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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 -
Oxidative Medicine and Cellular... 2022The harm of heart failure mainly causes patients to develop dyspnea, fatigue, fluid retention, and other symptoms, which impair patients' activity tolerance and lead to...
The harm of heart failure mainly causes patients to develop dyspnea, fatigue, fluid retention, and other symptoms, which impair patients' activity tolerance and lead to a dramatic decrease in patients' quality of life. The purpose of this study was to verify whether metoprolol regulates AKAP5 expression and test the role of AKAP5 postinjury in mitigating cardiac infarction-associated tissue remodeling and fibrosis. Sprague-Dawley (SD) rats underwent coronary artery ligation (CAL), which was followed immediately with metoprolol daily. And western blot and coimmunoprecipitation experiments were performed to detect the expression of related proteins in the sham-operated group, model group, and drug-treated group. HW/BW ratio and cardiac expression of COL1 and COL3 were increased in rats following CAL compared with shams. Treatment with metoprolol postinjury was associated with a decrease in HW/BW ratio and COL1/COL3 expression compared to uncontrolled rats. CAL resulted in decreased cardiac AKAP5 expression compared to the control group, while metoprolol treatment restored levels compared to baseline shams. Cardiac expression levels of NFATc3/p-NFATc3 and GATA4 were modest at baseline and increased with injury, whereas metoprolol suppressed gene expression to below injury-associated changes. Immunoprecipitation indicated that AKAP5 could bind and regulate PP2B. In summary, we know that metoprolol alleviates ischemic cardiac remodeling and fibrosis, and the mechanism of alleviating remodeling may improve cardiac AKAP5 expression and AKAP5-PP2B interaction.
Topics: A Kinase Anchor Proteins; Animals; Fibrosis; Heart; Heart Failure; Metoprolol; Quality of Life; Rats; Rats, Sprague-Dawley
PubMed: 36238650
DOI: 10.1155/2022/5993459 -
Journal of the American College of... Apr 2006
Review
Topics: Adrenergic beta-Antagonists; Carbazoles; Cardiac Output, Low; Carvedilol; Humans; Metoprolol; Propanolamines; Quality of Life
PubMed: 16630998
DOI: 10.1016/j.jacc.2006.01.054 -
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 -
Molecules (Basel, Switzerland) May 2021Pharmaceuticals are found in waterbodies worldwide. Conventional sewage treatment plants are often not able to eliminate these micropollutants. Hence, Advanced Oxidation...
Pharmaceuticals are found in waterbodies worldwide. Conventional sewage treatment plants are often not able to eliminate these micropollutants. Hence, Advanced Oxidation Processes (AOPs) have been heavily investigated. Here, metoprolol is exposed to UV irradiation, hydrogen peroxide, and ozonation. Degradation was analyzed using chemical kinetics both for initial and secondary products. Photo-induced irradiation enhanced by hydrogen peroxide addition accelerated degradation more than ozonation, leading to complete elimination. Degradation and transformation products were identified by high-performance liquid-chromatography coupled to high-resolution higher-order mass spectrometry. The proposed structures allowed to apply Quantitative Structure-Activity Relationship (QSAR) analysis to predict ecotoxicity. Degradation products were generally associated with a lower ecotoxicological hazard to the aquatic environment according to OECD QSAR toolbox and VEGA. Comparison of potential structural isomers suggested forecasts may become more reliable with larger databases in the future.
Topics: Algorithms; Bioreactors; Chromatography, High Pressure Liquid; Ecotoxicology; Environmental Monitoring; Hydrogen Peroxide; Hydrogen-Ion Concentration; Kinetics; Metoprolol; Oxygen; Ozone; Photochemistry; Photolysis; Quantitative Structure-Activity Relationship; Sewage; Software; Ultraviolet Rays; Wastewater; Water Pollutants, Chemical
PubMed: 34067394
DOI: 10.3390/molecules26113102 -
British Journal of Clinical Pharmacology Nov 2015The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after... (Clinical Trial)
Clinical Trial Comparative Study
AIMS
The aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB.
METHODS
A single-dose pharmacokinetic study of metoprolol tartrate 200 mg immediate release and controlled release was performed in 14 volunteers before and 6-8 months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB.
RESULTS
After administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24 h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24 h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity.
CONCLUSIONS
The disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation.
Topics: Administration, Oral; Adult; Biological Availability; Computer Simulation; Delayed-Action Preparations; Female; Gastric Bypass; Humans; Male; Metoprolol; Models, Biological
PubMed: 25917170
DOI: 10.1111/bcp.12666 -
Acta Medica Indonesiana 2007The prognosis remains poor for many patients with congestive heart failure, despite maximal medical treatment with ACE inhibitor, diuretics and digitalis. In heart... (Review)
Review
The prognosis remains poor for many patients with congestive heart failure, despite maximal medical treatment with ACE inhibitor, diuretics and digitalis. In heart failure, activation of sympathetic nervous system has been described as one of the most important pathophysiologic abnormalities in patients with congestive heart failure and as one of the most important mechanisms that may be responsible for progression of heart failure. The use of beta blockers which may inhibit sympathetic activity, might reduce the risk of disease progression in heart failure, improve symptoms and increase survival. Several large clinical trials with metoprolol, carvedilol and bisoprolol have shown that long term use of these agents can improve left ventricular function and symptoms of CHF, it may also reduce hospital readmission and decrease mortality. Current guidelines recommend the use of beta blocker in mild, moderate and severe CHF, in the absence of contraindications or tolerance in combination with ACE inhibitor and diuretics. Beta blocker should be initiated in patients after maximal medical therapy with diuretics, ACE inhibitor and digitalis and patients already stabilized and in compensated conditions. Beta blocker should be started in low doses and require slow titration over weeks or months before patients can attain maintenance doses.
Topics: Adrenergic beta-Antagonists; Bisoprolol; Carbazoles; Carvedilol; Heart Failure; Heart Ventricles; Humans; Metoprolol; Prognosis; Propanolamines
PubMed: 17297209
DOI: No ID Found -
Biomolecules Aug 2022De novo sterol synthesis is a critical homeostatic mechanism in the brain that begins during early embryonic development and continues throughout life. Multiple...
De novo sterol synthesis is a critical homeostatic mechanism in the brain that begins during early embryonic development and continues throughout life. Multiple medications have sterol-biosynthesis-inhibiting side effects, with potentially detrimental effects on brain health. Using LC-MS/MS, we investigated the effects of six commonly used beta-blockers on brain sterol biosynthesis in vitro using cell lines. Two beta-blockers, metoprolol (MTP) and nebivolol, showed extreme elevations of the highly oxidizable cholesterol precursor 7-dehydrocholesterol (7-DHC) in vitro across multiple cell lines. We followed up on the MTP findings using a maternal exposure model in mice. We found that 7-DHC was significantly elevated in all maternal brain regions analyzed as well as in the heart, liver and brain of the maternally exposed offspring. Since DHCR7-inhibiting/7-DHC elevating compounds can be considered teratogens, these findings suggest that MTP utilization during pregnancy might be detrimental for the development of offspring, and alternative beta-blockers should be considered.
Topics: Animals; Brain; Cholesterol; Chromatography, Liquid; Female; Metoprolol; Mice; Nebivolol; Oxidoreductases Acting on CH-CH Group Donors; Pregnancy; Tandem Mass Spectrometry; Teratogens
PubMed: 36139049
DOI: 10.3390/biom12091211 -
Arquivos Brasileiros de Cardiologia Jan 2021Image quality and radiation dose are optimized with a slow, steady heart rate (HR) when imaging the coronary arteries during cardiac computed tomography angiography...
BACKGROUND
Image quality and radiation dose are optimized with a slow, steady heart rate (HR) when imaging the coronary arteries during cardiac computed tomography angiography (CCTA). The safety, efficacy, and protocol for HR reduction with beta blocker medication is not well described in a pediatric patient population.
OBJECTIVE
Provide a safe and efficient metoprolol dose protocol to be used in pediatric outpatients undergoing CCTA.
METHODS
We conducted a retrospective review of all pediatric outpatients who received metoprolol during CCTA. Demographic and clinical characteristics were summarized and the average reduction in HR was estimated using a multivariate linear regression model. Images were evaluated on a 1-4 scale (1= optimal).
RESULTS
Seventy-eight pediatric outpatients underwent a CCTA scan with the use of metoprolol. The median age was 13 years, median weight of 46 kg, and 36 (46%) were male. The median doses of metoprolol were 1.5 (IQR 1.1, 1.8) mg/kg and 0.4 (IQR 0.2, 0.7) mg/kg for oral and intravenous administrations, respectively. Procedural dose-length product was 57 (IQR 30, 119) mGy*cm. The average reduction in HR was 19 (IQR 12, 26) beats per minute, or 23%. No complications or adverse events were reported.
CONCLUSION
Use of metoprolol in a pediatric outpatient setting for HR reduction prior to CCTA is safe and effective. A metoprolol dose protocol can be reproduced when a slower HR is needed, ensuring faster acquisition times, clear images, and associated reduction in radiation exposure in this population. (Arq Bras Cardiol. 2021; 116(1):100-105).
Topics: Adolescent; Child; Computed Tomography Angiography; Coronary Angiography; Coronary Artery Disease; Heart Rate; Humans; Male; Metoprolol; Outpatients; Radiation Dosage; Retrospective Studies
PubMed: 33566972
DOI: 10.36660/abc.20190892 -
Molecular Genetics and Metabolism Apr 2020Eliglustat is an oral substrate reduction therapy indicated for patients with Gaucher disease type 1. Based on in vitro data, clinical trials were conducted to assess... (Randomized Controlled Trial)
Randomized Controlled Trial
Eliglustat is an oral substrate reduction therapy indicated for patients with Gaucher disease type 1. Based on in vitro data, clinical trials were conducted to assess the potential for drug-drug interactions between eliglustat and digoxin (P-glycoprotein substrate), metoprolol (sensitive CYP2D6 substrate), a combined oral contraceptive (CYP3A substrate), and acid-reducing agents. Healthy subjects were enrolled in four Phase 1 clinical studies to evaluate the effect of eliglustat on the pharmacokinetics, safety, and tolerability of digoxin (N = 28), metoprolol (N = 14), and a combined oral contraceptive (N = 30) and the effect of acid-reducing agents on eliglustat pharmacokinetics, safety, and tolerability (N = 24). Coadministration resulted in increased exposure to digoxin (1.49-fold) and metoprolol (2-fold) with eliglustat, negligible effects on oral contraceptive pharmacokinetics with eliglustat, and a negligible effect of acid-reducing agents on eliglustat pharmacokinetics. Across all studies, eliglustat was well-tolerated. One serious adverse event (spontaneous abortion) and one discontinuation due to an adverse event (urinary tract infection) were reported, both during the acid-reducing agents study. When eliglustat is coadministered with medications that are P-glycoprotein or CYP2D6 substrates, lower doses of these concomitant medications may be required. Eliglustat may be coadministered with oral contraceptives and acid-reducing agents without dose modifications for either drug.
Topics: Adolescent; Adult; Contraceptives, Oral; Cross-Over Studies; Digoxin; Drug Interactions; Female; Humans; Male; Metoprolol; Middle Aged; Proton Pump Inhibitors; Pyrrolidines; Young Adult
PubMed: 32029355
DOI: 10.1016/j.ymgme.2020.01.001