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Scientific Reports Nov 2023Low dose aspirin is routinely taken with antihypertensive drugs such as olmesartan and metoprolol to avoid the cardiovascular and renal outcomes associated with high...
Low dose aspirin is routinely taken with antihypertensive drugs such as olmesartan and metoprolol to avoid the cardiovascular and renal outcomes associated with high blood pressure. The first spectrofluorimetric method for quantifying aspirin, olmesartan, and metoprolol in spiked human plasma is described here. The emission/excitation wavelengths of Aspirin, olmesartan, and metoprolol were 404 nm/290 nm, 372 nm/250 nm, and 302 nm/230 nm, respectively. The native fluorescence spectra of metoprolol do not overlap with those of aspirin or olmesartan, although the spectra of aspirin and olmesartan overlap. As a result, metoprolol could be measured directly in a mixture at 302 nm following excitation at 230 nm. Using synchronous fluorescence spectrometry at Δλ = 110 allowed for the determination of olmesartan at 364 nm with no interference from aspirin and metoprolol. Coupling the synchronous fluorescence spectrometry with second-order derivative allowed for the determination of aspirin at 426 nm with no interference from olmesartan and metoprolol. The suggested approach has been validated using ICH M10 criteria for bioanalytical method validation and was effectively utilized for quantification of tested medications in human plasma with reasonable accuracy and precision findings. Furthermore, using two greenness metrics, the Green Analytical Procedure Index and the Analytical GREEnness, the suggested method obtained a high greenness score.
Topics: Humans; Metoprolol; Aspirin; Spectrometry, Fluorescence; Antihypertensive Agents
PubMed: 37978204
DOI: 10.1038/s41598-023-46042-x -
International Journal of Molecular... Sep 2023Cardiac K4.3 channels contribute to the transient outward K current, I, during early repolarization of the cardiac action potential. Two different isoforms of K4.3 are...
Cardiac K4.3 channels contribute to the transient outward K current, I, during early repolarization of the cardiac action potential. Two different isoforms of K4.3 are present in the human ventricle and exhibit differential remodeling in heart failure (HF). Cardioselective betablockers are a cornerstone of HF with reduced ejection fraction therapy as well as ventricular arrhythmia treatment. In this study we examined pharmacological effects of betablockers on both K4.3 isoforms to explore their potential for isoform-specific therapy. K4.3 isoforms were expressed in Xenopus oocytes and incubated with the respective betablockers. Dose-dependency and biophysical characteristics were examined. HEK 293T-cells were transfected with the two K4.3 isoforms and analyzed with Western blots. Carvedilol (100 µM) blocked K4.3 L by 77 ± 2% and K4.3 S by 67 ± 6%, respectively. Metoprolol (100 µM) was less effective with inhibition of 37 ± 3% (K4.3 L) and 35 ± 4% (K4.3 S). Bisoprolol showed no inhibitory effect. Current reduction was not caused by changes in K4.3 protein expression. Carvedilol inhibited K4.3 channels at physiologically relevant concentrations, affecting both isoforms. Metoprolol showed a weaker blocking effect and bisoprolol did not exert an effect on K4.3. Blockade of repolarizing K4.3 channels by carvedilol and metoprolol extend their pharmacological mechanism of action, potentially contributing beneficial antiarrhythmic effects in normal and failing hearts.
Topics: Humans; Metoprolol; Bisoprolol; Carvedilol; Heart; Heart Failure; Protein Isoforms
PubMed: 37762145
DOI: 10.3390/ijms241813842 -
Pharmacology Research & Perspectives Oct 2023Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by...
Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.
Topics: Adult; Humans; Amiodarone; Heart Rate; Cross-Sectional Studies; Metoprolol; Bradycardia; Cytochrome P-450 CYP2D6
PubMed: 37732835
DOI: 10.1002/prp2.1137 -
Environmental Science & Technology Mar 2023The increasing use of chiral pharmaceuticals has led to their widespread presence in the environment. However, their toxicokinetics have rarely been reported. Therefore,...
The increasing use of chiral pharmaceuticals has led to their widespread presence in the environment. However, their toxicokinetics have rarely been reported. Therefore, the tissue-specific uptake and depuration kinetics of two pairs of pharmaceutical enantiomers, -(-)-metoprolol versus -(+)-metoprolol and -(+)-venlafaxine versus -(-)-venlafaxine, were studied in marine medaka () during a 28-day exposure and 14-day clearance period. The toxicokinetics of the studied pharmaceuticals, including uptake and depuration rate constants, depuration half-life (), and bioconcentration factor (BCF), were reported for the first time. The whole-fish results demonstrated a higher - than -venlafaxine bioaccumulation potential, whereas no significant difference was observed between - and -metoprolol. -desmethyl-metoprolol (ODM) and α-hydroxy-metoprolol (AHM) were the main metoprolol metabolites identified by suspect screening, and the ratios of ODM to AHM were 3.08 and 1.35 for - and -metoprolol, respectively. ,-Didesmethyl-venlafaxine (NODDV) and -desmethyl-venlafaxine (NDV) were the main venlafaxine metabolites, and the ratios of NODDV to NDV were 1.55 and 0.73 for - and -venlafaxine, respectively. The highest tissue-specific BCFs of the four enantiomers were all found in the eyes, meriting in-depth investigation.
Topics: Animals; Venlafaxine Hydrochloride; Oryzias; Metoprolol; Tissue Distribution; Pharmaceutical Preparations
PubMed: 36877486
DOI: 10.1021/acs.est.2c08379 -
Journal of the American Society of... Feb 2023Patients with obstructive hypertrophic cardiomyopathy (HCM) often experience symptoms of heart failure upon exertion despite having normal left ventricular (LV) ejection... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with obstructive hypertrophic cardiomyopathy (HCM) often experience symptoms of heart failure upon exertion despite having normal left ventricular (LV) ejection fractions. Longitudinal strain (LS) may be a more sensitive marker of systolic dysfunction in patients with LV hypertrophy. The aims of this study were to characterize LV segmental LS and global LS (GLS) at rest and during exercise and to assess if first-line treatment with β-blockers improves LV systolic performance.
METHODS
Twenty-nine patients with obstructive HCM and New York Heart Association functional class ≥ II symptoms were enrolled in a double-blind, placebo-controlled, randomized crossover trial. Patients received metoprolol 150 mg or placebo for two consecutive 2-week periods in random order. Echocardiographic assessment with speckle-tracking-derived LS was performed at rest and during peak exercise at the end of each treatment period.
RESULTS
During placebo treatment, resting values of segmental LS showed an apical-basal difference of -10.3% (95% CI, -12.7% to -7.8%; P < .0001), with a severely abnormal value of the basal segment of -9.3 ± 4.2%. Treatment with metoprolol was associated with more negative LS values of the apical segment (-2.8%; 95% CI, -4.2% to -1.3%; P < .001) and the mid segment (-1.1%; 95% CI, -2.0% to -0.3%; P = .007). During peak exercise there was a deterioration in LV GLS, but treatment with metoprolol was associated with more negative peak exercise LV GLS (-1.3 %; 95% CI, -2.6% to -0.1%; P = .03).
CONCLUSIONS
Systolic performance assessed by LV GLS showed impaired values at rest and during exercise, with severely depressed values of the basal and mid segments. Treatment with metoprolol improved LV GLS upon exercise, indicating a beneficial effect of β-blocker treatment on LV systolic function.
Topics: Humans; Metoprolol; Cardiomyopathy, Hypertrophic; Heart Ventricles; Echocardiography; Ventricular Function, Left; Adrenergic beta-Antagonists; Ventricular Dysfunction, Left
PubMed: 36444740
DOI: 10.1016/j.echo.2022.09.008 -
Aesthetic Plastic Surgery Aug 2023The aim of this study was to evaluate the effect of different metoprolol doses on fat graft survival.
AIM
The aim of this study was to evaluate the effect of different metoprolol doses on fat graft survival.
MATERIAL AND METHOD
A total of 10 Sprague-Dawley rats were used in the study. The dorsal regions of the rats were separated into four quadrants: right and left cranial, and right and left caudal. Each quadrant was determined as a separate group. Fat grafts were harvested from the groin areas and incubated in 5 ml solutions containing 0.9% sodium chloride (control group), 1 mg/mL metoprolol (Group 1), 2 mg/mL metoprolol (Group 2), and 3 mg/mL metoprolol (Group 3), respectively. The fat grafts were then placed in pockets dissected in each of the 4 dorsal quadrants. After 3 months all the rats were euthanized. The fat grafts were removed together with the surrounding area to which they had passed. Histopathological examination was made with hematoxylin and eosin (HE) and Masson Trichrome staining, and immunohistochemical examination with fibroblast growth factor-2 and perilipin staining.
RESULTS
In the examinations made with HE and Masson Trichrome staining, the scores of Group 2 and Group 3 were determined to be significantly higher than those of the control group (p < 0.05). The Group 3 scores were significantly higher than those of Group 1 (p < 0.05). In the examinations made with fibroblast growth factor-2 staining, the scores of Group 2 and Group 3 were determined to be significantly higher than those of the control group (p < 0.05). The Group 3 scores were significantly higher than those of Group 1 and Group 2 (p < 0.05). In the examinations made with perilipin staining, the scores in Groups 1, 2, and 3 were higher than those of the control group (p < 0.05).
CONCLUSION
Although metoprolol has previously been shown to prolong the survival of fat grafts, the results of this study demonstrated immunohistochemically that as the metoprolol dose increased, so the quality and vitality of fat graft also increased.
NO LEVEL ASSIGNED
This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Topics: Rats; Animals; Rats, Sprague-Dawley; Metoprolol; Graft Survival; Fibroblast Growth Factor 2; Perilipins
PubMed: 36811670
DOI: 10.1007/s00266-023-03271-9 -
Current Drug Metabolism 2022Astragaloside IV (AST) and metoprolol are often used together to treat cardiovascular diseases, while the herb-drug interaction (HDI) between them is still unclear.
BACKGROND
Astragaloside IV (AST) and metoprolol are often used together to treat cardiovascular diseases, while the herb-drug interaction (HDI) between them is still unclear.
OBJECTIVE
This study investigates the effect of AST on the pharmacokinetics of metoprolol in rats and its mechanism to predict the HDI.
METHOD
First, IC50 value of AST on nine CYP450 enzymes in human liver microsomes (HLMs) was determined by the cocktail method. We explored the effect of AST on the pharmacokinetics of metoprolol (metabolized by CYP2D6) in vivo. Twelve male SD rats were equally divided into two groups, with or without pretreatment of AST (3 mg/kg/day) for 7 days, and they received metoprolol (27 mg/kg) by oral administration. Blood samples were determined using HPLC. Finally, the mechanism of AST was explored.
RESULTS
AST exhibited a moderate inhibitory effect on CYP2D6 with IC value of 32.28 μM. The pharmacokinetic parameters of metoprolol were significantly altered by AST with the increase of AUC (538.81 ± 51.41 to 1088.34 ± 86.46 μg*min/mL, P<0.05) and C (6.21 ± 0.56 to 8.34 ± 0.87 μg/ml, P<0.05). The investigation of the mechanism showed AST to be an irreversible inhibitor of CYP2D6 with K value of 2.9 μM and K of 0.018 min, respectively.
CONCLUSION
AST was found to increase the plasma exposure of metoprolol in rats. AST reduced the metabolism of metoprolol by inhibiting CYP2D6 activity. The HDI might enhance when metoprolol and AST will be applied in combination.
Topics: Animals; Area Under Curve; Cytochrome P-450 CYP2D6; Herb-Drug Interactions; Male; Metoprolol; Rats; Rats, Sprague-Dawley; Saponins; Triterpenes
PubMed: 35088663
DOI: 10.2174/1389200223666220128143133 -
Clinical Cardiology Oct 2022This meta-analysis aims to look at the impact of early intravenous Metoprolol in ST-segment elevation myocardial infarction (STEMI) before percutaneous coronary... (Meta-Analysis)
Meta-Analysis Review
Effect of early metoprolol before PCI in ST-segment elevation myocardial infarction on infarct size and left ventricular ejection fraction. A systematic review and meta-analysis of clinical trials.
AIM
This meta-analysis aims to look at the impact of early intravenous Metoprolol in ST-segment elevation myocardial infarction (STEMI) before percutaneous coronary intervention (PCI) on infarct size, as measured by cardio magnetic resonance (CMR) and left ventricular ejection fraction.
METHODS
We searched the following databases: PubMed, Scopus, Cochrane library, and Web of Science. We included only randomized control trials that reported the use of early intravenous Metoprolol in STEMI before PCI on infarct size, as measured by CMR and left ventricular ejection fraction. RevMan software 5.4 was used for performing the analysis.
RESULTS
Following a literature search, 340 publications were found. Finally, 18 studies were included for the systematic review, and 8 clinical trials were included in the meta-analysis after the full-text screening. At 6 months, the pooled effect revealed a statistically significant association between Metoprolol and increased left ventricular ejection fraction (LVEF) (%) compared to controls (mean difference [MD] = 3.57, [95% confidence interval [CI] = 2.22-4.92], p < .00001), as well as decreased infarcted myocardium(g) compared to controls (MD = -3.84, [95% [CI] = -5.75 to -1.93], p < .0001). At 1 week, the pooled effect revealed a statistically significant association between Metoprolol and increased LVEF (%) compared to controls (MD = 2.98, [95% CI = 1.26-4.69], p = .0007), as well as decreased infarcted myocardium(%) compared to controls (MD = -3.21, [95% CI = -5.24 to -1.18], p = .002).
CONCLUSION
A significant decrease in myocardial infarction and increase in LVEF (%) was linked to receiving Metoprolol at 1 week and 6-month follow-up.
Topics: Humans; Metoprolol; Myocardial Infarction; Percutaneous Coronary Intervention; ST Elevation Myocardial Infarction; Stroke Volume; Ventricular Function, Left
PubMed: 36040709
DOI: 10.1002/clc.23894 -
Clinical and Translational Science May 2023Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied...
Females present a higher risk of adverse drug reactions. Sex-related differences in drug concentrations may contribute to these observations but they remain understudied given the underrepresentation of females in clinical trials. The aim of this study was to investigate whether anthropometric and socioeconomic factors and comorbidities could explain sex-related differences in concentrations and dosing for metoprolol and oxypurinol, the active metabolite of allopurinol. We conducted an analysis of two cross-sectional studies. Participants were self-described "White" adults taking metoprolol or allopurinol selected from the Montreal Heart Institute Hospital Cohort. A total of 1007 participants were included in the metoprolol subpopulation and 459 participants in the allopurinol subpopulation; 73% and 86% of the participants from the metoprolol and allopurinol subpopulations were males, respectively. Females presented higher age- and dose-adjusted concentrations of both metoprolol and oxypurinol (both p < 0.03). Accordingly, females presented higher unadjusted and age-adjusted concentration:dose ratio of both metoprolol and allopurinol/oxypurinol compared to males (all p < 3.0 × 10 ). Sex remained an independent predictor of metoprolol concentrations (p < 0.01), but not of oxypurinol concentrations, after adjusting for other predictors. In addition to sex, age, daily dose, use of moderate to strong CYP2D6 inhibitors, weight, and CYP2D6 genotype-inferred phenotype were associated with concentrations of metoprolol (all p < 0.01). Daily dose, weight, estimated glomerular filtration rate (eGFR), and employment status were associated with oxypurinol concentrations (all p < 0.01). Females present higher dose-adjusted concentrations of metoprolol and oxypurinol than males. This suggests the need for sex-specific dosing requirements for these drugs, although this hypothesis should be validated in prospective studies.
Topics: Male; Female; Animals; Allopurinol; Oxypurinol; Metoprolol; Prospective Studies; Cross-Sectional Studies; Dose-Response Relationship, Drug
PubMed: 36864560
DOI: 10.1111/cts.13497 -
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