ?

OpenAIRE

O'Shaughnessy, J.; Campone, M.; Brain, E.; Neven, P.; Hayes, D.; Bondarenko, I.; Griffin, T. W.; Martin, J.; De Porre, P.; Kheoh, T.; Yu, M. K.; Peng, W.; Johnston, S.

2015-01-01

Background Androgen receptor (AR) signaling and incomplete inhibition of estrogen signaling may contribute to metastatic breast cancer (MBC) resistance to a nonsteroidal aromatase inhibitor (NSAI; letrozole or anastrozole). We assessed whether combined inhibition of androgen biosynthesis with abiraterone acetate plus prednisone and estradiol synthesis with exemestane (E) may be of clinical benefit to postmenopausal patients with NSAI-pretreated estrogen receptor-positive (ER+) MBC. Patients a...

Neurokinin-1 receptor blocker CP-99 994 improved emesis induced by cisplatin via regulating the activity of gastric distention responsive neurons in the dorsal motor nucleus of vagus and enhancing gastric motility in rats.

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Sun, X; Xu, L; Guo, F; Luo, W; Gao, S; Luan, X

2017-10-01

Nowadays, chemotherapy induced nausea and vomiting (CINV) is still common in patients with cancer. It was reported that substance P mediated CINV via neurokinin-1 (NK 1 ) receptor and antagonists of NK 1 receptor has been proved useful for treating CINV but the mechanism are not fully understood. This study aimed to examine the role of NK 1 receptor blocker, CP-99 994, when administrated into dorsal motor nucleus of vagus (DMNV), on the cisplatin-induced emesis in rats and the possible mechanism. Rats' kaolin intake, food intake, and bodyweight were recorded every day; gastric contraction activity was recorded in conscious rats through a force transducer implanted into the stomach; gastric emptying was monitored using the phenol red method; single unit extracellular firing in the DMNV were recorded. DMNV microinjection of CP-99 994 reduced the changes of increased kaolin consumption and suppressed food intake in cisplatin-treated rats; enhanced the gastric contraction activity dose-dependently in control and cisplatin-treated rats but enhanced gastric emptying only in cisplatin-treated rats; reduced the firing rate of gastric distention inhibited (GD-I) neurons but increased the firing rate of GD excited (GD-E) neurons in the DMNV. The effects of CP-99 994 on gastric motility and neuronal activity were stronger in cisplatin-treated rats than those of control rats. Our results suggested that CP-99 994 could improve emesis induced by cisplatin by regulating gastric motility and gastric related neuronal activity in the DMNV. © 2017 John Wiley & Sons Ltd.

Factors affecting the development of adverse drug reactions to β-blockers in hospitalized cardiac patient population

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Mugoša S

2016-08-01

Full Text Available Snežana Mugoša,1,2 Nataša Djordjević,3 Nina Djukanović,4 Dragana Protić,5 Zoran Bukumirić,6 Ivan Radosavljević,7 Aneta Bošković,8 Zoran Todorović5,9 1Department of Pharmacotherapy, Faculty of Pharmacy, University of Montenegro, 2Clinical Trial Department, Agency for Medicines and Medical Devices of Montenegro, Podgorica, Montenegro; 3Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, 4High Medical School “Milutin Milanković”, Belgrade, 5Department of Pharmacology, Clinical Pharmacology and Toxicology, 6Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, 7Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia; 8Clinic for Heart Diseases, Clinical Centre of Montenegro, Podgorica, Montenegro; 9Department of Clinical Immunology and Allergy, Medical Center “Bežanijska kosa”, Belgrade, Serbia Abstract: The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6 poor metabolizer alleles (*3, *4, *5, and *6 on a Montenegrin population and its impact on developing adverse drug reactions (ADRs of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients’ medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9% patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001, with ADRs’ occurrence significantly

Weight loss has an additive effect on the proteinuria reduction of angiotensin II receptor blockers in hypertensive patients with chronic kidney disease

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Shin Young Ahn

2018-03-01

Full Text Available Background : Weight reduction is a lifestyle intervention that has been introduced for prevention and management of chronic kidney disease (CKD. We investigate the additive anti-proteinuric effect of weight reduction on the usage of angiotensin II receptor blockers (ARBs and its potential mechanisms in hypertensive CKD patients. Methods : This study is a subanalysis of data from an open-label, randomized, controlled clinical trial. Among the 235 participants, 227 were assigned to subgroups according to changes in body weight. Results : Fifty-eight participants (25.6% were assigned to group 1 (≥ 1.5% decrease in body weight after 16 weeks, 32 participants (14.1% were assigned to group 2 (1.5-0.1% decrease in body weight, and 136 participants (59.9% were assigned to group 3 (≥ 0.0% increase in body weight. Characteristics at enrollment were not different among the three groups, but mean differences in weight and percent changes in urinary sodium excretion over the period were statistically different (P < 0.001 and P = 0.017. Over the study period, unintentional weight loss independently increased the probability of reduced albuminuria (group 1, relative risk 6.234, 95% confidence interval 1.913-20.315, P = 0.002. Among urinary cytokines, only podocalyxin level decreased significantly in participants who lost weight (P = 0.013. Conclusion : We observed that weight loss had an additive effect on the anti-proteinuric effects of ARBs in nondiabetic hypertensive CKD patients, although it was minimal. An additive effect was shown in both obese and non-obese participants, and its possible mechanism is related to reduction of podocyte damage.

Endogenous endophthalmitis in a rheumatoid patient on tumor necrosis factor alpha blocker

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Agarwal Pankaj

2007-01-01

Full Text Available The development of anti-tumor necrosis factor (TNF therapies is a milestone in the therapy of rheumatic diseases. It is of concern whether all potential undesired complications of therapy have been evaluated within clinical trials which have led to treatment approval. Specialists prescribing TNF blockers should be aware of the unusual and severe complications that can occur. We describe a case of endogenous endophthalmitis in a rheumatoid patient on TNF alpha blocker.

Calcium channel blockers inhibit endogenous pyrogen fever in rats and rabbits.

Science.gov (United States)

Stitt, J T; Shimada, S G

1991-09-01

We have previously shown that febrile responses in both rats and rabbits are elicited by the intravenous injection of a semipurified endogenous pyrogen (EP) prepared from human monocytes. We are now presenting evidence that these febrile responses are mediated via activation of Ca2+ channels by EP. The febrile responses of male New Zealand White rabbits and Sprague-Dawley rats to a standard dose of EP were determined at their respective thermoneutral ambient temperatures. The animals were then treated with Ca2+ channel blocker verapamil (7.5 mg/kg iv) 30-60 min before the EP challenge. In every case the febrile response to EP was markedly attenuated after verapamil pretreatment, while administration of verapamil by itself had no detectable effect on body temperature. Another Ca2+ channel blocker, nifedipine (5 mg/kg iv), was shown to possess antipyretic activity in rats also. To localize where in the fever pathway these Ca2+ channel blockers were acting, we investigated the effect of verapamil at the same dose on fevers that were produced by microinjection of prostaglandin E (PGE) directly into the brain. These PGE fevers were unaffected by verapamil pretreatment, indicating that the antipyretic action of Ca2+ channel blockers occurs before the formation of PGE in response to EP stimulation. The most likely locus of action is the activation of the enzyme phospholipase A2, which regulates the production of arachidonic acid from cellular phospholipids in the prostanoid cascade.

Specific receptor for endothelin in cultured rat cardiocytes

International Nuclear Information System (INIS)

Hirata, Y.; Fukuda, Y.; Yoshimi, H.; Emori, T.; Shichiri, M.; Marumo, F.

1989-01-01

Specific binding sites for the endothelium-derived vasoconstrictor endothelin (ET) and its effect on cytosolic free Ca2+ concentrations [( Ca2+]i) were studied in a primary culture of cardiocytes from neonatal rats. Binding studies using 125 I-labeled-porcine ET as a radioligand revealed the presence of a single class of high-affinity binding sites for ET in cardiocytes with an apparent Kd of 6-9 x 10(-10) M and a Bmax of 50,000-80,000 sites/cell. Neither various vasoconstrictors nor Ca2+-channel blockers affected the binding. Pretreatment with ET substantially reduced the total number of ET receptors without changing their affinity. ET dose-dependently increased [Ca2+]i in fura-2-loaded cardiocytes. These data indicate that cardiocytes have specific ET receptors that are controlled by a down-regulation mechanism, and that ET induces a receptor-mediated increase in [Ca2+]i in cardiocytes

IMPLICATION OF THE FIXED COMBINATIONS IN THE HYPERTENSION TREATMENT

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Z. D. Kobalava

2010-01-01

Full Text Available The role of fixed combinations in the hypertension (HT treatment is discussed. Theoretical and practical aspects of combination therapy, principles of rational combination therapy are present. Current guidelines on the use of fixed dose combinations, including start antihypertensive therapy are analyzed. Classification of combinations, advantages and limitations of some of them implementation are also presented. Significance of beta-blocker bisoprolol and thiazide diuretic hydrochlorothiazide fixed combination (Lodoz is shown in HT treatment.

Beta-blocker therapy is not associated with symptoms of depression and anxiety in patients receiving an implantable cardioverter-defibrillator.

Science.gov (United States)

Hoogwegt, Madelein T; Kupper, Nina; Theuns, Dominic A M J; Jordaens, Luc; Pedersen, Susanne S

2012-01-01

Beta-blockers are frequently prescribed to implantable cardioverter-defibrillator (ICD) patients. Beta-blocker therapy has been proposed to induce emotional distress such as depression and anxiety, but a paucity of studies has examined the relationship between beta-blockers and distress. We investigated the association between beta-blocker therapy, including type and dosage, and symptoms of anxiety and depression in a consecutive cohort of patients receiving an ICD. Between 2003 and 2010, 448 consecutively implanted ICD patients were enrolled in the prospective Mood and personality as precipitants of arrhythmia in patients with an Implantable cardioverter Defibrillator: A prospective Study (MIDAS), of which 429 completed the Hospital Anxiety and Depression Scale (HADS) and the ICD Patient Concerns questionnaire (ICDC) at baseline. Eighty per cent of all patients received beta-blocker therapy. In univariate analysis, beta-blocker therapy was not significantly associated with symptoms of anxiety, depression, and ICD concerns (β = -0.030, β = 0.007, and β = -0.045, respectively; all P's >0.36). Type of beta-blocker showed a trend towards significance for mean levels of ICD concerns (P = 0.09). No association was found between dosage and emotional distress (all P's >0.21). After adjustment for relevant clinical and demographic variables, the association of beta-blocker therapy and symptoms of anxiety, depression, and ICD concerns remained non-significant (β = 0.009, β = 0.037, and β = 0.019, respectively; all P's >0.47). In patients receiving an ICD, beta-blocker therapy was not associated with symptoms of anxiety, depression, and ICD concerns. Research is warranted that further elucidates the link between beta-blocker therapy and emotional distress in this vulnerable patient group.

Changes of imidazoline receptors in spontaneously hypertensive rats

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Mar, Guang-Yuan; Chou, Ming-Ting; Chung, Hsien-Hui; Chiu, Nien-Hua; Chen, Mei-Fen; Cheng, Juei-Tang

2013-01-01

The role of imidazoline receptors in the regulation of vascular function remains unclear. In this study, we evaluated the effect of agmatine, an imidazoline receptor agonist, on systolic blood pressure (SBP) in spontaneously hypertensive rats (SHRs) and investigated the expressions of imidazoline receptors by Western blot. The isometric tension of aortic rings isolated from male SHRs was also estimated. Agmatine decreased SBP in a dose-dependent manner in SHRs but not in the normal group [Wistar–Kyoto (WKY) rats]. This reduction in SBP in SHRs was abolished by BU224, a selective antagonist of imidazoline I2-receptors. Higher expression of imidazoline receptors in SHR was observed. Moreover, agmatine-induced relaxation in isolated aortic rings precontracted with phenylephrine or KCl. This relaxation was also abolished by BU224 but was not modified by efaroxan, an imidazoline I1-receptor antagonist. Agmatine-induced relaxation was also attenuated by PNU 37883, a selective blocker of vascular ATP-sensitive potassium (KATP) channels. Additionally, vasodilatation by agmatine was reduced by an inhibitor of protein kinase A (PKA). We suggest that agmatine can lower blood pressure in SHRs through activation of the peripheral imidazoline I2-receptor, which is expressed more highly in SHRs. PMID:23176371

Barriers to Beta-Blocker Use and Up-Titration Among Patients with Heart Failure with Reduced Ejection Fraction.

Science.gov (United States)

Levitan, Emily B; Van Dyke, Melissa K; Loop, Matthew Shane; O'Beirne, Ronan; Safford, Monika M

2017-12-01

For patients with heart failure with reduced ejection fraction (HFrEF), guidelines recommend use of beta-blockers with gradual up-titration. However, many patients with HFrEF do not use beta-blockers and up-titration is rare. Our purpose was to identify and rank barriers to beta-blocker use and up-titration from the perspective of primary care physicians. We conducted 4 moderated, structured group discussions among 19 primary care physicians using the nominal group technique; 16 participants also completed a survey. Participants generated lists of barriers to beta-blocker use and up-titration among patients with HFrEF. Each participant had six votes with three votes assigned to the item ranked most important, two to the second most important item, and one to the third most important item. Investigators characterized items into themes. The percentage of available votes was calculated for each theme. Fifteen of 16 participating primary care physicians who completed the survey reported that management of beta-blockers was their responsibility. Treatment/side effects, particularly hypotension, were identified as the most important barrier for beta-blocker use (72% of available votes) followed by polypharmacy (11%), healthcare system barriers (10%), and comorbidities (6%). Barriers to up-titration included treatment/side effects (49% of available votes), patient communication/buy-in (21%), polypharmacy (13%), and healthcare system barriers (8%). Many barriers to guideline concordant use of beta-blockers among patients with HFrEF identified by primary care providers are not readily modifiable. Addressing these barriers may require development, testing, and dissemination of protocols for beta-blocker initiation and up-titration that are safe and appropriate in primary care.

Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention

NARCIS (Netherlands)

Battes, L.C.; Pedersen, S.S.; Oemrawsingh, R.M.; van Geuns, R.-J.M.; Al Amri, I.; Regar, E.; de Jaegere, P.T.; Serruys, P.W.; van Domburg, R.T.

2012-01-01

Background Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose–response

Beta-blocker therapy is not associated with symptoms of depression and anxiety in patients receiving an implantable cardioverter-defibrillator

NARCIS (Netherlands)

M.T. Hoogwegt (Madelein); N. Kupper (Nina); D.A.M.J. Theuns (Dominic); L.J.L.M. Jordaens (Luc); S.S. Pedersen (Susanne)

2012-01-01

textabstractBeta-blockers are frequently prescribed to implantable cardioverter-defibrillator (ICD) patients. Beta-blocker therapy has been proposed to induce emotional distress such as depression and anxiety, but a paucity of studies has examined the relationship between beta-blockers and distress.

Beta-blockers for prevention and treatment of retinopathy of prematurity in preterm infants.

Science.gov (United States)

Kaempfen, Siree; Neumann, Roland P; Jost, Kerstin; Schulzke, Sven M

2018-03-02

Retinopathy of prematurity (ROP) is a vision-threatening disease of preterm neonates. The use of beta-adrenergic blocking agents (beta-blockers), which modulate the vasoproliferative retinal process, may reduce the progression of ROP or even reverse established ROP. To determine the effect of beta-blockers on short-term structural outcomes, long-term functional outcomes, and the need for additional treatment, when used either as prophylaxis in preterm infants without ROP, stage 1 ROP (zone I), or stage 2 ROP (zone II) without plus disease or as treatment in preterm infants with at least prethreshold ROP. We searched the Cochrane Neonatal Review Group Specialized Register; CENTRAL (in the Cochrane Library Issue 7, 2017); Embase (January 1974 to 7 August 2017); PubMed (January 1966 to 7 August 2017); and CINAHL (January 1982 to 7 August 2017). We checked references and cross-references and handsearched abstracts from the proceedings of the Pediatric Academic Societies Meetings. We considered for inclusion randomised or quasi-randomised clinical trials that used beta-blockers for prevention or treatment of ROP in preterm neonates of less than 37 weeks' gestational age. We used the standard methods of Cochrane and the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence. We included three randomised trials (N = 366) in this review. Two of these studies were at high risk of bias. All studies reported on prevention of ROP and compared oral propranolol with placebo or no treatment. We found no trials assessing beta-blockers in infants with established stage 2 or higher ROP with plus disease.In one trial, study medication was started after one week of life, i.e. prior to the first ROP screening. The other two trials included preterm infants if they had stage 2 or lower ROP without plus disease. Based on the GRADE assessment, we considered evidence to be of low quality for the following outcomes: rescue treatment with anti-VEGF or

Combined blockade of ADP receptors and PI3-kinase p110β fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation.

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Stefanie Krajewski

Full Text Available Extracorporeal circulation (ECC and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2Y(12 and P(2Y(1 blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2Y(12 antagonist 2-MeSAMP, the P(2Y(1 antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls. Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2Y blockers (p<0.05, while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P(2Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05. P(2Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05. Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P(2Y and PI3K blockade (p<0.05. Combined blockade of P

[Combined treatment of BPS with tamsulosin and finasteride : Literature review and prescription data].

Science.gov (United States)

Höfner, K; Ulrich, S; Berges, R

2017-05-01

Combined therapy of benign prostatic syndrome (BPS) with α 1 -blockers and 5α-reductase (5AR)-inhibitors is recommended according to two leading studies on doxazosin/finasteride and tamsulosin/dutasteride for all 10 in Germany possible combinations (five α 1 -blockers and two 5AR inhibitors). Because tamsulosin and finasteride predominate in the treatment of BPS in Germany, the role of the combination tamsulosin/finasteride and its scientific basis from clinical studies has been investigated. A pharmacoepidemiological extrapolation from receipts of pharmacy data centres showed a strong increase of the combination tamsulosin/finasteride since 2003. As a free combination, tamsulosin/finasteride beside the fixed combination tamsulosin/dutasteride accounts to about 50% of all α 1 -blocker/5AR-inhibitor combinations today. Clinical studies on tamsulosin/finasteride have been published including controlled studies of the combination and both monotherapies. The results of improvement of lower urinary tract symptoms (LUTS), maximum urinary flow rate (Q max ), prostate volume (PV) and prostate-specific antigen (PSA) as well as adverse events and drug safety are in agreement with the leading studies. However, results due to chance cannot be excluded because of deficiencies in study design. A reliable comparison of the risk of progression between tamsulosin/finasteride and both monotherapies is lacking completely. Because of the great coherence and continuous evaluation of available data of all combinations, and with the established strong class effect of monotherapies, a continuation of the therapeutic practice with the combination tamsulosin/finasteride is possible.

[Treatment of arrhythmia in coronary patients and hypertensives with beta blockers and Depasan retard].

Science.gov (United States)

Kandziora, J

1981-05-14

In the ambulatory of an internal specialist a number of patients suffering from angina pectoris or hypertonia together with arrhythmic troubles received an initial treatment with beta-blockers over a period of 21 days. In cases in which arrhythmia persisted after this initial period the treatment was continued for another 21 days with the addition of Depasan retard in function of a second medicament. This combined treatment in form of an open study was extended to a total number of 50 patients presenting ventricular extrasystolia in 45 cases and in 5 cases absolute arrhythmia in addition to the main disease. Treatment with Depasan retard showed good or satisfactory results in 39 out of 45 patients suffering from ventricular extrasystoles, whilst no effect could be obtained in the 5 cases with absolute arrhythmia. No signs of incompatibility or unwanted interactions were observed in the course of this open study. Based on these results it can be concluded that Depasan retard should be recommended in those cases where on account of persistent arrhythmical troubles and especially extrasystoles, during a treatment with beta-blockers in patients suffering from angina pectoris or hypertonia, and additional treatment with anti-arrhythmical medicaments appears to be indicated.

Brain α1-adrenergic receptors: suitability of [125I]HEAT as a radioligand for in vitro autoradiography

International Nuclear Information System (INIS)

Jones, L.S.; Gauger, L.L.; Davis, J.N.

1983-01-01

[2-(β-4-Hydroxyphenyl)-ethylaminomethyl)-tetralone] (BE 2254, HEAT) is a new potent α 1 -adrenergic receptor blocker. The iodinated radioligand, [ 125 I]HEAT appears to be even more potent than HEAT (Engel and Hoyer, 1981; Glossman et al., 1981) and has proved useful for the studying of α 1 -adrenergic receptors in membrane preparations of rat brain. The authors report the suitability of [ 125 I]HEAT for α 1 -adrenergic binding site autoradiography and a degree of localization of α 1 -adrenergic receptor binding sites that has not been possible with [ 3 H]WB 4101 and [ 3 H]prazosin autoradiography. (Auth.)

The beta-receptor blocker metoprolol alters detoxification processes in the non-target organism Dreissena polymorpha

Energy Technology Data Exchange (ETDEWEB)

Contardo-Jara, Valeska, E-mail: contardo@igb-berlin.d [Dpt. Ecophysiology and Aquaculture, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Mueggelseedamm 301, 12587 Berlin (Germany); Pflugmacher, Stephan, E-mail: pflugmacher@igb-berlin.d [Dpt. Ecophysiology and Aquaculture, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Mueggelseedamm 301, 12587 Berlin (Germany); Nuetzmann, Gunnar, E-mail: nuetzmann@igb-berlin.d [Dpt. Ecohydrology, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Mueggelseedamm 301, 12587 Berlin (Germany); Kloas, Werner, E-mail: werner.kloas@igb-berlin.d [Dpt. Ecophysiology and Aquaculture, Leibniz-Institute of Freshwater Ecology and Inland Fisheries, Mueggelseedamm 301, 12587 Berlin (Germany); Wiegand, Claudia, E-mail: wiegand@biology.sdu.d [University of Southern Denmark Institute of Biology, Campusvej 55, 5230 Odense M (Denmark)

2010-06-15

Due to increasing amounts of pharmaceutically active compounds (PhACs) in the aquatic environment, their largely unknown effects to non-target organisms need to be assessed. This study examined physiological changes in the freshwater mussel Dreissena polymorpha exposed to increasing concentrations (0.534, 5.34, 53.4 and 534 mug L{sup -1}) of the beta-blocker metoprolol in a flow-through system for seven days. The two lower concentrations represent the environmentally relevant range. Surprisingly, metallothionein mRNA was immediately up-regulated in all treatments. For the two higher concentrations mRNA up-regulation in gills was found for P-glycoprotein after one day, and after four days for pi class glutathione S-transferase, demonstrating elimination and biotransformation processes, respectively. Additionally, catalase and superoxide dismutase were up-regulated in the digestive gland indicating oxidative stress. In all treated mussels a significant up-regulation of heat shock protein mRNA was observed in gills after four days, which suggests protein damage and the requirement for repair processes. Metoprolol was 20-fold bioaccumulated for environmentally relevant concentrations. - Evidence for significant physiological changes in an aquatic mollusc due to exposure to a pharmaceutically active compound detected by real-time PCR.

Adverse respiratory effect of acute β-blocker exposure in asthma: a systematic review and meta-analysis of randomized controlled trials.

Science.gov (United States)

Morales, Daniel R; Jackson, Cathy; Lipworth, Brian J; Donnan, Peter T; Guthrie, Bruce

2014-04-01

β-Blockers are avoided in asthma over concerns regarding acute bronchoconstriction. Risk is greatest following acute exposure, including the potential for antagonism of β2-agonist rescue therapy. A systematic review of databases was performed to identify all randomized, blinded, placebo-controlled clinical trials evaluating acute β-blocker exposure in asthma. Effect estimates for changes in respiratory function, symptoms, and β2-agonist response were pooled using random effects meta-analysis with heterogeneity investigated. Acute selective β-blockers in the doses given caused a mean change in FEV1 of −6.9% (95% CI, −8.5 to −5.2), a fall in FEV1 of ≥20% in one in eight patients (P=.03), symptoms affecting one in 33 patients (P=.18), and attenuation of concomitant β2-agonist response of −10.2% (95% CI, −14.0 to −6.4). Corresponding values for acute nonselective β-blockers in the doses given were −10.2% (95% CI, −14.7 to −5.6), one in nine patients (P=.02), one in 13 patients (P=.14), and −20.0% (95% CI, −29.4 to −10.7). Following investigation of heterogeneity, clear differences were found for celiprolol and labetalol. A dose-response relationship was demonstrated for selective β-blockers. Selective β-blockers are better tolerated but not completely risk-free. Risk from acute exposure may be mitigated using the smallest dose possible and β-blockers with greater β1-selectivity. β-Blocker-induced bronchospasm responded partially to β2-agonists in the doses given with response blunted more by nonselective β-blockers than selective β-blockers. Use of β-blockers in asthma could possibly be based upon a risk assessment on an individual patient basis.

Heart rate and use of beta-blockers in stable outpatients with coronary artery disease.

Directory of Open Access Journals (Sweden)

Ph Gabriel Steg

Full Text Available BACKGROUND: Heart rate (HR is an emerging risk factor in coronary artery disease (CAD. However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR. METHODS AND FINDINGS: CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of >50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%. Mean (SD age was 64.2 (10.5 years, HR by pulse was 68.3 (10.6 bpm, and by electrocardiogram was 67.2 (11.4 bpm. Overall, 44.0% had HR ≥ 70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR ≥ 70 bpm. HR ≥ 70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents. CONCLUSIONS: Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR ≥ 70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.

Autoantibodies Targeting AT1 Receptor from Patients with Acute Coronary Syndrome Upregulate Proinflammatory Cytokines Expression in Endothelial Cells Involving NF-κB Pathway

Directory of Open Access Journals (Sweden)

Weijuan Li

2014-01-01

Full Text Available Our study intended to prove whether agonistic autoantibodies to angiotensin II type 1 receptor (AT1-AAs exist in patients with coronary heart disease (CHD and affect the human endothelial cell (HEC by upregulating proinflammatory cytokines expression involved in NF-κB pathway. Antibodies were determined by chronotropic responses of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists (valsartan and AT1-EC2 as described previously. Interleukin-6 (IL-6, vascular cell adhesion molecule-1 (VCAM-1, and monocyte chemotactic protein-1 (MCP-1 expression were improved at both mRNA and protein levels in HEC, while NF-κB in the DNA level was improved detected by electrophoretic mobility shift assays (EMSA. These improvements could be inhibited by specific AT1 receptor blocker valsartan, NF-κB blocker pyrrolidine dithiocarbamate (PDTC, and specific short peptides from the second extracellular loop of AT1 receptor. These results suggested that AT1-AAs, via the AT1 receptor, induce expression of proinflammatory cytokines involved in the activation of NF-κB. AT1-AAs may play a great role in the pathogenesis of the acute coronary syndrome by mediating vascular inflammatory effects involved in the NF-κB pathway.

Use of an ACE inhibitor or angiotensin receptor blocker is a major risk factor for dehydration requiring readmission in the setting of a new ileostomy.

Science.gov (United States)

Charak, Gregory; Kuritzkes, Benjamin A; Al-Mazrou, Ahmed; Suradkar, Kunal; Valizadeh, Neda; Lee-Kong, Steven A; Feingold, Daniel L; Pappou, Emmanouil P

2018-03-01

Diverting ileostomies help prevent major complications related to anastomoses after colorectal resection but can cause metabolic derangement and hypovolemia, leading to readmission. This paper aims to determine whether angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use increased the risk of readmission, or readmission specifically for dehydration after new ileostomy creation. Retrospective analysis of patients undergoing diverting ileostomy at a tertiary-care hospital, 2009-2015. Primary outcome was 60-day readmission for dehydration; secondary outcomes included 60-day readmission for any cause, or for infection obstruction. Ninety-nine patients underwent diverting ileostomy creation, 59% with a primary diagnosis of colorectal cancer. The 60-day readmission rate was 36% (n = 36). Of readmitted patients, 39% (n = 14) were admitted for dehydration. Other readmission reasons were infection (33%) and obstruction (3%). The majority (64%, n = 9) of patients readmitted for dehydration were taking either an ACEi or an ARB. Compared to patients not readmitted for dehydration, those who were readmitted for dehydration were more likely to be on an ACEi or an ARB (11/85, 13% vs. 9/14, 64%). After controlling for covariates, ACEi or ARB use was significantly associated with risk of readmission (p readmission for dehydration. ACEi and ARB use is a significant risk factor for readmission for dehydration following diverting ileostomy creation. Consideration should be given to withholding these medications after ileostomy creation to reduce this risk.

Norepinephrine transporter blocker atomoxetine increases salivary alpha amylase

NARCIS (Netherlands)

Warren, C.M.; van den Brink, R.L.; Nieuwenhuis, S.; Bosch, J.A.

It has been suggested that central norepinephrine (NE) activity may be inferred from increases in salivary alpha-amylase (SAA), but data in favor of this proposition are limited. We administered 40mg of atomoxetine, a selective NE transporter blocker that increases central NE levels, to 24 healthy

Positive Modulatory Interactions of NMDA Receptor GluN1/2B Ligand Binding Domains Attenuate Antagonists Activity

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Douglas Bledsoe

2017-05-01

Full Text Available N-methyl D-aspartate receptors (NMDAR play crucial role in normal brain function and pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDAR contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that include six different gene products; four GluN2 (A–D and two GluN3 (A–B subunits. The heterogeneity of subunit combination facilities the distinct function of NMDARs. All GluN subunits contain an extracellular N-terminal Domain (NTD and ligand binding domain (LBD, transmembrane domain (TMD and an intracellular C-terminal domain (CTD. Interaction between the GluN1 and co-assembling GluN2/3 subunits through the LBD has been proven crucial for defining receptor deactivation mechanisms that are unique for each combination of NMDAR. Modulating the LBD interactions has great therapeutic potential. In the present work, by amino acid point mutations and electrophysiology techniques, we have studied the role of LBD interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, and allosteric modulators. The results reveal that agonists (glycine and glutamate potency was altered based on mutant amino acid sidechain chemistry and/or mutation site. Most antagonists inhibited mutant receptors with higher potency; interestingly, clinically used NMDAR channel blocker memantine was about three-fold more potent on mutated receptors (N521A, N521D, and K531A than wild type receptors. These results provide novel insights on the clinical pharmacology of memantine, which is used for the treatment of mild to moderate Alzheimer's disease. In addition, these findings demonstrate the central role of LBD interactions that can be exploited to develop novel NMDAR based therapeutics.

Experimental study of the role of blocking of 5-HT3 serotonin receptors and D2 dophamin receptors in the mechanism of early radiation vomiting in monkeys

International Nuclear Information System (INIS)

Martirosov, K.S.; Grigor'ev, Yu.G.; Zorin, V.V.; Andrianova, I.E.

2000-01-01

Specific activity of Latranum and Dimetphramidum is studied using experimental model of early radiation vomiting on 17 monkeys, mass 6-9 kg inherent on usual ration of vivarium. The experiments with M. fasciculata monkeys exposed to 137 Cs γ-radiation with a dose of 6.9 Gy showed that Latranum, a blocker of serotonin 5-HT 3 receptors, is a more efficient antimetric than Dimetphramidum, a D 2 dophamin lytic. This suggested by fewer animals with emetic reaction of by less severe vomiting in case they have any. The results agree well with a hypothesis that serotonin receptors are dominant in the chemoreceptor trigger zone of monkeys [ru

Platelet Glycoprotein IIb/IIIa Receptor Inhibition in Non-ST-Elevation Acute Coronary Syndromes : Early Benefit During Medical Treatment Only, With Additional Protection During Percutaneous Coronary Intervention

NARCIS (Netherlands)

K.M. Akkerhuis (Martijn); P. Théroux (Pierre); R.M. Califf (Robert); E.J. Topol (Eric); M.L. Simoons (Maarten); H. Boersma (Eric)

1999-01-01

textabstractBACKGROUND: Glycoprotein (GP) IIb/IIIa receptor blockers prevent life-threatening cardiac complications in patients with acute coronary syndromes without ST-segment elevation and protect against thrombotic complications associated with percutaneous coronary

Context-Dependent Modulation of αβγ and αβγ GABAA Receptors by Penicillin: Implications for Phasic and Tonic Inhibition

OpenAIRE

Feng, Hua-Jun; Botzolakis, Emmanuel J.; Macdonald, Robert L.

2008-01-01

Penicillin, an open-channel blocker of GABAA receptors, was recently reported to inhibit phasic, but not tonic, currents in hippocampal neurons. To distinguish between isoform-specific and context-dependent modulation as possible explanations for this selectivity, the effects of penicillin were evaluated on recombinant GABAA receptors expressed in HEK293T cells. When co-applied with saturating GABA, penicillin decreased peak amplitude, induced rebound, and prolonged deactivation of currents e...

SELECTIVE AND NONSELECTIVE β-BLOCKERS IN PRIMARY OPEN ANGLE GLAUCOMA THERAPY – RESULTS OF COLOR DOPPLER SONOGRAPHY

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Vukoslava Maričić-Došen

2002-12-01

Full Text Available Background. Primary open angle glaucoma (POAG is a syndrome of progressive optic neuropathy characterized by optic nerve head excavation and visual field defects. Poor correlation between IOP and progression of glaucoma disease sets vascular mechanism in the centre of attention. By Color Doppler sonography, quantification of blood flow changes in vessels, which supply optic nerve head, is possible. We wanted to find out whether there are changes in the circulation of central retinal artery and posterior ciliary arteries in patients with primary open angle glaucoma treated with selective or nonselective β -blockers.Methods. 44 patients (88 eyes were divided into two groups: group 1: 22 patients (44 eyes treated with selective β -blockers (Betaxolol 0.5% and group 2: 22 patients (44 eyes treated with nonselective β -blockers (Timolol 0.5%. Vascular indices (RI, PI were measured in the central retinal artery and posterior ciliary arteries.Results. We found decreased blood flow and increased vascular indices in both groups of patients, statistically significant difference between group 1 and group 2: blood flow velocity was higher and vascular indices were lower in group 1 (Betaxolol 0.5% compared to group 2 (Timolol 0..5%.Conclusions. Selective β -blockers (calcium channel blockers act more vasoactively and neuroprotectively comparing to nonselective β -blockers.

Improving documentation of a beta-blocker quality measure through an anesthesia information management system and real-time notification of documentation errors.

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Nair, Bala G; Peterson, Gene N; Newman, Shu-Fang; Wu, Wei-Ying; Kolios-Morris, Vickie; Schwid, Howard A

2012-06-01

Continuation of perioperative beta-blockers for surgical patients who are receiving beta-blockers prior to arrival for surgery is an important quality measure (SCIP-Card-2). For this measure to be considered successful, name, date, and time of the perioperative beta-blocker must be documented. Alternately, if the beta-blocker is not given, the medical reason for not administering must be documented. Before the study was conducted, the institution lacked a highly reliable process to document the date and time of self-administration of beta-blockers prior to hospital admission. Because of this, compliance with the beta-blocker quality measure was poor (-65%). To improve this measure, the anesthesia care team was made responsible for documenting perioperative beta-blockade. Clear documentation guidelines were outlined, and an electronic Anesthesia Information Management System (AIMS) was configured to facilitate complete documentation of the beta-blocker quality measure. In addition, real-time electronic alerts were generated using Smart Anesthesia Messenger (SAM), an internally developed decision-support system, to notify users concerning incomplete beta-blocker documentation. Weekly compliance for perioperative beta-blocker documentation before the study was 65.8 +/- 16.6%, which served as the baseline value. When the anesthesia care team started documenting perioperative beta-blocker in AIMS, compliance was 60.5 +/- 8.6% (p = .677 as compared with baseline). Electronic alerts with SAM improved documentation compliance to 94.6 +/- 3.5% (p documentation and (2) enhance features in the electronic medical systems to alert the user concerning incomplete documentation.

Role of ascorbic acid in reduction of the incidence of the atrial fibrillation in patients under B-blocker and undergoing coronary artery bypass graft operation in early post-operative period

Directory of Open Access Journals (Sweden)

Moataz E. Rezk, MD

2017-09-01

Conclusions: The incidence of post CABG AF, intensive care unit stay, need for inotropic support and ventilator stay were decreased by patients intake of vitamin C in combination with β -blockers pre-operatively.

Super cool X-1000 and Super cool Z-1000, two ice blockers, and their effect on vitrification/warming of mouse embryos.

Science.gov (United States)

Badrzadeh, H; Najmabadi, S; Paymani, R; Macaso, T; Azadbadi, Z; Ahmady, A

2010-07-01

To evaluate the survival and blastocyst formation rates of mouse embryos after vitrification/thaw process with different ice blocker media. We used X-1000 and Z-1000 separately and mixed using V-Kim, a closed vitrification system. Mouse embryos were vitrified using ethylene glycol based medium supplemented with Super cool X-1000 and/or Super cool Z-1000. Survival rates for the control, Super cool X-1000, Super cool Z-1000, and Super cool X-1000/Z-1000 groups were 74%, 72%, 68%, and 85% respectively, with no significant difference among experimental and control groups; however, a significantly higher survival rate was noticed in the Super cool X-1000/Z-1000 group when compared with the Super cool Z-1000 group. Blastocyst formation rates for the control, Super cool X-1000, Super cool Z-1000, and Super cool X-1000/Z-1000 groups were 71%, 66%, 65%, and 72% respectively. There was no significant difference in this rate among control and experimental groups. In a closed vitrification system, addition of ice blocker Super cool X-1000 to the vitrification solution containing Super cool Z-1000 may improve the embryo survival rate. We recommend combined ice blocker usage to optimize the vitrification outcome. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Prognostic Impact of Loop Diuretics in Patients With Chronic Heart Failure　- Effects of Addition of Renin-Angiotensin-Aldosterone System Inhibitors and β-Blockers.

Science.gov (United States)

Miura, Masanobu; Sugimura, Koichiro; Sakata, Yasuhiko; Miyata, Satoshi; Tadaki, Soichiro; Yamauchi, Takeshi; Onose, Takeo; Tsuji, Kanako; Abe, Ruri; Oikawa, Takuya; Kasahara, Shintaro; Nochioka, Kotaro; Takahashi, Jun; Shimokawa, Hiroaki

2016-05-25

It remains to be elucidated whether addition of renin-angiotensin-aldosterone system (RAAS) inhibitors and/or β-blockers to loop diuretics has a beneficial prognostic impact on chronic heart failure (CHF) patients. From the Chronic Heart failure Analysis and Registry in the Tohoku district 2 (CHART-2) Study (n=10,219), we enrolled 4,134 consecutive patients with symptomatic stage C/D CHF (mean age, 69.3 years, 67.7% male). We constructed Cox models for composite of death, myocardial infarction, stroke and HF admission. On multivariate inverse probability of treatment weighted (IPTW) Cox modeling, loop diuretics use was associated with worse prognosis with hazard ratio (HR) 1.28 (Pdiuretics were associated with worse prognosis with HR 1.32 and 1.56, respectively (both Pdiuretics. Chronic use of loop diuretics is significantly associated with worse prognosis in CHF patients in a dose-dependent manner, whereas the triple combination of RAAS inhibitor(s), MRA, and β-blocker(s) is associated with better prognosis when combined with low-dose loop diuretics. (Circ J 2016; 80: 1396-1403).

Renin-Angiotensin Inhibitors Decrease Recurrence after Transurethral Resection of Bladder Tumor in Patients with Nonmuscle Invasive Bladder Cancer.

Science.gov (United States)

Blute, Michael L; Rushmer, Timothy J; Shi, Fangfang; Fuller, Benjamin J; Abel, E Jason; Jarrard, David F; Downs, Tracy M

2015-11-01

52 in whom it was combined with angiotensin converting enzyme inhibitor/angiotensin receptor blocker. Multivariate analysis revealed that patients treated with bacillus Calmette-Guérin alone (HR 2.19, 95% CI 1.01-4.77, p = 0.04) showed worse recurrence-free survival compared to patients treated with bacillus Calmette-Guérin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (stage Ta HR 0.45, 95% CI 0.21-0.98, p = 0.04). Pharmacological inhibition of the renin-angiotensin system is associated with improved outcomes in patients with bladder cancer. Renin-angiotensin system inhibitor administration in nonmuscle invasive bladder cancer cases should be studied in a prospective randomized trial. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using metaanalysis

International Nuclear Information System (INIS)

Younis, Sidra; Javed, Qamar; Blumenberg, Miroslav

2015-01-01

EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways. Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors. The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis. This metaanalysis suggests that ‘combination therapies’ can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding

Beta-blockers do not impair the cardiovascular benefits of endurance training in hypertensives.

Science.gov (United States)

Westhoff, T H; Franke, N; Schmidt, S; Vallbracht-Israng, K; Zidek, W; Dimeo, F; van der Giet, M

2007-06-01

Aerobic physical exercise is broadly recommended as a helpful adjunct to obtain blood pressure control in hypertension. Beta-blockade interacts with heart rate, sympathetic tone, maximal workload and local lactate production. In the present randomized-controlled study, we compared the cardiovascular effects of an endurance training programme in elderly hypertensives with or without beta-blockers and developed a first approach to determine a lactate-based training heart rate in presence of beta-blockade. Fifty-two patients (23 with beta-blocker, 29 without beta-blocker) > or =60 years with systolic 24-h ambulatory blood pressure (ABP) > or =140 mm Hg and/or antihypertensive treatment were randomly assigned to sedentary activity or a heart-rate controlled 12-week treadmill exercise programme (lactate 2.0 mmol/l). In the exercise group, the training significantly decreased systolic and diastolic 24-h ABP, blood pressure on exertion (100 W) and increased endothelium-dependent vasodilation (flow-mediated vasodilation, FMD) and physical performance both in the presence and absence of beta-blockade (Pendurance training evokes comparable cardiovascular benefits in the presence and absence of beta-blockade including a marked improvement of endothelial function. In the present study, target training heart rate with beta-blockers is about 18% lower than without.

Transport of beta-blockers and calcium antagonists by diffusion in cat myocardium

DEFF Research Database (Denmark)

Haunsø, Stig; Sejrsen, Per; Svendsen, Jesper Hastrup

1991-01-01

Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion. In anesthet......Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion...

Mortality and Reinfarction among Patients Using Different Beta-Blockers for Secondary Prevention after a Myocardial Infarction

DEFF Research Database (Denmark)

Andersen, Søren Skøtt; Hansen, Morten Lock; Gislason, Gunnar H

2009-01-01

Objectives: To study differences in the clinical efficacy of various brands of beta-blocker in secondary prevention after a myocardial infarction (MI). Methods: All patients hospitalized with a first MI between 1995 and 2002 who were still alive 30 days after discharge and had had at least one...... prescription for a beta-blocker filled were identified by individual-level linkage of nationwide registries of hospitalizations and drugs dispensed from pharmacies. A total of 32,259 MI patients were included in the study. Multivariable Cox proportional hazard models were used to analyze the risks of death...... and recurrent MI related to treatment with different beta-blockers. Results: The risks for death and recurrent MI were similar in patients using different beta-blockers, except that mortality from all causes among patients with a prescription for sotalol was higher. Subgroup analyses of high-risk patients...

The pharmacological rationale for combining muscarinic receptor antagonists and beta-adrenoceptor agonists in the treatment of airway and bladder disease

NARCIS (Netherlands)

Dale, Philippa R.; Cernecka, Hana; Schmidt, Martina; Dowling, Mark R.; Charlton, Steven J.; Pieper, Michael P.; Michel, Martin C.

Muscarinic receptor antagonists and beta-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and beta-adrenoceptors are physiological antagonists for

Beta Blockers Suppress Dextrose-Induced Endoplasmic Reticulum Stress, Oxidative Stress, and Apoptosis in Human Coronary Artery Endothelial Cells.

Science.gov (United States)

Haas, Michael J; Kurban, William; Shah, Harshit; Onstead-Haas, Luisa; Mooradian, Arshag D

Beta blockers are known to have favorable effects on endothelial function partly because of their capacity to reduce oxidative stress. To determine whether beta blockers can also prevent dextrose-induced endoplasmic reticulum (ER) stress in addition to their antioxidative effects, human coronary artery endothelial cells and hepatocyte-derived HepG2 cells were treated with 27.5 mM dextrose for 24 hours in the presence of carvedilol (a lipophilic beta blockers with alpha blocking activity), propranolol (a lipophilic nonselective beta blockers), and atenolol (a water-soluble selective beta blockers), and ER stress, oxidative, stress and cell death were measured. ER stress was measured using the placental alkaline phosphatase assay and Western blot analysis of glucose regulated protein 78, c-Jun-N-terminal kinase (JNK), phospho-JNK, eukaryotic initiating factor 2α (eIF2α), and phospho-eIF2α and measurement of X-box binding protein 1 (XBP1) mRNA splicing using reverse transcriptase-polymerase chain reaction. Superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride (MCLA) chemiluminescence. Cell viability was measured by propidium iodide staining method. The ER stress, SO production, and cell death induced by 27.5 mM dextrose were inhibited by all 3 beta blockers tested. The antioxidative and ER stress reducing effects of beta blockers were also observed in HepG2 cells. The salutary effects of beta blockers on endothelial cells in reducing both ER stress and oxidative stress may contribute to the cardioprotective effects of these agents.

Angiotensin II, hypertension and angiotensin II receptor antagonism: Roles in the behavioural and brain pathology of a mouse model of Alzheimer's disease

NARCIS (Netherlands)

Wiesmann, M.; Roelofs, M.; Lugt, R. Van Der; Heerschap, A.; Kiliaan, A.J.; Claassen, J.A.H.R.

2017-01-01

Elevated angiotensin II causes hypertension and contributes to Alzheimer's disease by affecting cerebral blood flow. Angiotensin II receptor blockers may provide candidates to reduce (vascular) risk factors for Alzheimer's disease. We studied effects of two months of angiotensin II-induced

Factors associated with β-blocker initiation and discontinuation in a population-based cohort of seniors newly diagnosed with heart failure

Directory of Open Access Journals (Sweden)

Girouard C

2016-09-01

Full Text Available Catherine Girouard,1–3 Jean-Pierre Grégoire,1–3 Paul Poirier,2,4 Jocelyne Moisan1–3 1Chair on Adherence to Treatments, Université Laval, 2Faculty of Pharmacy, Université Laval, 3Population Health and Optimal Health Practices Research Unit, CHU de Québec Research Center, 4Quebec Heart and Lung Institute-Université Laval, Quebec City, QC, Canada Purpose: β-Blockers (bisoprolol, carvedilol, and metoprolol are the cornerstone of heart failure (HF management. The incidence rate of β-blocker initiation and discontinuation and their associated factors among seniors with a first HF diagnosis were assessed.Methods: A population-based inception cohort study that included all individuals aged ≥65 years with a first HF diagnosis in Quebec was conducted. β-Blockers initiation among 91,131 patients who were not using β-blockers at the time of HF diagnosis and discontinuation among those who initiated a β-blocker after HF diagnosis were assessed. Stepwise Cox regression analyses were used to calculate hazard ratios (HR and to identify factors associated with β-blocker initiation and discontinuation.Results: After HF diagnosis, 32,989 (36.2% individuals initiated a β-blocker. Of these, 15,408 (46.7% discontinued their β-blocker during the follow-up. Individuals more likely to initiate a β-blocker were those diagnosed in a recent calendar year (2009: HR, 2.11; 95% confidence interval [CI], 2.00–2.23 and diagnosed by a cardiologist (HR, 1.38; 95% CI, 1.34–1.42. Individuals less likely to initiate were those aged ≥90 years (HR, 0.65; 95% CI, 0.61–0.68 and those with chronic obstructive pulmonary disease (HR, 0.66; 95% CI, 0.64–0.68. Individuals more likely to discontinue were those with more than nine medical consultations (HR, 1.14; 95% CI, 1.10–1.18 and those with dementia (HR, 1.13; 95% CI, 1.01–1.27. Individuals less likely to discontinue were those diagnosed in a recent calendar year (2009: HR 0.74; 95% CI, 0.65–0.82 and

Impact of β-blocker selectivity on long-term outcomes in congestive heart failure patients with chronic obstructive pulmonary disease

Directory of Open Access Journals (Sweden)

Kubota Y

2015-03-01

Full Text Available Yoshiaki Kubota, Kuniya Asai, Erito Furuse, Shunichi Nakamura, Koji Murai, Yayoi Tetsuou Tsukada, Wataru Shimizu Department of Medicine (Division of Cardiology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan Background: Chronic obstructive pulmonary disease (COPD is present in approximately one-third of all congestive heart failure (CHF patients, and is a key cause of underprescription and underdosing of β-blockers, largely owing to concerns about precipitating respiratory deterioration. For these reasons, the aim of this study was to evaluate the impact of β-blockers on the long-term outcomes in CHF patients with COPD. In addition, we compared the effects of two different β-blockers, carvedilol and bisoprolol. Methods: The study was a retrospective, non-randomized, single center trial. Acute decompensated HF patients with COPD were classified according to the oral drug used at discharge into β-blocker (n=86; carvedilol [n=52] or bisoprolol [n=34] and non-β-blocker groups (n=46. The primary endpoint was all-cause mortality between the β-blocker and non-β-blocker groups during a mean clinical follow-up of 33.9 months. The secondary endpoints were the differences in all-cause mortality and the hospitalization rates for CHF and/or COPD exacerbation between patients receiving carvedilol and bisoprolol. Results: The mortality rate was higher in patients without β-blockers compared with those taking β-blockers (log-rank P=0.039, and univariate analyses revealed that the use of β-blockers was the only factor significantly correlated with the mortality rate (hazard ratio: 0.41; 95% confidence interval: 0.17–0.99; P=0.047. Moreover, the rate of CHF and/or COPD exacerbation was higher in patients treated with carvedilol compared with bisoprolol (log-rank P=0.033. In the multivariate analysis, only a past history of COPD exacerbation significantly increased the risk of re-hospitalization due to CHF and/or COPD exacerbation (adjusted hazard

Association of Beta-Blocker Use With Less Prevalent Joint Pain and Lower Opioid Requirement in People With Osteoarthritis.

Science.gov (United States)

Valdes, Ana M; Abhishek, Abhishek; Muir, Kenneth; Zhang, Weiya; Maciewicz, Rose A; Doherty, Michael

2017-07-01

Recent findings suggest that β-adrenergic blockers have antinociceptive properties. The aim of this study was to compare levels of large-joint pain between those taking adrenergic blockers and those taking other antihypertensive medications. Data from the Genetics of Osteoarthritis and Lifestyle (GOAL) study, a secondary-care cohort of osteoarthritis (OA) patients, were used. Joint pain was assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores in 873 individuals with symptomatic hip and/or knee OA and hypertension, who were taking ≥1 prescription antihypertensive medications. The association between adrenergic blocker prescription and at least moderate joint pain (WOMAC score anxiety, and depression. The use of β-adrenergic blockers was associated with lower WOMAC pain scores and with a lower prevalence of joint pain after adjustment for demographic variables and comorbidity (adjusted odds ratio [OR adj ] for pain 0.68 [95% confidence interval (95% CI) 0.51, 0.92]; P blockers (OR adj for pain 0.94 [95% CI 0.55, 1.58]) or with any other class of antihypertensive medications. Prescription of beta-blockers was also associated negatively with opioid use (OR adj for opioids 0.73 [95% CI 0.54, 0.98]; P beta-blockers is associated with less joint pain and a lower use of opioids and other analgesics in individuals with symptomatic large-joint OA. This observation needs to be confirmed by other studies. © 2016, American College of Rheumatology.

Recent developments in HPLC analysis of β-blockers in biological samples.

Science.gov (United States)

Saleem, Kishwar; Ali, Imran; Kulsum, Umma; Aboul-Enein, Hassan Y

2013-09-01

β-Adrenergic blockers represent a very important class of drugs that are used worldwide for treating various cardiac diseases. The present article describes the state-of-the art of analyses of β-adrenergic blockers using high-performance liquid chromatography (HPLC). Sample preparation techniques such as liquid-liquid extraction, solid-phase extraction and solid-phase microextraction have been discussed, which are essential prior to HPLC analysis. Additionally, applications of liquid chromatography coupled with tandem mass spectrometry are included. HPLC methods have been reported to include 0.6-26 min as the run times and 0.01 ng/mL to 25 µg/mL as detection limits. The most commonly used columns were C18 with various buffers as the mobile phases, along with various organic modifiers. The optimization of HPLC conditions has been discussed. It has been observed that the reported methods are quite satisfactory for the analyses of β-adrenergic blockers in biological samples. Future perspectives in the hyphenation of solid-phase microextraction-nano-liquid chromatography-tandem mass spectrometry have also been highlighted to achieve detections at nanogram and picogram levels. The present article is very useful for academicians, scientists, drug and pharmaceutical personnel and government regulatory authorities.

Evaluation of risk of falls and orthostatic hypotension in older, long-term topical beta-blocker users

NARCIS (Netherlands)

W.D. Ramdas (Wishal); N. van der Velde (Nathalie); T.J.M. van der Cammen (Tischa); R.C.W. Wolfs (Roger)

2009-01-01

textabstractBackground: Falls are a serious problem in the elderly, and have recently been described as cardiovascular-mediated side effects of beta-blocker eye drops. Therefore, we investigated the possible association between the long-term use of beta-blockers, prostaglandins and their

Preoperative depression symptom severity and its impact on adherence to preoperative beta-blocker therapy.

Science.gov (United States)

Schonberger, Robert B; Feinleib, Jessica; Holt, Natalie; Dai, Feng; Brandt, Cynthia; Burg, Matthew M

2014-12-01

To test the association among depression symptoms, distressed personality type, and preoperative beta-blocker nonadherence and to estimate the prevalence of untreated major depression in this population. Prospective observational study. A veterans hospital. One hundred twenty patients on outpatient beta-blocker therapy presenting for surgery. The Patient Health Questionnaire (PHQ)-9, the D-Scale-14 (DS14), and Modified Morisky Scale (MMS) questionnaires. Of 99 participants who presented for surgery, the incidence of preoperative nonadherence was 14.1% (95% confidence interval 7%-21%), consistent with prior research. Nonadherence was 9.5% among those with no depression, 27.8% among those with mild depression, and 28.6% among those with moderate-to-severe depression (Cochran-Armitage test for trend p = 0.03). Distressed personality type was found in 35% of the cohort (95% confidence interval 26-45%) and was not associated with beta-blocker nonadherence (Fisher's exact test, p = 0.24). Among participants with symptoms of major depressive disorder (n = 25, 25.3%), more than half (n = 14, 56%) had no indication of depression listed at their most recent primary care visit. Patients with symptoms of depression on chronic beta-blocker therapy are susceptible to medication nonadherence on the day of surgery. Most surgical patients with symptoms of major depression lack a diagnosis of depression. Preoperative depression screening may thus (1) identify a population at increased risk of beta-blocker withdrawal, and (2) identify patients who may benefit from anesthesiologist-initiated referral for this treatable condition. Copyright © 2014 Elsevier Inc. All rights reserved.

USE OF BETA-BLOCKERS IN THE PERIOPERATIVE PERIOD: HOW STRONG ARE THE EVIDENCES?

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V. V. Samoylenko

2015-09-01

Full Text Available Optimization of the pharmacotherapy in preoperative period is the cornerstone of the concept of risk modification of cardiovascular complications in the perioperative period. Therefore, special attention has recently been focused on the use of beta-blockers in the postoperative period. Nowadays convincing evidence base for the use of this class of drugs in the perioperative period that was the basis for the development of clinical guidelines is accumulated. Moreover, results of large randomized trials of beta-blockers are controversial. This has resulted in significant differences in the classes of recommendations and levels of evidence.Analysis of the results of basic researches and the provisions of recommendations of the international and national professional medical societies on the use of beta-blockers in patients with cardiovascular disease to reduce the risk of cardiac complications in the perioperative period for planned extracardiac surgical procedures is presented.

Synthesis of [{sup 18}F]-labelled nebivolol as a β{sub 1}-adrenergic receptor antagonist for PET imaging agent

Energy Technology Data Exchange (ETDEWEB)

Kim, Taek Soo; Park, Jeong Hoon; Lee, Jun Young; Yang, Seung Dae [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute (KAERI), Jeongeup (Korea, Republic of); Chang, Dong Jo [College of pharmacy, Sunchon National University, Suncheon (Korea, Republic of)

2017-02-15

Selective β{sub 1}-agonist and antagonists are used for the treatment of cardiac diseases including congestive heart failure, angina pectoris and arrhythmia. Selective β{sub 1}-antagonists including nebivolol have high binding affinity on β{sub 1}-adrenergic receptor, not β{sub 2}-receptor mainly expressed in smooth muscle. Nebivolol is one of most selective β{sub 1}-blockers in clinically used β{sub 1}- blockers including atenolol and bisoprolol. We tried to develop clinically useful cardiac PET tracers using a selective β{sub 1}-blocker. Nebivolol is C{sub 2}-symmetric and has two chromane moiety with a secondary amino alcohol and aromatic fluorine. We adopted the general synthetic strategy using epoxide ring opening reaction. Unlike formal synthesis of nebivolol, we prepared two chromane building blocks with fluorine and iodine which was transformed to diaryliodonium salt for labelling of {sup 18}F. Two epoxide building blocks were readily prepared from commercially available chromene carboxylic acids (1, 8). Then, the amino alcohol building block (15) was prepared by ammonolysis of epoxide (14) followed by coupling reaction with the other building block, epoxide (7). Diaryliodonium salt, a precursor for {sup 18}F-aromatic substitution, was synthesized in moderate yield which was readily subjected to {sup 18}F-aromatic substitution to give {sup 18}F-labelled nebivolol.

Fixed ratio combinations of glucagon like peptide 1 receptor agonists with basal insulin: a systematic review and meta-analysis.

Science.gov (United States)

Liakopoulou, Paraskevi; Liakos, Aris; Vasilakou, Despoina; Athanasiadou, Eleni; Bekiari, Eleni; Kazakos, Kyriakos; Tsapas, Apostolos

2017-06-01

Basal insulin controls primarily fasting plasma glucose but causes hypoglycaemia and weight gain, whilst glucagon like peptide 1 receptor agonists induce weight loss without increasing risk for hypoglycaemia. We conducted a systematic review and meta-analysis of randomised controlled trials to investigate the efficacy and safety of fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists. We searched Medline, Embase, and the Cochrane Library as well as conference abstracts up to December 2016. We assessed change in haemoglobin A 1c , body weight, and incidence of hypoglycaemia and gastrointestinal adverse events. We included eight studies with 5732 participants in the systematic review. Switch from basal insulin to fixed ratio combinations with a glucagon like peptide 1 receptor agonist was associated with 0.72% reduction in haemoglobin A 1c [95% confidence interval -1.03 to -0.41; I 2  = 93%] and 2.35 kg reduction in body weight (95% confidence interval -3.52 to -1.19; I 2  = 93%), reducing also risk for hypoglycaemia [odds ratio 0.70; 95% confidence interval 0.57 to 0.86; I 2  = 85%] but increasing incidence of nausea (odds ratio 6.89; 95% confidence interval 3.73-12.74; I 2  = 79%). Similarly, switching patients from treatment with a glucagon like peptide 1 receptor agonist to a fixed ratio combination with basal insulin was associated with 0.94% reduction in haemoglobin A 1c (95% confidence interval -1.11 to -0.77) and an increase in body weight by 2.89 kg (95% confidence interval 2.17-3.61). Fixed ratio combinations of basal insulin with glucagon like peptide 1 receptor agonists improve glycaemic control whilst balancing out risk for hypoglycaemia and gastrointestinal side effects.

Effects of combining opioids and clinically available NMDA receptor antagonists in the treatment of pain.

NARCIS (Netherlands)

Snijdelaar, D.G.

2005-01-01

This thesis concerns the effects of combining opioids with clinically available NMDA receptor antagonists in the treatment of acute and chronic pain. There are a number of problems with the use of opioids, such as, the development of tolerance/hyperalgesia, the reduced effectiveness in (central)

THE EFFECTS OF ACUTE AND CHRONIC STRESS ON ERYTHROCYTE DYNAMIC IN COMBINATION WITH ß–ADRENERGIC RECEPTORS BLOCKADE IN RATS

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Lucian Hritcu

2005-08-01

Full Text Available : 3 consecutive days propranolol hydrochloride administration (5 mg/kg b.w., subcutaneous injections under acute and chronic stress conditions causes changes of peripheral erythrocyte distribution in rats. The effects of acute stress and its combination with ȕ-adrenergic receptor blockade on erythrocyte dynamic were more pregnant beside the effects of chronic stress and its combination with ȕ-adrenergic receptor blockade, respectively. ȕ-adrenergic mechanisms were shown to be involved in regulation of erythrocyte dynamic in acute and chronic stress response.

Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy

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Wang ZY

2015-03-01

Full Text Available Zhi-Yu Wang,1 Meng Chen,1 Ling-Ling Zhu,2 Lu-Shan Yu,3 Su Zeng,3 Mei-Xiang Xiang,4 Quan Zhou1 1Department of Pharmacy, 2VIP Care Ward, Division of Nursing, the Second Affiliated Hospital, School of Medicine, 3Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, 4Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People’s Republic of China Background: Coprescribing of clopidogrel and other drugs is common. Available reviews have addressed the drug–drug interactions (DDIs when clopidogrel is as an object drug, or focused on combination use of clopidogrel and a special class of drugs. Clinicians may still be ignorant of those DDIs when clopidogrel is a precipitant drug, the factors determining the degree of DDIs, and corresponding risk management.Methods: A literature search was performed using PubMed, MEDLINE, Web of Science, and the Cochrane Library to analyze the pharmacokinetic DDIs of clopidogrel and new P2Y12 receptor inhibitors.Results: Clopidogrel affects the pharmacokinetics of cerivastatin, repaglinide, ferulic acid, sibutramine, efavirenz, and omeprazole. Low efficacy of clopidogrel is anticipated in the presence of omeprazole, esomeprazole, morphine, grapefruit juice, scutellarin, fluoxetine, azole antifungals, calcium channel blockers, sulfonylureas, and ritonavir. Augmented antiplatelet effects are anticipated when clopidogrel is coprescribed with aspirin, curcumin, cyclosporin, St John’s wort, rifampicin, and angiotensin-converting enzyme inhibitors. The factors determining the degree of DDIs with clopidogrel include genetic status (eg, cytochrome P540 [CYP]2B6*6, CYP2C19 polymorphism, CYP3A5*3, CYP3A4*1G, and CYP1A2-163C>A, species differences, and dose strength. The DDI risk does not exhibit a class effect, eg, the effects of clopidogrel on cerivastatin versus other statins, the effects of proton pump

Thyroid Storm with Heart Failure Treated with a Short-acting Beta-adrenoreceptor Blocker, Landiolol Hydrochloride.

Science.gov (United States)

Yamashita, Yugo; Iguchi, Moritake; Nakatani, Rieko; Usui, Takeshi; Takagi, Daisuke; Hamatani, Yasuhiro; Unoki, Takashi; Ishii, Mitsuru; Ogawa, Hisashi; Masunaga, Nobutoyo; Abe, Mitsuru; Akao, Masaharu

2015-01-01

Beta-adrenoreceptor blockers are essential in controlling the peripheral actions of thyroid hormones and a rapid heart rate in patients with thyroid storm, although they should be used with great caution when there is the potential for heart failure. A 67-year-old woman was diagnosed as having thyroid storm in addition to marked tachycardia with atrial fibrillation and heart failure associated with a reduced left ventricular function. The administration of an oral beta blocker, bisoprolol fumarate, induced hypotension and was not tolerable for the patient, whereas landiolol hydrochloride, a short-acting intravenous beta-adrenoreceptor blocker with high cardioselectivity and a short elimination half-life, was useful for controlling the patient's tachycardia and heart failure without causing hemodynamic deterioration.

Mechanical stress activates NMDA receptors in the absence of agonists.

Science.gov (United States)

Maneshi, Mohammad Mehdi; Maki, Bruce; Gnanasambandam, Radhakrishnan; Belin, Sophie; Popescu, Gabriela K; Sachs, Frederick; Hua, Susan Z

2017-01-03

While studying the physiological response of primary rat astrocytes to fluid shear stress in a model of traumatic brain injury (TBI), we found that shear stress induced Ca 2+ entry. The influx was inhibited by MK-801, a specific pore blocker of N-Methyl-D-aspartic acid receptor (NMDAR) channels, and this occurred in the absence of agonists. Other NMDA open channel blockers ketamine and memantine showed a similar effect. The competitive glutamate antagonists AP5 and GluN2B-selective inhibitor ifenprodil reduced NMDA-activated currents, but had no effect on the mechanically induced Ca 2+ influx. Extracellular Mg 2+ at 2 mM did not significantly affect the shear induced Ca 2+ influx, but at 10 mM it produced significant inhibition. Patch clamp experiments showed mechanical activation of NMDAR and inhibition by MK-801. The mechanical sensitivity of NMDARs may play a role in the normal physiology of fluid flow in the glymphatic system and it has obvious relevance to TBI.

Can non-selective beta-blockers prevent hepatocellular carcinoma in patients with cirrhosis?

DEFF Research Database (Denmark)

Thiele, Maja; Wiest, Reiner; Gluud, Lise Lotte

2013-01-01

Hepatocellular carcinoma is the main liver-related cause of death in patients with compensated cirrhosis. The early phases are asymptomatic and the prognosis is poor, which makes prevention essential. We propose that non-selective beta-blockers decrease the incidence and growth of hepatocellular...... and growth of hepatocellular carcinoma. Rodent and in vitro studies support the hypothesis, but clinical verification is needed. Different study designs may be considered. The feasibility of a randomized controlled trial is limited due to the necessary large number of patients and long follow......-up. Observational studies carry a high risk of bias. The meta-analytic approach may be used if the incidence and mortality of hepatocellular carcinoma can be extracted from trials on variceal bleeding and if the combined sample size and follow up is sufficient....

Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress.

Science.gov (United States)

Adamec, R; Muir, C; Grimes, M; Pearcey, K

2007-05-16

The roles of beta-NER (beta-noradrenergic receptor), GR (glucocorticoid) and mineral corticoid receptors (MR) in the consolidation of anxiogenic effects of predator stress were studied. One minute after predator stress, different groups of rats were injected (ip) with vehicle, propranolol (beta-NER blocker, 5 and 10 mg/kg), mifepristone (RU486, GR blocker, 20 mg/kg), spironolactone (MR blocker, 50 mg/kg), propranolol (5 mg/kg) plus RU486 (20 mg/kg) or the anxiolytic, chloradiazepoxide (CPZ, 10 mg/kg). One week later, rodent anxiety was assessed in elevated plus maze, hole board, light/dark box, social interaction and acoustic startle. Considering all tests except startle, propranolol dose dependently blocked consolidation of lasting anxiogenic effects of predator stress in all tests. GR receptor block alone was ineffective. However, GR block in combination with an ineffective dose of propranolol did blocked consolidation of predator stress effects in all tests, suggesting a synergism between beta-NER and GR. Surprisingly, MR block prevented consolidation of anxiogenic effects in all tests except the light/dark box. CPZ post stress was ineffective against the anxiogenic impact of predator stress. Study of startle was complicated by the fact that anxiogenic effects of stress on startle amplitude manifested as both an increase and a decrease in startle amplitude. Suppression of startle occurred in stressed plus vehicle injected groups handled three times prior to predator stress. In contrast, stressed plus vehicle rats handled five times prior to predator stress showed increases in startle, as did all predator stressed only groups. Mechanisms of consolidation of the different startle responses appear to differ. CPZ post stress blocked startle suppression but not enhancement of startle. Propranolol post stress had no effect on either suppression or enhancement of startle. GR block alone post stress prevented suppression of startle, but not enhancement. In contrast

Relationship between heart failure, concurrent chronic obstructive pulmonary disease and beta-blocker use

DEFF Research Database (Denmark)

Sessa, Maurizio; Mascolo, Annamaria; Mortensen, Rikke Nørmark

2018-01-01

Aims: To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these β-blockers...... with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with β-blockers....

Efficacy of α-blocker in improving ureteral stent-related symptoms: a meta-analysis of both direct and indirect comparison

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He F

2016-05-01

Full Text Available Feng He, Li-bo Man, Gui-zhong Li, Ning Liu Department of Urinary Surgery, Beijing Jishuitan Hospital, Beijing, People’s Republic of China Objective: To critically evaluate the efficacy of an α-blocker in improving ureteral-stent-related symptoms and preliminarily investigate the difference between different types of α-blockers. Methods: Relevant randomized controlled trials were identified through searching PubMed, the Cochrane Library, Embase, and other sources. After quality assessment and data abstraction, direct comparison based on the Ureteral Stent-related Symptom Questionnaire (USSQ between α-blockers and control was performed by RevMan 5.3. Indirect comparison between different types of α-blockers was performed by ITC 1.0. Sensitive and subgroup analyses were used to handle important clinical factors. Results: Sixteen randomized controlled trials containing 1,489 cases were included. Compared with control, α-blockers significantly reduced the overall urinary symptom, pain index, general health index, and scores related to sexual matters, while no significant difference was found in work performance and additional problem scores. Subgroup analysis showed that the duration of stent insertion, patient’s age, stent size, and the type of α-blocker had the potential to influence the outcomes. Through indirect comparison, we found alfuzosin and terazosin to be better than tamsulosin in pain relief and general health improvement. Conclusion: α-Blocker was effective in treating ureteral stent-related symptoms, as it improved the major indexes of USSQ post-insertion or post-removal. Alfuzosin and terazosin seemed to be better than tamsulosin, which needs further verification because of the lack of direct comparison currently. Keywords: α-blocker, tamsulosin, alfuzosin, terazosin, ureteral stent-related discomfort

Add-on Therapy With the α-Blockers Tamsulosin and Naftopidil Improves Voiding Function by Enhancing Neuronal Activity in Prostatic Hyperplasia Rats.

Science.gov (United States)

Ko, Il-Gyu; Hwang, Lakkyong; Jin, Jun-Jang; Kim, Sang-Hoon; Han, Jin Hee; Jeon, Jung Won; Cho, Sung Tae

2018-03-01

Benign prostatic hyperplasia (BPH) impacts quality of life in men by causing lower urinary tract symptoms. α1-Adrenoceptor (α1-AR) blockers improve lower urinary tract symptoms. We investigated the efficacy of add-on therapy with α1-AR blockers on BPH rats. Rats in the drug-treated groups were orally administered each drug once a day for 30 days after orchiectomy. To induce BPH, rats were castrated and testosterone (20 mg/kg) was injected subcutaneously once per day for 30 days. Cystometry was conducted to measure voiding contraction pressure and the interval contraction time, immunohistochemistry was performed to measure c-Fos and nerve growth factor (NGF) expression in the neuronal voiding centers, and nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry was used to measure nitric oxide synthase (NOS) expression. Orchiectomy and testosterone injection decreased voiding contraction pressure and the interval contraction time, suggesting BPH symptoms. Voiding contraction pressure and the interval contraction time were greater in the group that received the combination treatment (tamsulosin with naftopidil) than in the tamsulosin monotherapy or naftopidil monotherapy groups. c-Fos, NGF, and NOS expression in the neuronal voiding centers was enhanced by BPH induction. c-Fos, NGF, and NOS expression was suppressed by the combination treatment (tamsulosin with naftopidil) to a greater extent than was the case for tamsulosin monotherapy or naftopidil monotherapy. Combination therapy of tamsulosin and naftopidil showed greater efficacy for the treatment of BPH than tamsulosin monotherapy or naftopidil monotherapy; therefore, combination therapy can be considered as a novel therapeutic method for BPH.

Association of β-Blockers With Functional Outcomes, Death, and Rehospitalization in Older Nursing Home Residents After Acute Myocardial Infarction.

Science.gov (United States)

Steinman, Michael A; Zullo, Andrew R; Lee, Yoojin; Daiello, Lori A; Boscardin, W John; Dore, David D; Gan, Siqi; Fung, Kathy; Lee, Sei J; Komaiko, Kiya D R; Mor, Vincent

2017-02-01

Although β-blockers are a mainstay of treatment after acute myocardial infarction (AMI), these medications are commonly not prescribed for older nursing home residents after AMI, in part owing to concerns about potential functional harms and uncertainty of benefit. To study the association of β-blockers after AMI with functional decline, mortality, and rehospitalization among long-stay nursing home residents 65 years or older. This cohort study of nursing home residents with AMI from May 1, 2007, to March 31, 2010, used national data from the Minimum Data Set, version 2.0, and Medicare Parts A and D. Individuals with β-blocker use before AMI were excluded. Propensity score-based methods were used to compare outcomes in people who did vs did not initiate β-blocker therapy after AMI hospitalization. Functional decline, death, and rehospitalization in the first 90 days after AMI. Functional status was measured using the Morris scale of independence in activities of daily living. The initial cohort of 15 720 patients (11 140 women [70.9%] and 4580 men [29.1%]; mean [SD] age, 83 [8] years) included 8953 new β-blocker users and 6767 nonusers. The propensity-matched cohort included 5496 new users of β-blockers and an equal number of nonusers for a total cohort of 10 992 participants (7788 women [70.9%]; 3204 men [29.1%]; mean [SD] age, 84 [8] years). Users of β-blockers were more likely than nonusers to experience functional decline (odds ratio [OR], 1.14; 95% CI, 1.02-1.28), with a number needed to harm of 52 (95% CI, 32-141). Conversely, β-blocker users were less likely than nonusers to die (hazard ratio [HR], 0.74; 95% CI, 0.67-0.83) and had similar rates of rehospitalization (HR, 1.06; 95% CI, 0.98-1.14). Nursing home residents with moderate or severe cognitive impairment or severe functional dependency were particularly likely to experience functional decline from β-blockers (OR, 1.34; 95% CI, 1.11-1.61 and OR, 1.32; 95% CI, 1.10-1.59, respectively

Methylphenidate enhances NMDA-receptor response in medial prefrontal cortex via sigma-1 receptor: a novel mechanism for methylphenidate action.

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Chun-Lei Zhang

Full Text Available Methylphenidate (MPH, commercially called Ritalin or Concerta, has been widely used as a drug for Attention Deficit Hyperactivity Disorder (ADHD. Noteworthily, growing numbers of young people using prescribed MPH improperly for pleasurable enhancement, take high risk of addiction. Thus, understanding the mechanism underlying high level of MPH action in the brain becomes an important goal nowadays. As a blocker of catecholamine transporters, its therapeutic effect is explained as being due to proper modulation of D1 and α2A receptor. Here we showed that higher dose of MPH facilitates NMDA-receptor mediated synaptic transmission via a catecholamine-independent mechanism, in layer V∼VI pyramidal cells of the rat medial prefrontal cortex (PFC. To indicate its postsynaptic action, we next found that MPH facilitates NMDA-induced current and such facilitation could be blocked by σ1 but not D1/5 and α2 receptor antagonists. And this MPH eliciting enhancement of NMDA-receptor activity involves PLC, PKC and IP3 receptor mediated intracellular Ca(2+ increase, but does not require PKA and extracellular Ca(2+ influx. Our additional pharmacological studies confirmed that higher dose of MPH increases locomotor activity via interacting with σ1 receptor. Together, the present study demonstrates for the first time that MPH facilitates NMDA-receptor mediated synaptic transmission via σ1 receptor, and such facilitation requires PLC/IP3/PKC signaling pathway. This novel mechanism possibly explains the underlying mechanism for MPH induced addictive potential and other psychiatric side effects.

Bed blockers: A study on the elderly patients in a teaching hospital in India

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Praveen Kumar N

2010-07-01

Full Text Available A cross-sectional study of in-patients over the age of 60 years was conducted at district McGann Hospital, Shimoga on patients who were classified as bed blockers. Level of dependency and cognitive function of these patients were assessed using Barthel scale and Abbreviated mental test (AMT respectively. Median age of the study population was 67 years; majority of them were men. Most of them were admitted in the medical ward and the median time to be labeled as bed blocker was 32 days. These bed blockers were a weak group of patients with an average 3.1 pathology per case. Majority of them suffered from neurological disorders and cardiovascular disease. High level of dependence was noted with a mean Barthel score of 29.68 (Range 0 -100. Low levels of cognitive function was also noted among these patients with a mean AMT of 4.76 (Range 0 -10.These findings demonstrate that the bed blockers in McGann hospital suffer not only from genuine health problems but also have a high dependency level in activities of daily living which hamper their discharge to the community. Community based rehabilitation using an intersectoral approach may help at least the less dependent to return home.

Strategies for B-cell receptor repertoire analysis in Primary Immunodeficiencies:From severe combined immunodeficiency to common variable immunodeficiency

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Hanna eIJspeert

2015-04-01

Full Text Available The antigen receptor repertoires of B and T cells form the basis of the adaptive immune response. The repertoires should be sufficiently diverse to recognize all possible pathogens. However, careful selection is needed to prevent responses to self or harmless antigens. Limited antigen receptor repertoire diversity leads to immunodeficiency, whereas unselected or misdirected repertoires can result in autoimmunity. The antigen receptor repertoire harbors information about abnormalities in many immunological disorders. Recent developments in next generation sequencing allow the analysis of the antigen receptor repertoire in much greater detail than ever before. Analyzing the antigen receptor repertoire in patients with mutations in genes responsible for the generation of the antigen receptor repertoire will give new insights into repertoire formation and selection. In this perspective we describe strategies and considerations for analysis of the naive and antigen selected B-cell repertoires in primary immunodeficiency (PID patients with a focus on severe combined immunodeficiency (SCID and common variable immunodeficiency (CVID.

Beta-blocker use and fall risk in older individuals: Original results from two studies with meta-analysis

NARCIS (Netherlands)

Ham, Annelies C.; van Dijk, Suzanne C.; Swart, Karin M. A.; Enneman, Anke W.; van der Zwaluw, Nikita L.; Brouwer-Brolsma, Elske M.; van Schoor, Natasja M.; Carola Zillikens, M.; Lips, Paul; de Groot, Lisette C. P. G. M.; Hofman, Albert; Witkamp, Renger F.; Uitterlinden, André G.; Stricker, Bruno H.; van der Velde, Nathalie

2017-01-01

Aims To investigate the association between use of -blockers and beta-blocker characteristics - selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism - and fall risk. Methods Data from two prospective studies were used, including community-dwelling

Development of an amorphous surge blocker for a high voltage acceleration power supply of the neutral beam injectors

International Nuclear Information System (INIS)

Mizuno, Makoto; Ohara, Yoshihiro; Watanabe, Kazuhiro; Ozaki, Akira.

1993-10-01

An amorphous surge blocker for a high voltage acceleration power supply for the neutral beam injectors has been developed. Since the saturation magnetic flux density of the amorphous core is higher than that of the ferrite core, the surge blocker made of amorphous cores can be reduced in size appreciably compared to the conventional ferrite surge blocker. A 350 kV, 0.05 volt-second amorphous surge blocker was designed, fabricated and tested. The amorphous core was made by winding an amorphous tape with a film for the layer insulation and was heat-treated to recover the magnetic characteristics. The core is molded by epoxy resin and installed in a FRP insulator tube filled with SF 6 gas for the insulation. The volt-second measured was higher than the designed value and the electrical breakdown along the cores and between layers was not observed. This test result shows that the amorphous surge blocker is applicable for a dc acceleration power supply for high energy neutral beam injectors. (author)

Psychophysiological differentiation of two types of anxiety and its pharmacological modification by minor tranquillizer and beta-receptor-blocker.

Science.gov (United States)

Albus, M; Stahl, S; Müller-Spahn, F; Engel, R R

1986-08-01

To evaluate the influence of beta-blockers and/or minor tranquillizers on autonomic reactions during brief stress, 48 healthy subjects were randomised into 4 groups: A = 4 mg Pindolol, B = 1.5 mg Cloxazolam, C = Placebo, D = 4 mg Pindolol + 1.5 mg Cloxazolam. Subjects underwent four stress situations: Counting, noise, mental arithmetic and ergometry, each lasting 4 min with rest periods of 8 min in between. Electromyogram, finger pulse amplitude, heart rate, pulse wave velocity and electrodermal activity were recorded simultaneously on-line. Analysis of variance showed that the two drugs had significant main effects in different systems: Pindolol reduced heart rate, mainly during mental arithmetic and ergometry, Cloxazolam reduced electrodermal activity, mainly during noise. It can be concluded that different structured situations with a varying amount and type of anxiety induce different autonomic reactions; these reactions can be differentially modified by the drugs applied.

Analysis of solar blocker through portable X-ray fluorescence

International Nuclear Information System (INIS)

Ferreira, Diego de Dio; Melquiades, Fabio Luiz; Appoloni, Carlos Roberto; Lopes, Fabio; Lonni, Audrey Stinghen G.; Oliveira, Frederico Minardi de; Duarte, Jose C.

2009-01-01

This paper estimates the concentration of TiO 2 by Energy Dispersion X-ray fluorescence (EDXRF) viewing t obtain the FPS due to the physical barrier in the composition of solar blockers, and identifies possible present metals in the samples. A portable EDXRF equipment was used and 27 commercial of different brands and solar protection factors were analysed. Also, three formulations (A, B and C) were prepared and measured estimated in FPS-30 using 5% or TiO 2 . The quantification was performed through calibration curves with 1% to 30% standards of TiO 2 . As result, it was possible to determine the contribution to physical protection in the FPS, associated to the Ti concentration present in some solar blocker samples available in the market. Also, it was possible to detect the presence of various metals in solar protectors, such as Fe, Zn, Br and Sr, and identify chemical elements which were not mentioned and their formulation as well

Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

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Liu, Shuyuan; Yue, Longtao; Gu, Wenrui; Li, Xiuyun; Zhang, Liuping; Sun, Shujuan

2016-01-01

Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers), amlodipine (AML), nifedipine (NIF), benidipine (BEN) and flunarizine (FNZ) with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1) expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI) <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2). The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin) and YVC1 (encoding calcium channel protein in vacuole membrane).

Autoantibodies Specifically Against β1 Adrenergic Receptors and Adverse Clinical Outcome in Patients With Chronic Systolic Heart Failure in the β-Blocker Era: The Importance of Immunoglobulin G3 Subclass.

Science.gov (United States)

Nagatomo, Yuji; Li, Daniel; Kirsop, Jennifer; Borowski, Alan; Thakur, Akanksha; Tang, W H Wilson

2016-06-01

To elucidate the prevalence and role of β1 adrenergic receptor autoantibodies (β1AR-AAb) belonging to the immunoglobulin (Ig)G3 subclass in patients with heart failure (HF) treated with β-adrenergic blockers. Several cardiac AAbs have been reported to be present in sera from patients with dilated cardiomyopathy and other etiologies. Among AAbs, those recognizing β1AR-AAbs show agonist-like effects, have detrimental effects on cardiomyocytes, and may induce persistent myocardial damage. We quantify total IgG and IgG3 subclass β1AR-AAb in subjects with chronic stable HF with long-term follow-up. In our study cohort of 121 subjects, non-IgG3-β1AR-AAb and IgG3-β1AR-AAb were found to be positive in 20 (17%) and 26 patients (21%), respectively. The positive rate of IgG3-β1AR-AAb was significantly higher for those with nonischemic compared with ischemic HF etiology (27% vs 8%, P = .01), but the positive rate for non-IgG3-β1AR-AAb was similar between the 2 groups (18% vs 16%, respectively, P = NS). There were no significant differences in clinical and echocardiographic measures among total β1AR-AAb negative, non-IgG3-β1AR-AAb positive, and IgG3-β1AR-AAb positive groups at baseline. During 2.2 ± 1.2 years of follow-up, we observed similar rates of the composite endpoint of all-cause mortality, cardiac transplantation, or hospitalization resulting from HF between total IgG-β1AR-AAb negative and positive patients. However, the composite endpoint events were significantly more common in the patients without than in those with IgG3-β1AR-AAb (P = .048, log-rank test). Presence of IgG3-β1AR-AAb, not total IgG, was associated with paradoxically more favorable outcomes in our cohort of patients with chronic systolic HF largely treated by β-blockers. Copyright © 2016 Elsevier Inc. All rights reserved.

Combined effects of aging and inflammation on renin-angiotensin system mediate mitochondrial dysfunction and phenotypic changes in cardiomyopathies.

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Burks, Tyesha N; Marx, Ruth; Powell, Laura; Rucker, Jasma; Bedja, Djahida; Heacock, Elisa; Smith, Barbara J; Foster, D Brian; Kass, David; O'Rourke, Brian; Walston, Jeremy D; Abadir, Peter M

2015-05-20

Although the effects of aging and inflammation on the health of the cardiac muscle are well documented, the combined effects of aging and chronic inflammation on cardiac muscle are largely unknown. The renin-angiotensin system (RAS) has been linked independently to both aging and inflammation, but is understudied in the context of their collective effect. Thus, we investigated localized cardiac angiotensin II type I and type II receptors (AT(1)R, AT(2)R), downstream effectors, and phenotypic outcomes using mouse models of the combination of aging and inflammation and compared it to a model of aging and a model of inflammation. We show molecular distinction in the combined effect of aging and inflammation as compared to each independently. The combination maintained an increased AT(1)R:AT(2)R and expression of Nox2 and exhibited the lowest activity of antioxidants. Despite signaling pathway differences, the combined effect shared phenotypic similarities with aging including oxidative damage, fibrosis, and hypertrophy. These phenotypic similarities have dubbed inflammatory conditions as premature aging, but they are, in fact, molecularly distinct. Moreover, treatment with an AT(1)R blocker, losartan, selectively reversed the signaling changes and ameliorated adverse phenotypic effects in the combination of aging and inflammation as well as each independently.

The CC chemokine receptor 5 regulates olfactory and social recognition in mice.

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Kalkonde, Y V; Shelton, R; Villarreal, M; Sigala, J; Mishra, P K; Ahuja, S S; Barea-Rodriguez, E; Moretti, P; Ahuja, S K

2011-12-01

Chemokines are chemotactic cytokines that regulate cell migration and are thought to play an important role in a broad range of inflammatory diseases. The availability of chemokine receptor blockers makes them an important therapeutic target. In vitro, chemokines are shown to modulate neurotransmission. However, it is not very clear if chemokines play a role in behavior and cognition. Here we evaluated the role of CC chemokine receptor 5 (CCR5) in various behavioral tasks in mice using Wt (Ccr5⁺/⁺) and Ccr5-null (Ccr5⁻/⁻)mice. Ccr5⁻/⁻ mice showed enhanced social recognition. Administration of CC chemokine ligand 3 (CCL3), one of the CCR5-ligands, impaired social recognition. Since the social recognition task is dependent on the sense of olfaction, we tested olfactory recognition for social and non-social scents in these mice. Ccr5⁻/⁻ mice had enhanced olfactory recognition for both these scents indicating that enhanced performance in social recognition task could be due to enhanced olfactory recognition in these mice. Spatial memory and aversive memory were comparable in Wt and Ccr5⁻/⁻ mice. Collectively, these results suggest that chemokines/chemokine receptors might play an important role in olfactory recognition tasks in mice and to our knowledge represents the first direct demonstration of an in vivo role of CCR5 in modulating social behavior in mice. These studies are important as CCR5 blockers are undergoing clinical trials and can potentially modulate behavior. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia

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Zakrzewska, Joanna M; Palmer, Joanne; Morisset, Valerie

2017-01-01

BACKGROUND: Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker...

Effect of beta-blocker therapy on the risk of infections and death after acute stroke--a historical cohort study.

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Ilko L Maier

Full Text Available BACKGROUND: Infections are a frequent cause for prolonged hospitalization and increased mortality after stroke. Recent studies revealed a stroke-induced depression of the peripheral immune system associated with an increased susceptibility for infections. In a mice model for stroke, this immunosuppressive effect was reversible after beta-blocker administration. The aim of our study was to investigate the effect of beta-blocker therapy on the risk of infections and death after stroke in humans. METHODS: 625 consecutive patients with ischemic or hemorrhagic stroke, admitted to a university hospital stroke unit, were included in this historical cohort study. The effect of beta-blocker therapy on post-stroke pneumonia, urinary tract infections and death was investigated using multivariable Poisson and Cox regression models. RESULTS: 553 (88.3% patients were admitted with ischemic stroke, the remaining 72 (11.7% had a hemorrhagic stroke. Median baseline NIHSS was 8 (IQR 5-16 points. 301 (48.2% patients received beta-blocker therapy. There was no difference in the risk of post-stroke pneumonia between patients with and without beta-blocker therapy (Rate Ratio = 1.00, 95%CI 0.77-1.30, p = 0.995. Patients with beta-blocker therapy showed a decreased risk for urinary tract infections (RR = 0.65, 95%CI 0.43-0.98, p = 0.040. 7-days mortality did not differ between groups (Hazard Ratio = 1.36, 95%CI 0.65-2.77, p = 0.425, while patients with beta-blocker therapy showed a higher 30-days mortality (HR = 1.93, 95%CI 1.20-3.10, p = 0.006. CONCLUSIONS: Beta-blocker therapy did not reduce the risk for post-stroke pneumonia, but significantly reduced the risk for urinary tract infections. Different immune mechanisms underlying both diseases might explain these findings that need to be confirmed in future studies.

Impact of Tamsulosin, Tolterodine and drug-combination on the ...

African Journals Online (AJOL)

Objectives: To compare the role of alpha-blocker (Tamsulosin) monotherapy, anticholinergic (Tolterodine) monotherapy or combination of both drugs versus analgesics in improving post-ureteroscopy (URS) lower urinary tract symptoms related to double-J ureteral stent. Patients and methods: Between January 2009 and ...

The use of guideline recommended beta-blocker therapy in primary prevention implantable cardioverter defibrillator patients

DEFF Research Database (Denmark)

Ruwald, Anne Christine; Gislason, Gunnar Hilmar; Vinther, Michael

2017-01-01

Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st-time prim......Aims: We aimed to examine the use of guideline recommended beta-blocker therapy prior to and after primary prevention implantable cardioverter defibrillator (ICD) implantation in a 'real-life' setting. Methods and results: From the Danish Pacemaker and ICD Registry we identified all 1st......-time primary prevention ICD and cardiac resynchronization therapy defibrillator (CRT-D) implantations in Denmark from 2007-12 (n = 2935). Use of beta-blocker, type and dose was acquired through the Danish Prescription Registry. According to guideline recommendations, we defined target daily doses as ≥50 mg...... carvedilol and ≥200 mg metoprolol. Prior to implantation 2427 of 2935 (83%) patients received beta-blocker therapy, with 2166 patients (89%) having initiated treatment 3 months or more prior to implantation. The majority of patients was prescribed carvedilol (52%) or metoprolol (41%). Patients on carvedilol...

Long-term effects of beta-blocker use on lung function in Japanese patients with chronic obstructive pulmonary disease

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Oda N

2017-04-01

Full Text Available Naohiro Oda,1 Nobuaki Miyahara,1,2 Hirohisa Ichikawa,3 Yasushi Tanimoto,4 Kazuhiro Kajimoto,5 Makoto Sakugawa,6 Haruyuki Kawai,7 Akihiko Taniguchi,1 Daisuke Morichika,1 Mitsune Tanimoto,1 Arihiko Kanehiro,1 Katsuyuki Kiura1 1Department of Allergy and Respiratory Medicine, Okayama University Hospital, 2Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, 3Department of Respiratory Medicine, KKR Takamatsu Hospital, Takamatsu, 4Department of Respiratory Medicine, National Hospital Organization Minami-Okayama Medical Center, Okayama, 5Department of Respiratory Medicine, Kobe Red Cross Hospital, Kobe, 6Department of Respiratory Medicine, Okayama Red Cross Hospital, 7Department of Respiratory Medicine, Okayama Saiseikai Hospital, Okayama, Japan Background: Some recent studies have suggested that beta-blocker use in patients with chronic obstructive pulmonary disease (COPD is associated with a reduction in the frequency of acute exacerbations. However, the long-term effects of beta-blocker use on lung function of COPD patients have hardly been evaluated. Patients and methods: We retrospectively reviewed 31 Japanese COPD patients taking beta-blockers for >1 year and 72 patients not taking them. The association between beta-blocker use and the annual change in forced expiratory volume in 1 second (FEV1 was assessed. Results: At baseline, patient demographic characteristics were as follows: 97 males (mean age 67.0±8.2 years; 32 current smokers; and Global Initiative for Chronic Obstructive Lung disease (GOLD stages I: n=26, II: n=52, III: n=19, and IV: n=6. Patients taking beta-blockers exhibited a significantly lower forced vital capacity (FVC, FEV1, and %FVC, and a more advanced GOLD stage. The mean duration of beta-blocker administration was 2.8±1.7 years. There were no differences in the annual change in FEV1 between patients who did and did not use beta-blockers (-7.6±93.5 mL/year vs -4.7±118.9 m

A Comparative Study of the Management of Stage 2 hypertension by Combined therapy with Losartan, Amlodipine and Hydrochlorothiazide

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Reza Jafarzadeh Esfehani

2012-09-01

Full Text Available Background: The most effective and accurate treatment of hypertensive patients reduces cardiovascular events and improves the quality of life. Objective: This study compared the efficacy and safety of combined (combination therapy with an angiotensin-receptor blocker (ARB a calcium-channel blocker (CCB (Losartan / Amloidipine 50/10mg vs maximal combination doses of ARB with hydrochlorothiazide (Losartan /HCTZ 100/25 mg and maximal combination doses of CCB with HCTZ (Amlodipine /HCTZ 10/25 mg in the management of stage 2 hypertension. Methods: This randomized clinical trial (RTC comprised 478 hypertensive patients with mean age 50.5±5.21 years, and took place between January 2010 and December 2011 in Vasei Hospital clinic in Sabzevar. Antihypertensive drugs were washed out after 5 days of discontinuation of drugs and the patients with mean blood pressure in sitting position ≥ 160 and <200 mmHg in systole and ≥ 100 and <110 mmHg in diastole were randomized into three groups: Losartan / Amlodipine 50/10 mg (n =164 , Losartan / HCTZ 100/25 mg (n =155 and Amlodipine / HCTZ 10/25 mg (n =159. The end point was reaching the blood pressure below 140/90 within 56 days of treatment in each group. Results: There was a significant difference in systolic blood pressure reductions between treatment groups (P<0.001 and also there was a significant difference between groups in reducing diastolic blood pressure (P<0.01. The highest systolic and diastolic blood pressure reduction respectively was found in Amlodipine/losartane and losartane/HTCZ group. The ANCOVA analysis revealed that only treatment regimen had a significant effect (P=0.01 and other factor including Age, Gender, Diabetes Mellitus, Smoking and High serum cholesterol didn’t have significant effect on blood pressure reduction. Conclusion: ARB/CCB combination therapy reduced blood pressure more effectively than the maximal doses of ARB or CCB with HCTZ in stage 2 hypertensive patients within

Non-selective beta-blockers may reduce risk of hepatocellular carcinoma

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Thiele, Maja; Albillos, Agustín; Abazi, Rozeta

2015-01-01

BACKGROUND & AIMS: Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB...

Has beta-blocker use increased in patients with heart failure in internal medicine settings? Prognostic implications: RICA registry.

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González-García, Andrés; Montero Pérez-Barquero, Manuel; Formiga, Francesc; González-Juanatey, José R; Quesada, M Angustias; Epelde, Francisco; Oropesa, Roberto; Díez-Manglano, Jesús; Cerqueiro, José M; Manzano, Luis

2014-03-01

Underuse of beta-blockers has been reported in elderly patients with heart failure. The aim of this study was to evaluate the current prescription of beta-blockers in the internal medicine setting, and its association with morbidity and mortality in heart failure patients. The information analyzed was obtained from a prospective cohort of patients hospitalized for heart failure (RICA registry] database, patients included from March 2008 to September 2011) with at least one year of follow-up. We investigated the percentage of patients prescribed beta-blockers at hospital discharge, and at 3 and 12 months, and the relationship of beta-blocker use with mortality and readmissions for heart failure. Patients with significant valve disease were excluded. A total of 515 patients were analyzed (53.5% women), with a mean age of 77.1 (8.7) years. Beta-blockers were prescribed in 62.1% of patients at discharge. A similar percentage was found at 3 months (65.6%) and 12 months (67.9%) after discharge. All-cause mortality and the composite of all-cause mortality and readmission for heart failure were significantly lower in patients treated with beta-blockers (hazard ratio=0.59, 95% confidence interval, 0.41-0.84 vs hazard ratio=0.64, 95% confidence interval, 0.49-0.83). This decrease in mortality was maintained after adjusting by age, sex, ejection fraction, functional class, comorbidities, and concomitant treatment. The findings of this study indicate that beta-blocker use is increasing in heart failure patients (mainly elderly) treated in the internal medicine setting, and suggest that the use of these drugs is associated with a reduction in clinical events. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Angiotensin II Receptor Blockers

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... 2010. Mann JFE, et al. Renin-angiotensin system inhibition in the treatment of hypertension. http://www.uptodate. ... profit organization and proceeds from Web advertising help support our mission. Mayo Clinic does not endorse any ...

Analysis of Prescriptions of Alpha-Blockers and Phosphodiesterase 5 Inhibitors from the Urology Department and Other Departments

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Dong Hyuk Kang

2011-12-01

Full Text Available PurposeWe analyzed the prescriptions of alpha-blockers and phosphodiesterase 5 inhibitors (PDE5Is in the urology department as well as in other departments of the general hospital.MethodsWe investigated the frequency of prescription of alpha-blockers and PDE5Is from 3 general hospitals from January 1, 2007 to December 31, 2009. For alpha-blockers, data were collected from patients to whom alpha-blockers were prescribed from among patients recorded as having benign prostatic hyperplasia according to the 5th Korean Standard Classification of Diseases. For PDE5Is, data were collected from patients to whom PDE5Is were prescribed by the urology department and by other departments. Alpha-blockers were classified into tamsulosin, alfuzosin, doxazosin, and terazosin, whereas PDE5Is were classified into sildenafil, tadalafil, vardenafil, udenafil, and mirodenafil.ResultsAlpha-blockers were prescribed to 11,436 patients in total over 3 years, and the total frequency of prescriptions was 68,565. Among other departments, the nephrology department had the highest frequency of prescription of 3,225 (4.7%, followed by the cardiology (3,101, 4.5%, neurology (2,576, 3.8%, endocrinology (2,400, 3.5%, pulmonology (1,102, 1.6%, and family medicine (915, 1.3% departments in order. PDE5Is were prescribed to 2,854 patients in total over 3 years, and the total frequency of prescriptions was 10,558. The prescription frequency from the urology department was 4,900 (46.4%. Among other departments, the endocrinology department showed the highest prescription frequency of 3,488 (33.0%, followed by the neurology (542, 5.1%, cardiology (467, 4.4%, and family medicine (407, 3.9% departments in order.ConclusionsA high percentage of prescriptions of alpha-blockers and PDE5Is were from other departments. For more specialized medical care by urologists is required in the treatment of lower urinary tract symptoms and erectile dysfunction.

Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand-Receptor Complexes.

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Hatmal, Ma'mon M; Taha, Mutasem O

2018-04-23

We previously combined molecular dynamics (classical or simulated annealing) with ligand-receptor contacts analysis as a means to extract valid pharmacophore model(s) from single ligand-receptor complexes. However, molecular dynamics methods are computationally expensive and time-consuming. Here we describe a novel method for extracting valid pharmacophore model(s) from a single crystallographic structure within a reasonable time scale. The new method is based on ligand-receptor contacts analysis following energy relaxation of a predetermined set of randomly deformed complexes generated from the targeted crystallographic structure. Ligand-receptor contacts maintained across many deformed/relaxed structures are assumed to be critical and used to guide pharmacophore development. This methodology was implemented to develop valid pharmacophore models for PI3K-γ, RENIN, and JAK1. The resulting pharmacophore models were validated by receiver operating characteristic (ROC) analysis against inhibitors extracted from the CHEMBL database. Additionally, we implemented pharmacophores extracted from PI3K-γ to search for new inhibitors from the National Cancer Institute list of compounds. The process culminated in new PI3K-γ/mTOR inhibitory leads of low micromolar IC 50 s.

MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor

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Drew J. Puxty

2017-07-01

Full Text Available Previous research has shown that a single dose of MDMA induce a dissociative state, by elevating feelings of depersonalization and derealization. Typically, it is assumed that action on the 5-HT2A receptor is the mechanism underlying these psychedelic experiences. In addition, other studies have shown associations between dissociative states and biological parameters (heart rate, cortisol, which are elevated by MDMA. In order to investigate the role of the 5-HT2 receptor in the MDMA-induced dissociative state and the association with biological parameters, a placebo-controlled within-subject study was conducted including a single oral dose of MDMA (75 mg, combined with placebo or a single oral dose of the 5-HT2 receptor blocker ketanserin (40 mg. Twenty healthy recreational MDMA users filled out a dissociative states scale (CADSS 90 min after treatments, which was preceded and followed by assessment of a number of biological parameters (cortisol levels, heart rate, MDMA blood concentrations. Findings showed that MDMA induced a dissociative state but this effect was not counteracted by pre-treatment with ketanserin. Heart rate was the only biological parameter that correlated with the MDMA-induced dissociative state, but an absence of correlation between these measures when participants were pretreated with ketanserin suggests an absence of directional effects of heart rate on dissociative state. It is suggested that the 5-HT2 receptor does not mediate the dissociative effects caused by a single dose of MDMA. Further research is needed to determine the exact neurobiology underlying this effect and whether these effects contribute to the therapeutic potential of MDMA.

Functional interactions between 7TM receptors in the renin-angiotensin system--dimerization or crosstalk?

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Lyngsø, Christina; Erikstrup, Niels; Hansen, Jakob L

2008-01-01

. The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7...... be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very......The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt- and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure...

The challenge of analyzing beta-blocker drugs in sludge and wastewater.

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Scheurer, Marco; Ramil, Maria; Metcalfe, Chris D; Groh, Stefanie; Ternes, Thomas A

2010-01-01

In this study, different approaches were used to assess and overcome the severe effects of interference from the sample matrix from different types of sludges and wastewater on the analysis of nine beta-blockers and the beta sympathomimetic clenbuterol. The partitioning of the target compounds into sludge was investigated in wastewater treatment plants (WWTPs) in both Canada and Germany to evaluate whether this is an important mechanism for removal from sewage. Due to ion suppression in the electro spray interface, absolute recoveries were for certain compounds even lower than 20%. By using surrogate standards, acceptable relative recoveries of >75% were achieved for WWTP influents and effluents and for sludges. These matrix effects underline the need to use appropriate surrogate standards to aid in analyte quantitation. Using the developed methods, beta-blockers were detected at concentrations up to 2 microg/L in WWTP effluents, with metoprolol, sotalol, and atenolol present as the dominant compounds. Removal rates within WWTPs were highly inconsistent and ranged from 1-69%. Propranolol showed the greatest degree of partitioning into sludge with solid/water partition coefficients of one order of magnitude higher than those for all other compounds. However, even for propranolol, sorption did not contribute significantly to the overall elimination in WWTPs. It is likely that the removal of beta-blockers during waste water treatment can be attributed primarily to microbial biodegradation.

T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers.

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Wai-Ping Fung-Leung

Full Text Available Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.3 channels in human T cells during activation results in reduced calcium entry, cytokine production, and proliferation. The aim of the present study was to further explore the effects of Kv1.3 blockers on the response of different human T cell subsets under various stimulation conditions. Our studies show that, unlike the immune suppressor cyclosporine A, the inhibitory effect of Kv1.3 blockers was partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulations. T cell responses to allergens including house dust mites and ragweed were partially reduced by Kv1.3 blockers. The effect of Kv1.3 inhibition was dependent on T cell subsets, with stronger effects on CCR7- effector memory compared to CCR7+ central memory CD4 T cells. Calcium entry studies also revealed a population of CD4 T cells resistant to Kv1.3 blockade. Activation of CD4 T cells was accompanied with an increase in Kv1.3 currents but Kv1.3 transcripts were found to be reduced, suggesting a posttranscriptional mechanism in the regulation of Kv1.3 activities. In summary, Kv1.3 blockers inhibit T cell activation in a manner that is highly dependent on the T cell identity and stimulation strength, These findings suggest that Kv1.3 blockers inhibit T cells in a unique, conditional manner, further refining our understanding of the therapeutic potential of Kv1.3 blockers.

Reaction of β-blockers and β-agonist pharmaceuticals with aqueous chlorine. Investigation of kinetics and by-products by liquid chromatography quadrupole time-of-flight mass spectrometry.

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Quintana, José Benito; Rodil, Rosario; Cela, Rafael

2012-06-01

The degradation of two β-blockers (atenolol and propranolol) and one β-receptor agonist (salbutamol) during water chlorination was investigated by liquid chromatography-mass spectrometry (LC-MS). An accurate-mass quadrupole time-of-flight system (QTOF) was used to follow the time course of the pharmaceuticals and also used in the identification of the by-products. The degradation kinetics of these drugs was investigated at different concentrations of chlorine, bromide and sample pH by means of a Box-Behnken experimental design. Depending on these factors, dissipation half-lives varied in the ranges 68-145 h for atenolol, 1.3-33 min for salbutamol and 42-8362 min for propranolol. Normally, an increase in chlorine dosage and pH resulted in faster degradation of these pharmaceuticals. Moreover, the presence of bromide in water samples also resulted in a faster transformation of atenolol at low chlorine doses. The use of an accurate-mass high-resolution LC-QTOF-MS system permitted the identification of a total of 14 by-products. The transformation pathway of β-blockers/agonists consisted mainly of halogenations, hydroxylations and dealkylations. Also, many of these by-products are stable, depending on the chlorination operational parameters employed.

Protection against death and renal failure by renin-angiotensin system blockers in patients with diabetes and kidney disease.

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Shen, Jian; Huang, Yan-Mei; Song, Xin-Nan; Hong, Xue-Zhi; Wang, Min; Ling, Wei; Zhang, Xiao-Xi; Zhao, Hai-Lu

2016-07-01

Angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) are widely used to block the renin-angiotensin system (RAS). Yet it remains uncertain whether these drugs are equally effective and safe. Systematic reviews and meta-analyses of ACEis/ARBs in diabetes and kidney disease published in PubMed, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases were searched for clinical outcomes including all-cause mortality, end-stage renal disease (ESRD), hyperkalemia and cough. Eight meta-analyses included 2177-61,264 patients with follow-up of 6-108 months. RAS blockers reduced mortality (relative risk ratio (RR), 0.90, 95% confidence interval (CI), 0.86-0.95) without heterogeneity. The death protection was significant specifically with ACEis (RR, 0.85, 95% CI, 0.79-0.91), but not with ARBs. Protection against ESRD was homogenously evident by ARBs (RR, 0.79, 95% CI, 0.73-0.87), ACEis (RR, 0.79, 95% , 0.64-0.94), and both (RR, 0.79, 95% CI, 0.73-0.87). Significant side effects were hyperkalemia by ARBs (RR, 2.44, 95% CI, 1.13-5.26), and cough by ACEis (RR, 2.38, 95% CI, 1.75-3.22) CONCLUSIONS: In patients with diabetes and kidney disease, ACEis and ARBs are consistently protective for the development of ESRD. Use of ACEis alone additionally reduces deaths and increases the risk for cough. Use of ARBs alone increases the risk for hyperkalemia without additional benefit of death protection. © The Author(s) 2016.

Comparative Effects of an Angiotensin II Receptor Blocker (ARB)/Diuretic vs. ARB/Calcium-Channel Blocker Combination on Uncontrolled Nocturnal Hypertension Evaluated by Information and Communication Technology-Based Nocturnal Home Blood Pressure Monitoring　- The NOCTURNE Study.

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Kario, Kazuomi; Tomitani, Naoko; Kanegae, Hiroshi; Ishii, Hajime; Uchiyama, Kazuaki; Yamagiwa, Kayo; Shiraiwa, Toshihiko; Katsuya, Tomohiro; Yoshida, Tetsuro; Kanda, Kiyomi; Hasegawa, Shinji; Hoshide, Satoshi

2017-06-23

Nocturnal blood pressure (BP) is an independent risk factor of cardiovascular events. The NOCTURNE study, a multicenter, randomized controlled trial (RCT) using our recently developed information and communication technology (ICT) nocturnal home BP monitoring (HBPM) device, was performed to compare the nocturnal HBP-lowering effects of differential ARB-based combination therapies in 411 Japanese patients with nocturnal hypertension (HT).Methods and Results:Patients with nocturnal BP ≥120/70 mmHg at baseline even under ARB therapy (100 mg irbesartan daily) were enrolled. The ARB/CCB combination therapy (irbesartan 100 mg+amlodipine 5 mg) achieved a significantly greater reduction in nocturnal home systolic BP (primary endpoint) than the ARB/diuretic combination (daily irbesartan 100 mg+trichlormethiazide 1 mg) (-14.4 vs. -10.5 mmHg, P<0.0001), independently of urinary sodium excretion and/or nocturnal BP dipping status. However, the change in nocturnal home systolic BP was comparable among the post-hoc subgroups with higher salt sensitivity (diabetes, chronic kidney disease, and elderly patients). This is the first RCT demonstrating the feasibility of clinical assessment of nocturnal BP by ICT-nocturnal HBPM. The ARB/CCB combination was shown to be superior to ARB/diuretic in patients with uncontrolled nocturnal HT independently of sodium intake, despite the similar impact of the 2 combinations in patients with higher salt sensitivity.

Mortality benefit of long-term angiotensin-converting enzyme inhibitors or angiotensin receptor blockers after successful percutaneous coronary intervention in non-ST elevation acute myocardial infarction.

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González-Cambeiro, María Cristina; López-López, Andrea; Abu-Assi, Emad; Raposeiras-Roubín, Sergio; Peña-Gil, Carlos; García-Acuña, José; González-Juanatey, Ramón

2016-12-01

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been shown to reduce mortality after myocardial infarction (MI). Current guidelines recommend their prescription in all patients after MI. Limited data are available on whether ACEIs/ARBs still improve prognosis in the contemporary era of non-ST elevation MI (NSTEMI) management. We aimed to evaluate the mortality benefit of ACEIs/ARBs in NSTEMI patients treated successfully with percutaneous coronary intervention (PCI). We analyzed 2784 patients with NSTEMI treated successfully with in-hospital PCI. Two groups were formed based on ACEI/ARB prescription at discharge. Two propensity score (PS) analyses were performed to control for differences in covariates: one with adjustment among the entire cohort, and the other with PS matching (n=1626). The outcome variable was all-cause mortality at four-year follow-up. There were 1902 (68.3%) patients prescribed ACEIs/ARBs at discharge. When adjusted by PS, ACEI/ARB use was associated with a hazard ratio (HR) for mortality of 0.75 (0.60-0.94; absolute risk reduction [ARR] 4.0%) in the whole cohort (p=0.01). After one-to-one PS matching (n=813 in each group), the mortality rate was significantly lower in patients prescribed ACEIs/ARBs, with HR of 0.77 (0.63-0.94; ARR 3.8%) (p=0.03). In this observational study of patients with NSTEMI, all of them treated successfully by PCI, the use of ACEIs/ARBs was significantly associated with a lower risk of four-year all-cause mortality. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Use of statins and beta-blockers after acute myocardial infarction according to income and education

DEFF Research Database (Denmark)

Rasmussen, Jeppe Nørgaard; Gislason, Gunnar H; Rasmussen, Søren

2007-01-01

OBJECTIVE: To study the initiation of and long-term refill persistency with statins and beta-blockers after acute myocardial infarction (AMI) according to income and education. DESIGN AND SETTING: Linkage of individuals through national registers of hospitalisations, drug dispensation, income...... and education. PARTICIPANTS: 30 078 patients aged 30-74 years surviving first hospitalisation for AMI in Denmark between 1995 and 2001. MAIN OUTCOME MEASURES: Initiation of statin or beta-blocker treatment (out-patient claim of prescriptions within 6 months of discharge) and refill persistency (first break.......66-0.82) and medium (HR 0.82; 95% CI 0.74-0.92) income compared with low income, whereas there was a trend in the opposite direction concerning a break in beta-blocker treatment. There was no gradient in re-initiation of treatment. CONCLUSION: Patients with low compared with high income less frequently initiated...

Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review

NARCIS (Netherlands)

Brewster, Lizzy M.; Seedat, Yackoob K.

2013-01-01

Clinicians are encouraged to take an individualized approach when treating hypertension in patients of African ancestry, but little is known about why the individual patient may respond well to calcium blockers and diuretics, but generally has an attenuated response to drugs inhibiting the

Alterations in expression of Cat-315 epitope of perineuronal nets during normal ageing, and its modulation by an open-channel NMDA receptor blocker, memantine.

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Yamada, Jun; Ohgomori, Tomohiro; Jinno, Shozo

2017-06-15

The perineuronal net (PNN), a specialized aggregate of the extracellular matrix, is involved in neuroprotection against oxidative stress, which is now recognized as a major contributor to age-related decline in brain functions. In this study, we investigated the age-related molecular changes of PNNs using monoclonal antibody Cat-315, which recognizes human natural killer-1 (HNK-1) glycan on aggrecan-based PNNs. Western blot analysis showed that the expression levels of Cat-315 epitope in the hippocampus were higher in middle-aged (MA, 12-month-old) mice than in young adult (YA, 2-month-old) mice. Although there were no differences in the expression levels of Cat-315 epitope between old age (OA, 20-month-old) and MA mice, Cat-315 immunoreactivity was also detected in astrocytes of OA mice. To focus on Cat-315 epitope in PNNs, we used YA and MA mice in the following experiments. Optical disector analysis showed that there were no differences in the numbers of Cat-315-positive (Cat-315 + ) PNNs between YA and MA mice. Fluorescence intensity analysis indicated that Cat-315 immunoreactivity in PNNs increased with age in the dorsal hippocampus, which is mainly involved in cognitive functions. Administration of an open-channel blocker of NMDA receptor, memantine, reduced the expression levels of Cat-315 epitope in the hippocampus. Furthermore, the numbers of glutamatergic and GABAergic terminals colocalized with Cat-315 epitope around parvalbumin-positive neurons were decreased by memantine. These findings provide novel insight into the involvement of PNNs in normal brain ageing, and suggest that memantine may counteract the age-related alterations in expression levels of Cat-315 epitope via regulation of its subcellular localization. © 2017 Wiley Periodicals, Inc.

Long-term changes of renal function in relation to ace inhibitor/angiotensin receptor blocker dosing in patients with heart failure and chronic kidney disease.

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Fröhlich, Hanna; Nelges, Christoph; Täger, Tobias; Schwenger, Vedat; Cebola, Rita; Schnorbach, Johannes; Goode, Kevin M; Kazmi, Syed; Katus, Hugo A; Cleland, John G F; Clark, Andrew L; Frankenstein, Lutz

2016-08-01

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have become cornerstones of therapy for chronic heart failure (CHF). Guidelines advise high target doses for ACEIs/ARBs, but fear of worsening renal function may limit dose titration in patients with concomitant chronic kidney disease (CKD). In this retrospective observational study, we identified 722 consecutive patients with systolic CHF, stable CKD stage III/IV (estimated glomerular filtration rate [eGFR] 15-60 mL min(-1) 1.73 m(-2)) and chronic ACEI/ARB treatment from the outpatient heart failure clinics at the Universities of Hull, UK, and Heidelberg, Germany. Change of renal function, worsening CHF, and hyperkalemia at 12-month follow-up were analyzed as a function of both baseline ACEI/ARB dose and dose change from baseline. ΔeGFR was not related to baseline dose of ACEI/ARB (P = .58), or to relative (P = .18) or absolute change of ACEI/ARB dose (P = .21) during follow-up. Expressing change of renal function as a categorical variable (improved/stable/decreased) as well as subgroup analyses with respect to age, sex, New York Heart Association functional class, left ventricular ejection fraction, diabetes, concomitant aldosterone antagonists, CKD stage, hypertension, ACEI vs ARB, and congestion status yielded similar results. There was no association of dose/dose change with incidence of either worsening CHF or hyperkalemia. In patients with systolic CHF and stable CKD stage III/IV, neither continuation of high doses of ACEI/ARB nor up-titration was related to adverse changes in longer-term renal function. Conversely, down-titration was not associated with improvement in eGFR. Use of high doses of ACEI/ARB and their up-titration in patients with CHF and CKD III/IV may be appropriate provided that the patient is adequately monitored. Copyright © 2016 Elsevier Inc. All rights reserved.

Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors attenuates the exercise pressor reflex in rats with freely perfused hindlimb muscles.

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Stone, Audrey J; Copp, Steven W; Kim, Joyce S; Kaufman, Marc P

2015-12-01

In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 μg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 μg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS (n = 5), APETx2 (n = 6), nor L161982 (n = 6) attenuated the reflex. In contrast, combined blockade of these receptors (n = 7) attenuated the peak (↓27%, P reflex. Combined blockade injected intravenously had no effect on the reflex. We conclude that combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs. Copyright © 2015 the American Physiological Society.

Frequent premature ventricular contractions in an orbital spaceflight participant.

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Jennings, Richard T; Stepanek, Jan P; Scott, Luis R; Voronkov, Yury I

2010-06-01

Commercial spaceflight participants on orbital flights typically are older than career astronauts and they often have medical conditions that have not been studied at high g or in microgravity. This is a case report of a 56-yr-old orbital spaceflight participant with essential tremor and frequent premature ventricular contractions that occurred at rates up to 7000 per day. Before training and spaceflight, he was required to complete extensive clinical investigations to demonstrate normal cardiac structures and the absence of cardiac pathology. The evaluation included signal averaged ECG, transthoracic stress echocardiography, exercise tolerance tests, electrophysiological studies, cardiac MRI, electron beam CT, Holter monitoring, and overnight oximetry. While no cardiac pathology was demonstrated, the Russian medical team required that the PVCs be treated prior to training and spaceflight. For the initial flight, a selective beta-1 receptor beta blocker was used and for the second a calcium channel blocker was used in combination with a nonselective beta blocker for tremor control. Analogue environment testing assured that this combination of medications was compatible. The spaceflight participant's PVCs were incompletely suppressed with a low-dose selective beta-1 blocker, but were well suppressed by a calcium channel blocker. He tolerated in-flight periodic use of a nonselective beta blocker in combination with a calcium channel blocker. In-flight ECG and blood pressure monitoring results were normal, and an ECG obtained midmission and on landing day showed successful PVC suppression. He did not have any cardiac difficulty with launch, on-orbit operations, entry, or recovery

Clinical tolerability of generic versus brand beta blockers in heart failure with reduced left ventricular ejection fraction: a retrospective cohort from heart failure clinic.

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Chanchai, Rattanachai; Kanjanavanit, Rungsrit; Leemasawat, Krit; Amarittakomol, Anong; Topaiboon, Paleerat; Phrommintikul, Arintaya

2018-01-01

Background: Beta-blockers have been shown to decrease mortality and morbidity in heart failure with reduced ejection fraction (HFrEF) patients. However, the side effects are also dose-related, leading to the underdosing. Cost constraint may be one of the limitations of appropriate beta-blocker use; this can be improved with generic drugs. However, the effects in real life practice have not been investigated. Methods and results: This study aimed to compare the efficacy and safety of generic and brand beta-blockers in HFrEF patients. We performed a retrospective cohort analysis in HFrEF patients who received either generic or brand beta-blocker in Chiang Mai Heart Failure Clinic. The primary endpoint was the proportion of patients who received at least 50% target dose of beta-blocker between generic and brand beta-blockers. Adverse events were secondary endpoints. 217 patients (119 and 98 patients received generic and brand beta-blocker, respectively) were enrolled. There were no differences between groups regarding age, gender, etiology of heart failure, New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF), rate of receiving angiotensin converting enzyme inhibitor (ACEI), angiotensin recepter blocker (ARB), or spironolactone. Patients receiving brand beta-blockers had lower resting heart rate at baseline (74.9 and 84.2 bpm, p  = .001). Rate of achieved 50% target dose and target daily dose did not differ between groups (40.4 versus 44.5% and 48.0 versus 55.0%, p  > .05, respectively). Rate of side effects was not different between groups (32.3 versus 29.5%, p  > .05) and the most common side effect was hypotension. Conclusion: This study demonstrated that beta-blocker tolerability was comparable between brand and generic formulations. Generic or brand beta-blockers should be prescribed to HFrEF patients who have no contraindications.

Synergistic Effect of Fluconazole and Calcium Channel Blockers against Resistant Candida albicans.

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Shuyuan Liu

Full Text Available Candidiasis has increased significantly recently that threatens patients with low immunity. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of fungal resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapy is one of the most widely used and effective strategy to alleviate this problem. In this paper, we were aimed to evaluate the combined antifungal effects of four CCBs (calcium channel blockers, amlodipine (AML, nifedipine (NIF, benidipine (BEN and flunarizine (FNZ with fluconazole against C. albicans by checkerboard and time-killing method. In addition, we determined gene (CCH1, MID1, CNA1, CNB1, YVC1, CDR1, CDR2 and MDR1 expression by quantitative PCR and investigated the efflux pump activity of resistant candida albicans by rhodamine 6G assay to reveal the potential mechanisms. Finally, we concluded that there was a synergy when fluconazole combined with the four tested CCBs against resistant strains, with fractional inhibitory concentration index (FICI <0.5, but no interaction against sensitive strains (FICI = 0.56 ~ 2. The mechanism studies revealed that fluconazole plus amlodipine caused down-regulating of CNA1, CNB1 (encoding calcineurin and YVC1 (encoding calcium channel protein in vacuole membrane.

The non-biphenyl-tetrazole angiotensin AT1 receptor antagonist eprosartan is a unique and robust inverse agonist of the active state of the AT1 receptor.

Science.gov (United States)

Takezako, Takanobu; Unal, Hamiyet; Karnik, Sadashiva S; Node, Koichi

2018-03-23

Conditions such as hypertension and renal allograft rejection are accompanied by chronic, agonist-independent, signalling by angiotensin II AT 1 receptors. The current treatment paradigm for these diseases entails the preferred use of inverse agonist AT 1 receptor blockers (ARBs). However, variability in the inverse agonist activities of common biphenyl-tetrazole ARBs for the active state of AT 1 receptors often leads to treatment failure. Therefore, characterization of robust inverse agonist ARBs for the active state of AT 1 receptors is necessary. To identify the robust inverse agonist for active state of AT 1 receptors and its molecular mechanism, we performed site-directed mutagenesis, competition binding assay, inositol phosphate production assay and molecular modelling for both ground-state wild-type AT 1 receptors and active-state N111G mutant AT 1 receptors. Although candesartan and telmisartan exhibited weaker inverse agonist activity for N111G- compared with WT-AT 1 receptors, only eprosartan exhibited robust inverse agonist activity for both N111G- and WT- AT 1 receptors. Specific ligand-receptor contacts for candesartan and telmisartan are altered in the active-state N111G- AT 1 receptors compared with the ground-state WT-AT 1 receptors, suggesting an explanation of their attenuated inverse agonist activity for the active state of AT 1 receptors. In contrast, interactions between eprosartan and N111G-AT 1 receptors were not significantly altered, and the inverse agonist activity of eprosartan was robust. Eprosartan may be a better therapeutic option than other ARBs. Comparative studies investigating eprosartan and other ARBs for the treatment of diseases caused by chronic, agonist-independent, AT 1 receptor activation are warranted. © 2018 The British Pharmacological Society.

Vanilloid receptor expressed in the sarcoplasmic reticulum of rat skeletal muscle

International Nuclear Information System (INIS)

Xin Hong; Tanaka, Hideyuki; Yamaguchi, Maki; Takemori, Shigeru; Nakamura, Akio; Kohama, Kazuhiro

2005-01-01

Vanilloid receptor subtype 1 (VR1) was cloned as a capsaicin receptor from neuronal cells of dorsal root ganglia. VR1 was subsequently found in a few non-neuronal tissues, including skeletal muscle [Onozawa et al., Tissue distribution of capsaicin receptor in the various organs of rats, Proc. Jpn. Acad. Ser. B 76 (2000) 68-72]. We confirmed the expression of VR1 in muscle cells using the RT-PCR method and Western blot analysis. Immunostaining studies with a confocal microscope and an electron microscope indicated that VR1 was present in the sarcoplasmic reticulum (SR), a store of Ca 2+ . The SR releases Ca 2+ to cause a contraction when a muscle is excited. However, SR still releases a small amount of Ca 2+ under relaxed conditions. We found that this leakage was enhanced by capsaicin and was antagonized by capsazepine, a capsaicin blocker, indicating that leakage of Ca 2+ occurs through a channel composed of VR1

Effects of Tumor Necrosis Factor Blocker on Salicylate-Induced Tinnitus in Mice.

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Hwang, Juen-Haur; Huang, David Chang-Wei; Lu, Yin-Chang; Yang, Wei-Shiung; Liu, Tien-Chen

2017-06-01

Neuroinflammation is considered a novel mechanism for acute tinnitus. Here, we investigated the effects of a tumor necrosis factor (TNF) blocker on the gene expression of inflammatory-cytokine in the cochlea in a tinnitus animal model. Enbrel® (30 mg/kg, intraperitoneally (i.p.)) were administrated to the mice with the salicylate induced tinnitus for 3 days. Tinnitus score and mRNA expression levels of TNFR1, TNFR2, and N-methyl-d-aspartate receptor subunit 2B (NR2B) and its downstream regulatory element antagonist modulator (DREAM) in the cochlea of mice were measured and compared to the control. The tinnitus score significantly decreased in the Enbrel® treated group. The mRNA levels of both TNFR1 and TNFR2 were significantly lower in the treatment than in the control group. The mRNA levels of NR2B and DREAM followed a similar trend. we found that treatment with 30 mg/ kg Enbrel® decreased salicylate-induced behavior associated with tinnitus and reduced the mRNA expression levels of TNFR1/R2, NR2B, and DREAM in the cochlea of mice. These findings supported the hypothesis that neuroinflammation might be a novel mechanism for salicylate-induced tinnitus.

Comparison the Efficacy of Four Different Alpha Blockers in the Treatment of Benign Prostatic Hyperplasia

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Fatih Fırat

2011-05-01

Full Text Available Aim: Benign prostatic hyperplasia (BPH also known as nodular hyperplasia, benign enlargement of the prostate refers to the increase in size of the prostate in middle aged and elderly men. Although four different types of specific alpha blocker have been used in the treatment of BPH it remains controversial that which alpha adrenergic blocker is effective than others. The aim of this study is to compare the efficacy of 4 different alpha blockers agents on the treatment of BPH. Material and Methods: Between June 2005 and December 2008 a total of 135 consecutive patients with diagnosed of BPH were evaluated in our clinic. Patients were randomized into four groups according to alpha blocker types as fallows: group I, doxazosin 4 mg; group II, tamsulosin 0.4 mg; group III, terazosin 5 mg; and group IV, alfuzosin 10 mg. All patients were followed up with International Prostatic Symptom Score (IPSS, maximal urinary flow rates (Qmax and adverse effects were determined at baseline and again at least 3 months as efficacy parameters. Results: The mean age of the patients were 59.8±5.4 years, 58.9±6.4 years, 58.7±5.1 years, and 59.2±5.5 years in group I, group II, group III, and group IV, respectively (p>0.05. After 3 months treatment with alpha blockers the improvements in IPSS were found as 2.73, 3.73, 3.55 and 4.44 in group I, group II, group III, and group IV, respectively. Maximum urine flow rates increased as 2.81 ml/sec, 3.24 ml/sec, 3.88 ml/sec and 4.49 ml/sec in group I, group II, group III, and group IV, respectively. However, among 4 alpha blockers statistically significant difference was found only between doxazosin and alfuzosin groups according to uroflowmetry and IPSS results. According to these results, when compared adverse effect, the significant difference was observed only in tamsulosine group. Conclusions: As a result we can say that except retrograde ejaculation in tamsulosine group, adverse effects are not different between the

Adjunctive medical therapy with α-blocker after extracorporeal shock wave lithotripsy of renal and ureteral stones: a meta-analysis.

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Mingchao Li

Full Text Available Although some trials assessed the efficacy and safety of the α-blocker in facilitating renal and ureteral stones expulsion after extracorporeal shock wave lithotripsy (ESWL, the role of the α-blocker in facilitating upper urinary calculi expulsion after ESWL remain controversial.To determine the efficacy and safety of the α-blocker in facilitating renal and ureteral stones expulsion after ESWL.A literature search was carried out using the PubMed database, EMBASE and the Cochrane Library database to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality. Pooled effect estimates were obtained using a fixed- and random-effects meta-analysis.The meta-analysis included 23 RCTs, α-blocker significantly enhanced expulsion rate of upper urinary tract calculi after ESWL (P<0.00001; RR 1.21; 95% CI 1.12-1.31, significantly promoted steinstrasse expulsion (P=0.03; RR 1.25; 95% CI 1.03-1.53, significantly shortened the discharge time of upper urinary tract calculi (P=0.0001; MD -2.12; 95% CI -3.20--1.04, significantly reduced the patient's pain VAS score (P=0.001; RR -1.0; 95% CI -1.61--0.39. Compared with the control group, dizziness (P=0.002; RR 5.48; 95% CI 1.91-15.77, anejaculation (P=0.02; RR 12.17; 95% CI 1.61-91.99 and headache (P=0.04; RR 4.03; 95% CI 1.04-15.72 in the α-blocker group was associated with a higher incidence.Treatment with α-blocker after ESWL appears to be effective in enhancing expulsion rate of upper urinary tract calculi, shortening the discharge time of upper urinary tract calculi, reducing the patient's pain. The side effects of α-blocker were light and few.

Use of calcium channel blockers in hypertension.

Science.gov (United States)

Conlin, P R; Williams, G H

1998-01-01

During the past 20 years the number of subclasses of calcium channel blockers has increased from one to four. Three classes have only a single clinically approved compound: verapamil, diltiazem, and mibefradil. The fourth class, dihydropyridines, contains numerous compounds. All agents are effective in lowering blood pressure in short-term studies, and side effects that trouble the patient are infrequent. Long-term studies in hypertensive patients are limited. Short-acting agents such as nifedipine have been associated with an increased cardiovascular risk in some, but not all studies. These agents also probably create a compliance problem for hypertensive patients because of the need for multiple daily doses and their unpleasant side effects, e.g., ankle edema, palpitations, and flushing. Therefore, they are not useful or indicated for the treatment of hypertensive patients. No data have suggested that long-acting dihydropyridines or nondihydropyridine calcium channel blockers share the same fate. Indeed, several lines of evidence suggest the opposite: they have a cardioprotective effect. However, definitive information will require the completion of several long-term trials, including ALLHAT, CONVINCE, HOT, INSIGHT and NORDIL. Finally, it is important to reflect on the lessons learned from the controversy associated with the potential risks of calcium channel blockers. First, disagreements are common when one uses case-controlled studies and are reflective of the poor precision of the methods used. What is statistically relevant in one study may not hold true for another and may have no clinical relevance, particularly if the relative risk is less than 2. Investigators need to temper their enthusiasm to reflect this reality. Second, at the cutting edge of science there is probably relatively little agreement about what is correct among equally competent scientists. All have bias in their positions and should both recognize and admit so to themselves and their

Efficacy evaluation of a pollen blocker cream against dust-mite allergy: A multicenter, randomized, double-blind, placebo-controlled crossover trial.

Science.gov (United States)

Li, Yanqing; Cheng, Lei; Chen, Xiaoning; Yang, Beibei; Wang, Dehui

2015-01-01

To further evaluate the efficacy and safety of a pollen blocker cream against dust-mite allergy. A multicenter, randomized, double-blind, placebo-controlled, crossover trial was conducted in a Chinese population. Patients diagnosed with perennial allergic rhinitis, sensitive to dust-mite allergy including Dermatophagoides farinae and Dermatophagoides pteronyssinus were randomly allocated to receive a pollen blocker cream or placebo, which was applied and spread evenly to the lower internal nose region three times daily for a total of 30 days. The primary outcome measurements for efficacy were total nasal symptom score (TNSS) and individual nasal symptom score (iNSS). Adverse events were also monitored. After application of a pollen blocker, the mean TNSS decreased from 23.1 to 13.8, the decrease of the pollen blocker group (9.3) was highly significant compared with the placebo group (5.2; p 0.05), and no severe systematic reactions were observed. Pollen Blocker is a safe and effective alternative to the drugs for treatment of AR, especially for Chinese people allergic to dust-mite allergy.

Beta-1-Selective Beta-Blockers and Cognitive Functions in Patients With Coronary Artery Disease: A Cross-Sectional Study.

Science.gov (United States)

Burkauskas, Julius; Noreikaite, Aurelija; Bunevicius, Adomas; Brozaitiene, Julija; Neverauskas, Julius; Mickuviene, Narseta; Bunevicius, Robertas

2016-01-01

The association between current beta-1-selective beta-blocker use and cognitive function was evaluated in 722 patients with coronary artery disease without dementia. Beta-1-selective beta-blocker use was associated with worse incidental learning independently of sociodemographic characteristics, clinical coronary artery disease severity, and depression/anxiety.

Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

Energy Technology Data Exchange (ETDEWEB)

Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad (Pfizer)

2013-03-07

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

Functional expression of ionotropic purinergic receptors on mouse taste bud cells.

Science.gov (United States)

Hayato, Ryotaro; Ohtubo, Yoshitaka; Yoshii, Kiyonori

2007-10-15

Neurotransmitter receptors on taste bud cells (TBCs) and taste nerve fibres are likely to contribute to taste transduction by mediating the interaction among TBCs and that between TBCs and taste nerve fibres. We investigated the functional expression of P2 receptor subtypes on TBCs of mouse fungiform papillae. Electrophysiological studies showed that 100 microm ATP applied to their basolateral membranes either depolarized or hyperpolarized a few cells per taste bud. Ca(2+) imaging showed that similarly applied 1 mum ATP, 30 microm BzATP (a P2X(7) agonist), or 1 microm 2MeSATP (a P2Y(1) and P2Y(11) agonist) increased intracellular Ca(2+) concentration, but 100 microm UTP (a P2Y(2) and P2Y(4) agonist) and alpha,beta-meATP (a P2X agonist except for P2X(2), P2X(4) and P2X(7)) did not. RT-PCR suggested the expression of P2X(2), P2X(4), P2X(7), P2Y(1), P2Y(13) and P2Y(14) among the seven P2X subtypes and seven P2Y subtypes examined. Immunohistostaining confirmed the expression of P2X(2). The exposure of the basolateral membranes to 3 mm ATP for 30 min caused the uptake of Lucifer Yellow CH in a few TBCs per taste bud. This was antagonized by 100 microm PPADS (a non-selective P2 blocker) and 1 microm KN-62 (a P2X(7) blocker). These results showed for the first time the functional expression of P2X(2) and P2X(7) on TBCs. The roles of P2 receptor subtypes in the taste transduction, and the renewal of TBCs, are discussed.

Beta-blocker therapy in patients with left ventricular systolic dysfunction and chronic obstructive lung disease in an ambulatory care setting

Directory of Open Access Journals (Sweden)

Billups SJ

2009-12-01

Full Text Available Objective: To evaluate beta blocker persistence six months after beta-blocker initiation or dose titration in heart failure (HF patients with COPD compared to those without COPD. Secondary objectives included comparison of beta-blocker dose achieved, changes in left ventricular ejection fraction (LVEF and incidence of hospitalizations or emergency department (ED visits during follow-up.Methods: We conducted a matched, retrospective, cohort study including 86 patients with COPD plus concomitant HF (LVEF ≤40% and 137 patients with HF alone. All patients were followed in an outpatient HF clinic. Eligible patients had a documented LVEF ≤40% and were initiated or titrated on a beta-blocker in the HF clinic. Patients were matched based on LVEF (categorized as ≤ 20% or 21-40%, gender, and age (> or ≤70 years. The primary outcome was beta blocker persistence at 6 months. Secondary outcomes were dose achieved, LVEF, and incidence of hospitalizations or ED visits. Results: There were no differences between the COPD and non-COPD groups in beta-blocker persistence at six-month follow-up (94.2% vs. 93.4% respectively, adjusted p=0.842. The proportion of patients who achieved a daily metoprolol dose equivalent of at least 100 mg was similar between the groups (adjusted p=0.188. The percent of patients with at least one ED visit or hospitalization in the six-month post-titration period was substantial but similar between the groups (53.5% and 48.2% for COPD and non-COPD patients, respectively, adjusted p=0.169. Conclusion: Our results support the use of beta-blockers in the population of heart failure patients with COPD and without reactive airway disease.

The ACE-2/Ang1-7/Mas cascade enhances bone structure and metabolism following angiotensin-II type 1 receptor blockade.

Science.gov (United States)

Abuohashish, Hatem M; Ahmed, Mohammed M; Sabry, Dina; Khattab, Mahmoud M; Al-Rejaie, Salim S

2017-07-15

The renin angiotensin system (RAS) regulates numerous systemic functions and is expressed locally in skeletal tissues. Angiotensin1-7 (Ang1-7) is a beneficial member of the RAS, and the therapeutic effects of a large number of angiotensin receptors blockers (ARBs) are mediated by an Ang1-7-dependent cascade. This study examines whether the reported osteo-preservative effects of losartan are mediated through the angiotensin converting enzyme2 (ACE-2)/Ang1-7/Mas pathway in ovariectomized (OVX) rats. Sham and OVX animals received losartan (10mg/kg/d p.o.) for 6 weeks. A specific Mas receptor blocker (A-779) was delivered via mini-osmotic pumps during the losartan treatment period. Serum and urine bone metabolism biomarker levels were measured. Bone trabecular and cortical morphometry were quantified in distal femurs, whereas mineral contents were estimated in ashed bones, serum and urine. Finally, the expression of RAS components, the receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) was determined. Losartan significantly improved the elevated bone metabolism marker levels and altered trabecular and cortical structures in OVX animals, and restored normal urinary and skeletal mineral levels. Mas receptor inhibition significantly abolished all osteo-protective effects of losartan and enhanced the deleterious effects of OVX. Losartan enhanced OVX-induced up-regulation of ACE-1, AngII, angiotensin type 1 (AT 1 ) receptor and RANKL expression, and increased ACE-2, Ang1-7, Mas and OPG expression in OVX animals. However, A-779 significantly eradicated the effects of losartan on RAS components and RANKL/OPG expression. Thus, Ang1-7 are involved in the osteo-preservative effects of losartan via Mas receptor, which may add therapeutic value to this well-known antihypertensive agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

Science.gov (United States)

Kolarova, Anna; Ringer, Ralph; Täuber, Martin G; Leib, Stephen L

2003-01-01

Background Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 μl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus. Results Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16–25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60–31.8]; (P = NS) and 9.8 [1.7–27.3] (controls: 10.5 [2.4–21.75]) in animals treated with high dose RO 25-6981 (P = NS). Conclusions Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures. PMID:13129439

Early initiation of beta blockers following primary endoscopic therapy for bleeding esophageal varices in cirrhotics

International Nuclear Information System (INIS)

Salim, A.; Malik, K.; Farooq, M.O.; Butt, U.; Butt, A.K.

2017-01-01

Beta-blockers provide secondary prophylaxis following endoscopic therapy for variceal bleeding. Guidelines recommend starting beta-blockers 6 days after endoscopy to prevent masking hemodynamic signs of rebleeding. We aimed to see safety of earlier initiation of beta-blockers. Methods: Cirrhotic patients with upper GI bleed were given I.V vasoactive agents until undergoing endoscopy. Patients with only esophageal varices as source of bleed were recruited. Vasoactive agents were discontinued following variceal banding. The patients were observed for 12-18 hours, discharged on oral carvedilol 6.25 mg BID and monitored for 6 weeks for rebleeding and mortality. Results: 50 patients were included, 27 (54%) male and 23 (46%) female. Average age was 43+3 years. Etiology of cirrhosis was HCV in 42 (84%), HBV in 6 (12%), HCV and HBV in 2 (4%) and indeterminate in 1 (2%) patient. 17 (34%) patients had Child A, 22 (44%) Child B and 11 (22%) had Child C disease. Hospital stay was under 24 hours in 24 (48%), 24-48 hours in 15 (30%) and 48-72 hours in 11 (22%) patients. 5 (10%) patients underwent EGD within 6 hours of admission, 28 (56%) within 12 hours, 14 (28%) within 24 hours and 3 (6%) within 36 hours. No rebleeding, mortality or drug related adverse effects were noted during 6 weeks after discharge. Conclusions:Our study proves possibility of shorter management of variceal bleeding by having a 12-18 hour monitoring after endoscopic banding, followed by beta-blocker initiation and discharge. This will safely reduce physical and financial burden on health services. Background: Beta-blockers provide secondary prophylaxis following endoscopic therapy for variceal bleeding. Guidelines recommend starting beta-blockers 6 days after endoscopy to prevent masking hemodynamic signs of re-bleeding. We aimed to see safety of earlier initiation of beta-blockers. Methods: Cirrhotic patients with upper GI bleed were given intravenous vasoactive agents until undergoing endoscopy. Patients

Long-term compliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction

DEFF Research Database (Denmark)

Gislason, Gunnar H; Rasmussen, Jeppe Nørgaard; Abildstrøm, Steen Z

2006-01-01

AIMS: To study initiation, dosages, and compliance with beta-blockers, angiotensin-converting enzyme (ACE)-inhibitors, and statins in patients after acute myocardial infarction (AMI) and to identify likely targets for improvement. METHODS AND RESULTS: Patients admitted with first AMI between 1995...... and 2002 were identified by linking nationwide administrative registers. A total of 55 315 patients survived 30 days after discharge and were included; 58.3% received beta-blockers, 29.1% ACE-inhibitors, and 33.5% statins. After 1, 3, and 5 years, 78, 64, and 58% of survivors who had started therapy were...... still receiving beta-blockers, 86, 78, and 74% were receiving ACE-inhibitors, and 85, 80, and 82% were receiving statins, respectively. Increased age and female sex were associated with improved compliance. The dosages prescribed were generally 50% or less of the dosages used in clinical trials...

SU-F-J-211: Scatter Correction for Clinical Cone-Beam CT System Using An Optimized Stationary Beam Blocker with a Single Scan

International Nuclear Information System (INIS)

Liang, X; Zhang, Z; Xie, Y; Gong, S; Niu, T; Zhou, Q

2016-01-01

Purpose: X-ray scatter photons result in significant image quality degradation of cone-beam CT (CBCT). Measurement based algorithms using beam blocker directly acquire the scatter samples and achieve significant improvement on the quality of CBCT image. Within existing algorithms, single-scan and stationary beam blocker proposed previously is promising due to its simplicity and practicability. Although demonstrated effectively on tabletop system, the blocker fails to estimate the scatter distribution on clinical CBCT system mainly due to the gantry wobble. In addition, the uniform distributed blocker strips in our previous design results in primary data loss in the CBCT system and leads to the image artifacts due to data insufficiency. Methods: We investigate the motion behavior of the beam blocker in each projection and design an optimized non-uniform blocker strip distribution which accounts for the data insufficiency issue. An accurate scatter estimation is then achieved from the wobble modeling. Blocker wobble curve is estimated using threshold-based segmentation algorithms in each projection. In the blocker design optimization, the quality of final image is quantified using the number of the primary data loss voxels and the mesh adaptive direct search algorithm is applied to minimize the objective function. Scatter-corrected CT images are obtained using the optimized blocker. Results: The proposed method is evaluated using Catphan@504 phantom and a head patient. On the Catphan©504, our approach reduces the average CT number error from 115 Hounsfield unit (HU) to 11 HU in the selected regions of interest, and improves the image contrast by a factor of 1.45 in the high-contrast regions. On the head patient, the CT number error is reduced from 97 HU to 6 HU in the soft tissue region and image spatial non-uniformity is decreased from 27% to 5% after correction. Conclusion: The proposed optimized blocker design is practical and attractive for CBCT guided radiation

SU-F-J-211: Scatter Correction for Clinical Cone-Beam CT System Using An Optimized Stationary Beam Blocker with a Single Scan

Energy Technology Data Exchange (ETDEWEB)

Liang, X; Zhang, Z; Xie, Y [Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, GuangDong (China); Gong, S; Niu, T [Department of Radiation Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang (China); Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang (China); Zhou, Q [Department of Radiation Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang (China)

2016-06-15

Purpose: X-ray scatter photons result in significant image quality degradation of cone-beam CT (CBCT). Measurement based algorithms using beam blocker directly acquire the scatter samples and achieve significant improvement on the quality of CBCT image. Within existing algorithms, single-scan and stationary beam blocker proposed previously is promising due to its simplicity and practicability. Although demonstrated effectively on tabletop system, the blocker fails to estimate the scatter distribution on clinical CBCT system mainly due to the gantry wobble. In addition, the uniform distributed blocker strips in our previous design results in primary data loss in the CBCT system and leads to the image artifacts due to data insufficiency. Methods: We investigate the motion behavior of the beam blocker in each projection and design an optimized non-uniform blocker strip distribution which accounts for the data insufficiency issue. An accurate scatter estimation is then achieved from the wobble modeling. Blocker wobble curve is estimated using threshold-based segmentation algorithms in each projection. In the blocker design optimization, the quality of final image is quantified using the number of the primary data loss voxels and the mesh adaptive direct search algorithm is applied to minimize the objective function. Scatter-corrected CT images are obtained using the optimized blocker. Results: The proposed method is evaluated using Catphan@504 phantom and a head patient. On the Catphan©504, our approach reduces the average CT number error from 115 Hounsfield unit (HU) to 11 HU in the selected regions of interest, and improves the image contrast by a factor of 1.45 in the high-contrast regions. On the head patient, the CT number error is reduced from 97 HU to 6 HU in the soft tissue region and image spatial non-uniformity is decreased from 27% to 5% after correction. Conclusion: The proposed optimized blocker design is practical and attractive for CBCT guided radiation

[Controversies and dilemmas on the use of beta-blockers in treatment of associated cardiovascular disease in patients with chronic obstructive pulmonary disease].

Science.gov (United States)

Pescaru, Camelia; Tudorache, Voicu; Oancea, Cristian

2010-01-01

In the last decade, chronic obstructive pulmonary disease (COPD) has been considered a syndrome with multiple phenotypical facets and systemic components. Chronic diseases are associated, in time, with several comorbidities. Cardiovascular disease represents the most common comorbidity in COPD, increases its handicap and mortality indices. Most entities associated with cardiovascular disease require treatment with beta-blockers. However, beta-blockers are a "two-edged sword" when administered in obstructive pulmonary disorder. The use of beta-blockers should be assessed by their action on three areas: their effect on FEV1, their effect on bronchial hyperreactivity, the result obtained when additionally administering beta-agonists. The result of beta-blocker administration is influenced by the involvement of several other factors: the cardioselectivity of the beta-blocker, the dosage, the concomitant administration of beta-agonists, the stage of the disease (stable or exacerbation of COPD), smoker status etc. Their administration under strict monitoring results in a decreased morbidity and mortality, including in patients who had undergone cardiovascular surgery. The overall conclusion is that beta-blockers may be administered in COPD associated with cardiac comorbidity, but this administration requires utmost care.

[Benefits of spironolactone as the optimal treatment for drug resistant hypertension. Pathway-2 trial review].

Science.gov (United States)

Prado, J C; Ruilope, L M; Segura, J

Pathway-2 is the first randomised, double-blind and crossover trial that compares spironolactone as a fourth drug with alfa-blocker, beta-blocker and placebo. This study shows that spironolactone is the drug with more possibilities of success for the management of patients with difficult-to-treat hypertension in patients with a combination of three drugs and poor control. The results validate the widespread treatment with mineralocorticoid receptor antagonists in resistant hypertension. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Importance of beta-blocker dose in prevention of ventricular tachyarrhythmias, heart failure hospitalizations, and death in primary prevention implantable cardioverter-defibrillator recipients

DEFF Research Database (Denmark)

Ruwald, A C; Gislason, G H; Vinther, M

2018-01-01

Aims: There is a paucity of studies investigating a dose-dependent association between beta-blocker therapy and risk of outcome. In a nationwide cohort of primary prevention implantable cardioverter-defibrillator (ICD) patients, we aimed to investigate the dose-dependent association between beta-blocker...... therapy and risk of ventricular tachyarrhythmias (VT/VF), heart failure (HF) hospitalizations, and death. Methods and results: Information on ICD implantation, endpoints, comorbidities, beta-blocker usage, type, and dose were obtained through Danish nationwide registers. The two major beta-blockers...... carvedilol and metoprolol were examined in three dose levels; low (metoprolol ≤ 25 mg; carvedilol ≤ 12.5 mg), intermediate (metoprolol 26-199 mg; carvedilol 12.6-49.9 mg), and high (metoprolol ≥ 200 mg; carvedilol ≥ 50 mg). Time to events was investigated utilizing multivariate Cox models with beta-blocker...

Non-selective vs. selective beta-blocker treatment and the risk of thrombo-embolic events in patients with heart failure

NARCIS (Netherlands)

de Peuter, Olav R.; Souverein, Patrick C.; Klungel, Olaf H.; Büller, Harry R.; de Boer, Anthonius; Kamphuisen, Pieter W.

2011-01-01

Aims Heart failure (HF) is associated with a prothrombotic state, resulting in an increased risk for thrombo-embolic events. Studies suggest a reduced prothrombotic state when non-selective beta-blockers relative to selective beta-blockers are given. We studied the influence of non-selective

Frequent rhabdomyolysis in anti-NMDA receptor encephalitis.

Science.gov (United States)

Lim, Jung-Ah; Lee, Soon-Tae; Kim, Tae-Joon; Moon, Jangsup; Sunwoo, Jun-Sang; Byun, Jung-Ick; Jung, Keun-Hwa; Jung, Ki-Young; Chu, Kon; Lee, Sang Kun

2016-09-15

The aim of this study was to analyze the clinical presentation and provocation factors of rhabdomyolysis in anti-NMDAR encephalitis. Among the 16 patients with anti-NMDAR encephalitis in our institutional cohort, nine patients had elevated CK enzyme levels and clinical evidence of rhabdomyolysis. Rhabdomyolysis was more frequent after immunotherapy. The use of dopamine receptor blocker (DRB) increased the risk of rhabdomyolysis. None of the patients without rhabdomyolysis received DRBs. Rhabdomyolysis is a frequent complication in anti-NMDAR encephalitis and more common after immunotherapy and the use of DRBs increases the risk. Therefore, DRBs should be administered carefully in patients with anti-NMDAR encephalitis. Copyright © 2016 Elsevier B.V. All rights reserved.

Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

Science.gov (United States)

Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

2016-01-01

An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

Activation of Phosphatidylinositol-Linked Dopamine Receptors Induces a Facilitation of Glutamate-Mediated Synaptic Transmission in the Lateral Entorhinal Cortex.

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Iulia Glovaci

Full Text Available The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3 receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36 completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is

The structurally novel Ca2+ channel blocker Ro 40-5967, which binds to the [3H] desmethoxyverapamil receptor, is devoid of the negative inotropic effects of verapamil in normal and failing rat hearts

International Nuclear Information System (INIS)

Clozel, J.P.; Veniant, M.; Osterrieder, W.

1990-01-01

Ro 40-5967 is a structurally novel Ca 2+ channel blocker that binds to the verapamil-type receptor of cardiac membranes but that has been shown in isolated guinea-pig hearts to be about ten times less potent a negative inotropic agent than verapamil. The goals of the present study were to confirm these findings in vitro in isolated perfused rat hearts as well as in vivo in conscious rats and to compare Ro 40-5967 to verapamil. The effects of Ro 40-5967 and verapamil were tested not only in normal rats, but also in rats with heart failure induced by chronic myocardial infarction. In isolated Langendorff hearts (without heart failure), no decrease of contractility was observed with Ro 40-5967 up to complete AV block. In contrast, verapamil decreased contractility with an IC50 of 100 nM. In isolated, electrically stimulated rat papillary muscles, the IC50 values for the decrease of contractile force were 15,000 and 440 nM for Ro 40-5967 and verapamil, respectively. In vivo, Ro 40-5967 did not decrease left ventricular contractility (as assessed by changes of dP/dt max +) in rats without and with heart failure. In contrast, verapamil was markedly negative inotropic in both conditions

Effects of prostatic inflammation on LUTS and alpha blocker treatment outcomes

Directory of Open Access Journals (Sweden)

Ha Na Lee

2014-06-01

Full Text Available Purpose To evaluate the association between prostatic inflammation and lower urinary tract symptoms (LUTS, and to identify the effects of prostatic inflammation on the treatment with an alpha blocker. Materials and Methods 111 Participants who were aged ≥ 50 years, the presence of LUTS (maximal flow rate < 20 m/s, IPSS ≥ 11, and an elevated PSA level (3-20ng/mL were treated with tamsulosin 0.2mg once daily for 3 months after prostate biopsies. Prostatic inflammation was scored as none (0, mild (I, moderate (II, or marked (III. LUTS parameters including urine flow rates, IPSS, PSA, and prostate volume were evaluated. Results Inflammation grading resulted in 25, 60, and 26 patients that were grade 0, I, and II, respectively. Lower grade inflammation was related to higher urine flow rate at baseline. Patients with higher inflammation grades had larger prostate volumes, larger total and transitional zone volumes, and higher PSA levels. Overall, urine flow rates and residual urine volume were improved after 3 months of alpha blocker therapy. Eighty percent of patients with grade 0 inflammation, 73% of patients with grade I inflammation, and 92.3% of patients with grade II inflammation showed improvement of LUTS after treatment. Longer duration of treatment was related to a decreased chance of improvement of LUTS. Patients with increased IPSS voiding subscales could be predictive of improvement of LUTS. Conclusions Patients with high grade inflammation had lower flow rates and higher prostatic volumes than patients with low grade inflammation. Inflammation grade did not affect the outcomes of alpha blocker treatment.

Conversion to Silodosin in Men on Conventional α1 -Blockers for Symptomatic Benign Prostatic Hyperplasia.

Science.gov (United States)

Tanaka, Masahiko; Niimi, Aya; Tomita, Kyoichi; Homma, Yukio

2010-04-01

α1 -blockers have commonly been used as first-line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective α1A -adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional α1 -blockers to silodosin in men with BPH. Conversion to silodosin was proposed to consecutive patients on conventional α1 -blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Eighty-one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conversion to silodosin may be beneficial in men who are dissatisfied with conventional α1 -blockers for BPH, and be particularly useful in improving voiding symptoms. © 2010 Blackwell Publishing Asia Pty Ltd.

Presynaptic Glycine Receptors Increase GABAergic Neurotransmission in Rat Periaqueductal Gray Neurons

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Kwi-Hyung Choi

2013-01-01

Full Text Available The periaqueductal gray (PAG is involved in the central regulation of nociceptive transmission by affecting the descending inhibitory pathway. In the present study, we have addressed the functional role of presynaptic glycine receptors in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs were recorded in mechanically dissociated rat PAG neurons using a conventional whole-cell patch recording technique under voltage-clamp conditions. The application of glycine (100 µM significantly increased the frequency of sEPSCs, without affecting the amplitude of sEPSCs. The glycine-induced increase in sEPSC frequency was blocked by 1 µM strychnine, a specific glycine receptor antagonist. The results suggest that glycine acts on presynaptic glycine receptors to increase the probability of glutamate release from excitatory nerve terminals. The glycine-induced increase in sEPSC frequency completely disappeared either in the presence of tetrodotoxin or Cd2+, voltage-gated Na+, or Ca2+ channel blockers, suggesting that the activation of presynaptic glycine receptors might depolarize excitatory nerve terminals. The present results suggest that presynaptic glycine receptors can regulate the excitability of PAG neurons by enhancing glutamatergic transmission and therefore play an important role in the regulation of various physiological functions mediated by the PAG.

Beta receptor-mediated modulation of the late positive potential in humans.

Science.gov (United States)

de Rover, Mischa; Brown, Stephen B R E; Boot, Nathalie; Hajcak, Greg; van Noorden, Martijn S; van der Wee, Nic J A; Nieuwenhuis, Sander

2012-02-01

Electrophysiological studies have identified a scalp potential, the late positive potential (LPP), which is modulated by the emotional intensity of observed stimuli. Previous work has shown that the LPP reflects the modulation of activity in extrastriate visual cortical structures, but little is known about the source of that modulation. The present study investigated whether beta-adrenergic receptors are involved in the generation of the LPP. We used a genetic individual differences approach (experiment 1) and a pharmacological manipulation (experiment 2) to test the hypothesis that the LPP is modulated by the activation of β-adrenergic receptors. In experiment 1, we found that LPP amplitude depends on allelic variation in the β1-receptor gene polymorphism. In experiment 2, we found that LPP amplitude was modulated by the β-blocker propranolol in a direction dependent on subjects' level of trait anxiety: In participants with lower trait anxiety, propranolol led to a (nonsignificant) decrease in the LPP modulation; in participants with higher trait anxiety, propranolol increased the emotion-related LPP modulation. These results provide initial support for the hypothesis that the LPP reflects the downstream effects, in visual cortical areas, of β-receptor-mediated activation of the amygdala.

Propagation of cortical spreading depression into the hippocampus: The role of the entorhinal cortex.

Science.gov (United States)

Martens-Mantai, Tanja; Speckmann, Erwin-Josef; Gorji, Ali

2014-07-22

Propagation of cortical spreading depression (CSD) to the subcortical structures could be the underlying mechanism of some neurological deficits in migraine with aura. The entorhinal cortex (EC) as a gray matter bridge between the neocortex and subcortical regions plays an important role in this propagation. In vitro combined neocortex-hippocampus brain slices were used to study the propagation pattern of CSD between the neocortex and the hippocampus. The effects of different compounds as well as tetanic electrical stimulations in the EC on propagation of CSD to the hippocampus were investigated. Repetitive induction of CSD by KCl injection in the somatosensory cortex enhanced the probability of CSD entrance to the hippocampus via EC. Local application of AMPA receptor blocker CNQX and cannabinoid receptor agonist WIN 55212-2 in EC facilitated the propagation of CSD to the hippocampus, whereas application of NMDA receptor blocker APV and GABA A receptor blocker bicuculline in this region reduced the probability of CSD penetration to the hippocampus. Application of tetanic stimulation in EC also facilitated the propagation of CSD entrance to the hippocampus. Our data suggest the importance of synaptic plasticity of EC in filtering the propagation of CSD into subcortical structures and possibly the occurrence of concomitant neurological deficits. Synapse, 2014. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

Enantiopure Indolo[2,3-a]quinolizidines: Synthesis and Evaluation as NMDA Receptor Antagonists

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Nuno A. L. Pereira

2016-08-01

Full Text Available Enantiopure tryptophanol is easily obtained from the reduction of its parent natural amino acid trypthophan (available from the chiral pool, and can be used as chiral auxiliary/inductor to control the stereochemical course of a diastereoselective reaction. Furthermore, enantiopure tryptophanol is useful for the syntheses of natural products or biological active molecules containing the aminoalcohol functionality. In this communication, we report the development of a small library of indolo[2,3-a]quinolizidines and evaluation of their activity as N-Methyl d-Aspartate (NMDA receptor antagonists. The indolo[2,3-a]quinolizidine scaffold was obtained using the following key steps: (i a stereoselective cyclocondensation of (S- or (R-tryptophanol with appropriate racemic δ-oxoesters; (ii a stereocontrolled cyclization on the indole nucleus. The synthesized enantiopure indolo[2,3-a]quinolizidines were evaluated as NMDA receptor antagonists and one compound was identified to be 2.9-fold more potent as NMDA receptor blocker than amantadine (used in the clinic for Parkinson’s disease. This compound represents a hit compound for the development of novel NMDA receptor antagonists with potential applications in neurodegenerative disorders associated with overactivation of NMDA receptors.

Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease.

Science.gov (United States)

Fuwa, Daisuke; Fukuda, Michio; Ogiyama, Yoshiaki; Sato, Ryo; Mizuno, Masashi; Miura, Toshiyuki; Abe-Dohmae, Sumiko; Michikawa, Makoto; Kobori, Hiroyuki; Ohte, Nobuyuki

2016-01-01

Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (t(Na)), although 24-hour urinary Na excretion (U(Na)V) remained constant. Daily urinary angiotensinogen excretion (U(AGT)V, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r(2)=0.26) and t(Na) (r(2)=0.25) correlated with baseline 24-hour U(AGT)V. Changes in filtered Na load correlated with changes in nighttime systolic BP (r(2)=0.17), but not with changes in daytime systolic BP. The change in the t(Na) to filtered Na load ratio was influenced by the change in daytime U(Na)V (β=-0.67, F=16.8), rather than the change in nighttime U(Na)V. Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of U(AGT)V by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events. © The Author(s) 2016.

Aliskiren and valsartan combination therapy for the management of hypertension

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Benjamin J Epstein

2010-08-01

Full Text Available Benjamin J EpsteinDepartments of Pharmacotherapy and Translational Research and Medicine, Colleges of Pharmacy and Medicine, University of Florida, Gainesville, Florida, USA and East Coast Institute for Research, Jacksonville, Florida, USAAbstract: Combination therapy is necessary for most patients with hypertension, and agents that inhibit the renin-angiotensin-aldosterone system (RAAS are mainstays in hypertension management, especially for patients at high cardiovascular and renal risk. Single blockade of the RAAS with an angiotensin-converting enzyme (ACE inhibitor or angiotensin receptor blocker (ARB confers some cardiorenal protection; however, these agents do not extinguish the RAAS as evidenced by a reactive increase in plasma renin activity (PRA, a cardiovascular risk marker, and incomplete cardiorenal protection. Dual blockade with an ACE inhibitor and an ARB offers no additional benefit in patients with hypertension and normal renal and left ventricular function. Indeed, PRA increases synergistically with dual blockade. Aliskiren, the first direct renin inhibitor (DRI to become available has provided an opportunity to study the merit of DRI/ARB combination treatment. By blocking the first and rate-limiting step in the RAAS, aliskiren reduces PRA by at least 70% and buffers the compensatory increase in PRA observed with ACE inhibitors and ARBs. The combination of a DRI and an ARB or an ACE inhibitor is an effective approach for lowering blood pressure; available data indicate that such combinations favorably affect proteinuria, left ventricular mass index, and brain natriuretic peptide in patients with albuminuria, left ventricular hypertrophy, and heart failure, respectively. Ongoing outcome studies will clarify the role of aliskiren and aliskiren-based combination RAAS blockade in patients with hypertension and those at high cardiorenal risk.Keywords: aliskiren, valsartan, single-pill combination, hypertension, renin

Pilot-Reported Beta-Blockers Identified by Forensic Toxicology Analysis of Postmortem Specimens

Science.gov (United States)

2017-01-01

This study compared beta-blockers reported by pilots with the medications found by postmortem toxicology analysis of specimens received from fatal aviation accidents between 1999 and 2015. Several studies have compared drugs using the standard approa...

WE-AB-207A-09: Optimization of the Design of a Moving Blocker for Cone-Beam CT Scatter Correction: Experimental Evaluation

Energy Technology Data Exchange (ETDEWEB)

Chen, X; Ouyang, L; Jia, X; Zhang, Y; Wang, J [UT Southwestern Medical Center, Dallas, TX (United States); Yan, H [Cyber Medical Corporation, Xi’an (China)

2016-06-15

Purpose: A moving blocker based strategy has shown promising results for scatter correction in cone-beam computed tomography (CBCT). Different geometry designs and moving speeds of the blocker affect its performance in image reconstruction accuracy. The goal of this work is to optimize the geometric design and moving speed of the moving blocker system through experimental evaluations. Methods: An Elekta Synergy XVI system and an anthropomorphic pelvis phantom CIRS 801-P were used for our experiment. A blocker consisting of lead strips was inserted between the x-ray source and the phantom moving back and forth along rotation axis to measure the scatter signal. Accoriding to our Monte Carlo simulation results, three blockers were used, which have the same lead strip width 3.2mm and different gap between neighboring lead strips, 3.2, 6.4 and 9.6mm. For each blocker, three moving speeds were evaluated, 10, 20 and 30 pixels per projection (on the detector plane). Scatter signal in the unblocked region was estimated by cubic B-spline based interpolation from the blocked region. CBCT image was reconstructed by a total variation (TV) based algebraic iterative reconstruction (ART) algorithm from the partially blocked projection data. Reconstruction accuracy in each condition is quantified as CT number error of region of interest (ROI) by comparing to a CBCT reconstructed image from analytically simulated unblocked and scatter free projection data. Results: Highest reconstruction accuracy is achieved when the blocker width is 3.2 mm, the gap between neighboring lead strips is 9.6 mm and the moving speed is 20 pixels per projection. RMSE of the CT number of ROIs can be reduced from 436 to 27. Conclusions: Image reconstruction accuracy is greatly affected by the geometry design of the blocker. The moving speed does not have a very strong effect on reconstruction result if it is over 20 pixels per projection.

Bradykinin receptor blockade restores the baroreflex control of renal sympathetic nerve activity in cisplatin-induced renal failure rats.

Science.gov (United States)

Abdulla, M H; Duff, M; Swanton, H; Johns, E J

2016-11-01

This study investigated the effect of renal bradykinin B1 and B2 receptor blockade on the high- and low-pressure baroreceptor reflex regulation of renal sympathetic nerve activity (RSNA) in rats with cisplatin-induced renal failure. Cisplatin (5 mg/kg) or saline was given intraperitoneally 4 days prior to study. Following chloralose/urethane anaesthesia, rats were prepared for measurement of mean arterial pressure (MAP), heart rate and RSNA and received intrarenal infusions of either Lys-[des-Arg 9 , Leu 8 ]-bradykinin (LBK), a bradykinin B1 receptor blocker, or bradyzide (BZ), a bradykinin B2 receptor blocker. RSNA baroreflex gain curves and renal sympatho-inhibitory responses to volume expansion (VE) were obtained. In the control and renal failure groups, basal MAP (89 ± 3 vs. 80 ± 8 mmHg) and RSNA (2.0 ± 0.3 vs. 1.7 ± 0.6 μV.s) were similar but HR was lower in the latter group (331 ± 8 vs. 396 ± 9 beats/min). The baroreflex gain for RSNA in the renal failure rats was 39% (P renal failure rats. Intrarenal LBK infusion in the renal failure rats normalized the VE induced renal sympatho-inhibition whereas BZ only partially restored the response. These findings suggest that pro-inflammatory bradykinin acting at different receptors within the kidney generates afferent neural signals which impact differentially within the central nervous system on high- and low-pressure regulation of RSNA. © 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-γ-dependent activity

International Nuclear Information System (INIS)

Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro; Yasuda, Osamu; Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei; Ogawa, Hisao; Kim-Mitsuyama, Shokei

2011-01-01

Highlights: → Telmisartan, an angiotensin receptor blocker, acts as a partial PPARγ agonist. → The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NFκB activation and TNF α. → PPARγ activity of telmisartan was involved in the normalization of vascular PPARγ downregulation in diabetic mice. → We provided the first evidence indicating that PPARγ activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor γ (PPARγ) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPARγ agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPARγ activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPARγ antagonist), and losartan with no PPARγ activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NFκB) activation and tumor necrosis factor α. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPARγ activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of vascular PPARγ in db/db mice and this effect of telmisartan was cancelled by the coadministration

Nationwide trends in the prescription of beta-blockers and angiotensin-converting enzyme inhibitors after myocardial infarction in Denmark, 1995-2002

DEFF Research Database (Denmark)