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The Cochrane Database of Systematic... Jan 2016Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial in children. However, congestive... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial in children. However, congestive heart failure in children differs from that in adults in terms of characteristics, aetiology, and drug clearance. Therefore, paediatric needs must be specifically investigated. This is an update of a Cochrane review previously published in 2009.
OBJECTIVES
To assess the effect of beta-adrenoceptor-blockers (beta-blockers) in children with congestive heart failure.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS up to November 2015. Bibliographies of identified studies were checked. No language restrictions were applied.
SELECTION CRITERIA
Randomised, controlled, clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted and assessed data from the included trials.
MAIN RESULTS
We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block. A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement with beta-blockers.However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure; heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in meta-analyses.
AUTHORS' CONCLUSIONS
There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future trials.
Topics: Adolescent; Adrenergic beta-Antagonists; Carbazoles; Carvedilol; Child; Child, Preschool; Heart Failure; Humans; Infant; Infant, Newborn; Metoprolol; Propanolamines; Propranolol; Randomized Controlled Trials as Topic
PubMed: 26820557
DOI: 10.1002/14651858.CD007037.pub3 -
Clinical and Translational Science Apr 2022Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been...
Large, observational genetic studies are commonly used to identify genetic factors associated with diseases and disease-related traits. Such cohorts have not been commonly used to identify genetic predictors of drug dosing or concentrations, perhaps because of the heterogeneity in drug dosing and formulation, and the random timing of blood sampling. We hypothesized that large sample sizes relative to traditional pharmacokinetic studies would compensate for this variability and enable the identification of pharmacogenetic predictors of drug concentrations. We performed a cross-sectional, proof-of-concept association study to replicate the well-established association between metoprolol concentrations and CYP2D6 genotype-inferred metabolizer phenotypes in participants from the Montreal Heart Institute Hospital Cohort undergoing metoprolol therapy. Plasma concentrations of metoprolol and α-hydroxymetoprolol (α-OH-metoprolol) were measured in samples collected randomly regarding the previous metoprolol dose. A total of 999 individuals were included. The metoprolol daily dose ranged from 6.25 to 400 mg (mean 84.3 ± 57.1 mg). CYP2D6-inferred phenotype was significantly associated with both metoprolol and α-OH-metoprolol in unadjusted and adjusted models (all p < 10 ). Models for metoprolol daily dose showed consistent results. Our study suggests that randomly drawn blood samples from biobanks can serve as a new approach to discover genetic associations related to drug concentrations and dosing, with potentially broader implications for genomewide association studies on the pharmacogenomics of drug metabolism.
Topics: Cross-Sectional Studies; Cytochrome P-450 CYP2D6; Genotype; Humans; Metoprolol; Phenotype
PubMed: 35122397
DOI: 10.1111/cts.13230 -
Journal of Clinical Pharmacology May 2016The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk... (Clinical Trial)
Clinical Trial
The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker.
Topics: Adrenergic beta-Antagonists; Adult; Cytochrome P-450 CYP2D6; Delayed-Action Preparations; Female; Genotype; Humans; Lactation; Metoprolol; Milk, Human; Postpartum Period; Pregnancy; Young Adult
PubMed: 26461463
DOI: 10.1002/jcph.631 -
British Journal of Clinical Pharmacology Jun 2020CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain. (Meta-Analysis)
Meta-Analysis Review
AIMS
CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain.
METHODS
We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta-analyses were performed on the impact of CYP2D6-inferred phenotypes on heart rate (HR) reduction, diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all-type adverse events and bradycardia.
RESULTS
Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta-analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (P = .017), and of SBP and DBP by 3 mmHg (P = .0048) for PM compared to non-PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4-fold for PM, although significant heterogeneity was observed regarding bradycardia, which limits the scope of this finding.
CONCLUSION
Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6-inferred phenotypes.
Topics: Cytochrome P-450 CYP2D6; Genotype; Humans; Metoprolol; Phenotype; Polymorphism, Genetic
PubMed: 32090368
DOI: 10.1111/bcp.14247 -
Drug and Chemical Toxicology Jul 2022The β-adrenoceptor blockers may have anti-oxidant properties or induce β-arrestin recruitment beyond classical desensitization of receptor/G protein coupling, offering...
The β-adrenoceptor blockers may have anti-oxidant properties or induce β-arrestin recruitment beyond classical desensitization of receptor/G protein coupling, offering potential therapeutic benefits. Here, we investigated the effects of carvedilol, metoprolol and propranolol in an animal model of cisplatin-induced nephrotoxicity. Rats received the β-blockers (3 or 12 mg/kg/day) with or without cisplatin, and kidney function was investigated using renal scintigraphy, histopathology, and serum variables. Metoprolol and propranolol as well as low-dose carvedilol did not alter kidney function, per se. Meanwhile, high-dose carvedilol reduced renal accumulation of Technetium-99m (99mTc)-labeled dimercaptosuccinic acid (99mTc-DMSA) without significant effect on other variables. Furthermore, low-dose carvedilol prevented cisplatin-induced reduction of tracer uptake, but high-dose of this drug aggravated the situation. In this regard, both low and high -doses of carvedilol significantly inhibited cisplatin effects on kidney histology, BUN and creatinine levels. Also, high-dose propranolol inhibited cisplatin adverse effects on radiotracer uptake, histological manifestations, BUN and creatinine levels, while metoprolol failed to cause a notable effect. Taken together, carvedilol and high-dose propranolol may offer potential benefits in cisplatin nephrotoxicity.
Topics: Adrenergic beta-Antagonists; Animals; Carvedilol; Cisplatin; Creatinine; Kidney; Metoprolol; Propranolol; Rats; Technetium Tc 99m Dimercaptosuccinic Acid
PubMed: 33198524
DOI: 10.1080/01480545.2020.1846551 -
Spectrochimica Acta. Part A, Molecular... Nov 2022Metoprolol combined with ivabradine have been determined up to nanogram level simultaneously relied on the synchronous fluorescence spectra. First derivative amplitudes...
Metoprolol combined with ivabradine have been determined up to nanogram level simultaneously relied on the synchronous fluorescence spectra. First derivative amplitudes of the synchronous spectrofluorimetric spectra are recorded at Δλ = 40 nm using ethanol as diluting solvent. Metoprolol can be measured at 286 nm which is the zero-crossing point of ivabradine, and the later can be measured at 296 nm. The calibration plots were found to be linear over the ranges of concentrations: 100.0-1000.0 ng/mL and 10.0-200.0 ng/mL for metoprolol and ivabradine, respectively. Validation of the procedure was performed using the International Council of Harmonization guidelines. Values of LODs were found to be 28.89, 2.80 ng/mL and LOQs were 87.56, 8.49 ng/mL for metoprolol and ivabradine, respectively. As the two drugs are co-administered safely and effectively to reduce heart rate, angina attacks, the current methodology is utilized for the concurrent analysis of them in their single ingredient pharmaceutical preparations, synthetic mixtures, and biological fluids. The designed method, being cost-effective and simple procedure, is the first method for metoprolol and ivabradine simultaneous analysis. The results agreed statistically with the comparison methods.
Topics: Fluorometry; Ivabradine; Metoprolol; Spectrometry, Fluorescence
PubMed: 35717932
DOI: 10.1016/j.saa.2022.121482 -
Physiological Reports Mar 2020Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as β-blockers....
PURPOSE
Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as β-blockers. β-blocker efficacy is heterogenous, with second generation β-blocker metoprolol selectively inhibiting β -AR, while third generation β-blocker carvedilol has α -AR inhibition, antioxidant, and anti-apoptotic actions alongside nonselective β-AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction.
METHODS
Echocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol.
RESULTS
Patients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between β-blockers. Both β-blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function.
CONCLUSIONS
Metoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats.
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Animals; Carvedilol; Coronary Artery Bypass; Diabetes Mellitus, Type 2; Disease Models, Animal; Female; Heart; Humans; Male; Metoprolol; Middle Aged; Rats, Zucker; Treatment Outcome
PubMed: 32170823
DOI: 10.14814/phy2.14394 -
British Journal of Pharmacology Feb 2023Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage....
BACKGROUND AND PURPOSE
Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil β adrenoceptors (β1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that β1AR blockade will improve stroke outcomes.
EXPERIMENTAL APPROACH
Rats were subjected to middle cerebral artery occlusion-reperfusion to evaluate the effect on stroke of the selective β1AR blocker metoprolol (12.5 mg·kg ) when injected i.v. 10 min before reperfusion.
KEY RESULTS
Magnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1 ). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via β1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil-depleted rats upon stroke. In patients suffering an ischaemic stroke, β1AR blockade by metoprolol reduced circulating neutrophil-platelet co-aggregates.
CONCLUSIONS AND IMPLICATIONS
Our findings describe that β1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored.
Topics: Rats; Animals; Metoprolol; Neutrophils; Neuroinflammatory Diseases; Brain Ischemia; Stroke; Ischemic Stroke; Receptors, Adrenergic
PubMed: 36181002
DOI: 10.1111/bph.15963 -
CPT: Pharmacometrics & Systems... Dec 2020Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from... (Clinical Trial)
Clinical Trial Comparative Study
Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.
Topics: Administration, Oral; Adrenergic beta-1 Receptor Antagonists; Adult; Aged; Blood Pressure; Cytochrome P-450 CYP2D6; Female; Genotype; Heart Rate; Humans; Male; Metoprolol; Middle Aged; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; Prospective Studies
PubMed: 33067866
DOI: 10.1002/psp4.12563 -
Journal of Veterinary Pharmacology and... Mar 2022Cardiac drugs with defined pharmacological parameters in horses are limited. The objective of this study was to characterize the pharmacokinetic properties and...
Cardiac drugs with defined pharmacological parameters in horses are limited. The objective of this study was to characterize the pharmacokinetic properties and cardiovascular effects of intravenous and oral metoprolol tartrate (MET) in horses. In a 2-period randomized cross-over design, MET was administered IV (0.04 mg/kg) and PO (6 mg/kg) once to six healthy adult horses. Horses were monitored via continuous telemetry and non-invasive blood pressure (NIBP). Blood samples were serially collected for 72 h post-administration, and concentrations were determined by LC-MS/MS. Pharmacokinetics were modeled using a 3-compartment model and non-linear least squares regression. Median (range) MET concentration was 110 (40.1-197) ng/ml collected 1 min (0.0167 h) after a bolus IV administration. Maximum concentration (C ) after PO administration was 2135 (1590-4170) ng/ml at 0.5 (0.25-0.5) hours. Oral bioavailability was 54% (17-100%). Median apparent volume of distribution was 0.39 (0.17-0.58) l/kg, clearance was 12.63 (11.41-18.94) ml/kg/min, and elimination half-life was 21.1 (7.46-34.36) minutes. No clinically relevant effects of IV or PO metoprolol were noted on cardiac rhythm or NIBP. Sweating was the most common side effect. The metoprolol doses used in this study achieve plasma concentrations reported to achieve ß-blockade in humans.
Topics: Administration, Oral; Animals; Area Under Curve; Chromatography, Liquid; Cross-Over Studies; Half-Life; Horses; Injections, Intravenous; Metoprolol; Tandem Mass Spectrometry
PubMed: 34913168
DOI: 10.1111/jvp.13037