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The Science of the Total Environment Dec 2023The incidence of diseases of affluence, such as diabetes mellitus, cardiovascular diseases, high blood pressure, and high cholesterol has been reported to rise....
The incidence of diseases of affluence, such as diabetes mellitus, cardiovascular diseases, high blood pressure, and high cholesterol has been reported to rise. Consequently, the concentrations of residues of drugs designed to treat these diseases have been rising in water bodies. Moreover, the toxicity of these pharmaceuticals towards fish and other non-target organisms can be even enhanced by microplastic particles that are reportedly present in surface water. Therefore, the aim of this study was to describe the effects of three highly prescribed drugs, in particular metoprolol, enalapril, and metformin on fish early-life stages. Also, it was hypothesized that polystyrene microparticles will increase the toxicity of metoprolol to fish early-life stages. Embryonal acute toxicity tests on Danio rerio and Cyprinus carpio were carried out in order to describe the possible toxic effects of metoprolol, enalapril, and metformin. Also, the acute toxicity of polystyrene microparticles and the combination of metoprolol with polystyrene microparticles were tested on D. rerio embryos. Additionally, a 31-day long embryo-larval subchronic toxicity test was carried out with C. carpio in order to describe the long-term effects of low concentrations of metoprolol. The results of the study show that both metoprolol and enalapril have the potential to disrupt the early development of the heart in the embryonal stages of fish. Also, enalapril and metformin together with polystyrene microparticles seem to possibly disrupt the reproduction cycle and act as endocrine disruptors. Both pure polystyrene microparticles and the combination of them with metoprolol affect inflammatory processes in organisms. Additionally, metformin alters several metabolism pathways in fish early-life stages. The results of the study bring new evidence that even low, environmentally-relevant concentrations of pharmaceuticals have the potential to disrupt the early development of fish, particularly on a molecular level.
Topics: Animals; Metoprolol; Microplastics; Carps; Plastics; Polystyrenes; Zebrafish; Enalapril; Metformin; Water; Pharmaceutical Preparations; Water Pollutants, Chemical
PubMed: 37595903
DOI: 10.1016/j.scitotenv.2023.166378 -
Heart & Lung : the Journal of Critical... 2024COVID patients continue to experience unremitting symptoms that extend far beyond the initial illness. While there is rapid accumulation of data on acute COVID treatment...
BACKGROUND
COVID patients continue to experience unremitting symptoms that extend far beyond the initial illness. While there is rapid accumulation of data on acute COVID treatment in hospitalized patients, little is known regarding post-COVID management.
OBJECTIVES
To describe our center's experience treating post-COVID sub-syndromes encountered in Post-COVID Lung Clinic.
METHODS
We retrospectively reviewed data on 98 post-COVID patients evaluated in our clinic between 07/01/2020-12/31/2022. We encountered three distinct post-COVID subtypes: 1) respiratory complaints associated with increased O2 requirements and abnormal CT findings (post-COVID interstitial lung disease [ILD]), 2) respiratory complaints associated with tachycardia (post-COVID dyspnea-tachycardia syndrome [DTS]). Post-COVID ILD patients (n = 28) received steroids in combination with cell cycle inhibitor (mycophenolate mofetil-MMF). Post-COVID DTS patients (n = 16) were treated with metoprolol. 3) A third, undifferentiated group presented with mild respiratory complaints and normal spirometry (n = 17) and was followed in clinic without initiation of a specific treatment.
RESULTS
In treated post-COVID ILD patients, mean oxygen requirements at rest (1.96 ± 1.79 L/NC) decreased to 0.89 ± 1.29 L/NC at 6 months follow-up, p = 0.005. In patients with post-COVID DTS, mean heart rate at rest decreased (98 ± 15 bpm to 79 ± 11 bpm) at 6 months follow-up, p = 0.023. 60 % of patients reported an improvement in exertional dyspnea.
CONCLUSIONS
Our descriptive study presents a single center outpatient COVID-19 clinic experience. We encountered 3 post-COVID sub-syndromes and describe their treatments: post-COVID interstitial lung disease [ILD] treated with a novel regimen of MMF and steroids, post COVID dyspnea-tachycardia syndrome [DTS] treated with metoprolol, and a third subgroup with mild undifferentiated symptoms without specific treatment.
Topics: Humans; COVID-19; Male; Female; Retrospective Studies; Middle Aged; Aged; Dyspnea; SARS-CoV-2; Lung Diseases, Interstitial; Ambulatory Care; Tachycardia; Post-Acute COVID-19 Syndrome; Metoprolol
PubMed: 38759575
DOI: 10.1016/j.hrtlng.2024.05.004 -
Fundamental & Clinical Pharmacology Feb 2024Catecholamines and β-adrenergic receptors (β-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This... (Review)
Review
The role of β-adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do β-adrenergic receptor agonists and antagonists protect the heart?
BACKGROUND
Catecholamines and β-adrenergic receptors (β-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This systematic review analyzed the molecular mechanisms of the cardioprotective activity of β-AR ligands.
METHODS
We performed an electronic search of topical articles using PubMed databases from 1966 to 2023. We cited original in vitro and in vivo studies and review articles that documented the cardioprotective properties of β-AR agonists and antagonists.
RESULTS
The infarct-reducing effect of β-AR antagonists did not depend on a decrease in the heart rate. The target for β-blockers is not only cardiomyocytes but also neutrophils. β1-blockers (metoprolol, propranolol, timolol) and the selective β2-AR agonist arformoterol have an infarct-reducing effect in coronary artery occlusion (CAO) in animals. Antagonists of β1- and β2-АR (metoprolol, propranolol, nadolol, carvedilol, bisoprolol, esmolol) are able to prevent reperfusion cardiac injury. All β-AR ligands that reduced infarct size are the selective or nonselective β1-blockers. It was hypothesized that β1-AR blocking promotes an increase in cardiac tolerance to I/R. The activation of β1-AR, β2-AR, and β3-AR can increase cardiac tolerance to I/R. The cardioprotective effect of β-AR agonists is mediated via the activation of kinases and reactive oxygen species production.
CONCLUSIONS
It is unclear why β-blockers with the similar receptor selectivity have the infarct-sparing effect while other β-blockers with the same selectivity do not affect infarct size. What is the molecular mechanism of the infarct-reducing effect of β-blockers in reperfusion? Why did in early studies β-blockers decrease the mortality rate in patients with acute myocardial infarction (AMI) and without reperfusion and in more recent studies β-blockers had no effect on the mortality rate in patients with AMI and reperfusion? The creation of more effective β-AR ligands depends on the answers to these questions.
PubMed: 38423796
DOI: 10.1111/fcp.12988 -
Cell Reports. Medicine May 2024Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been...
Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM.
Topics: Humans; Induced Pluripotent Stem Cells; Cardiomyopathy, Hypertrophic; Cardiac Myosins; Child; Myocytes, Cardiac; Myosin Heavy Chains; Carrier Proteins; Genotype; Myosins; Male; Female; Sarcomeres
PubMed: 38642550
DOI: 10.1016/j.xcrm.2024.101520 -
Hypertrophic obstructive cardiomyopathy caused by Fabry disease: implications for surgical myectomy.ESC Heart Failure Dec 2023Hypertrophic obstructive cardiomyopathy can be the phenotype of storage disorders as Fabry disease cardiomyopathy. In this instance, its recognition through GLA gene...
Hypertrophic obstructive cardiomyopathy can be the phenotype of storage disorders as Fabry disease cardiomyopathy. In this instance, its recognition through GLA gene analysis and preventive administration of enzyme replacement therapy may reduce heart failure risk of surgical septal myectomy (SSM). A 59-year-old man was referred for SSM as dyspnoea and low threshold muscle fatigue associated to severe left ventricular outflow obstruction (gradient of 100 mmHg) due to both interventricular septal hypertrophy and mitral leaflet systolic anterior motion were not controlled by metoprolol 100 mg bid. Electrocardiogram showed sinus rhythm and a complete left bundle branch block. Cardiac magnetic resonance imaging showed a preserved left ventricular (LV) contractility (ejection fraction 70%) but failed to reveal reduced T1 mapping and fibrosis of postero-lateral LV wall suggesting Fabry disease cardiomyopathy. Cardiac catheterization and coronary angiography documented increased LV end-diastolic pressure but normal coronary arteries. SSM was followed by acute renal and heart failure with left ventricular ejection fraction declining to 35%. Histology of SSM showed regularly arranged severely enlarged cardiomyocytes containing extensive vacuoles that were intensely positive to immunofluorescence with anti-Gb3 antibodies and appeared at electron microscopy to consist of myelin bodies suggesting the diagnosis of FD. This entity was confirmed by low blood levels of alpha-galactosidase A (0.8 nmol/mL/h; NV > 1), high values of Lyso-Gb3 (5.85 nmol/L; NV < 2.3), and the presence of the pathogenic mutation c.644A>G in the exon 5 of GLA gene. This study emphasizes the importance of a genetic screening for FD before SSM be considered for hypertrophic obstructive cardiomyopathy.
Topics: Male; Humans; Middle Aged; Fabry Disease; Stroke Volume; Ventricular Function, Left; Cardiomyopathy, Hypertrophic; Myocytes, Cardiac; Heart Failure
PubMed: 37715354
DOI: 10.1002/ehf2.14427 -
Aesthetic Plastic Surgery Dec 2023Permissive hypotension, defined as mean arterial pressure (MAP) of 60-70 mm Hg, has been regarded as favorable among surgeons performing rhinoplasty. Furthermore,... (Review)
Review
BACKGROUND/PURPOSE
Permissive hypotension, defined as mean arterial pressure (MAP) of 60-70 mm Hg, has been regarded as favorable among surgeons performing rhinoplasty. Furthermore, management of blood pressure has been shown to promote greater visualization of the surgical field and decrease postoperative complications, such as ecchymosis and edema. While multiple therapies have been utilized to achieve permissive hypotension, it remains unclear how modalities compare in terms of safety and efficacy. The purpose of this study was to conduct a systematic review to better understand the specific modalities and associated outcomes in managing blood pressure during rhinoplasty.
METHODS
A systematic literature review was conducted in order to identify and assess therapeutics utilized in achieving permissive hypotension during rhinoplasty. Variables collected included year of publication, journal, article title, organization of study, patient sample, treatment modality, associated outcomes (i.e., intraoperative bleeding, edema, and ecchymosis), adverse events, complications, and satisfaction. Articles were then categorized by the level of evidence as set forth by the American Society of Plastic Surgeons. Any conflicts were resolved through discussion and full-text review among co-authors. Of note, the search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. No funding was required to conduct this review of the literature.
RESULTS
Initial review yielded sixty-five articles. Title and abstract review followed by standardized application of inclusion and exclusion criteria resulted in a total of ten studies for analysis. Articles discussed multiple therapies for management of blood pressure during rhinoplasty, including dexmedetomidine, dexamethasone, gabapentin, labetalol, nitroglycerine, remifentanil, magnesium sulfate, clonidine, and metoprolol. Overall, intraoperative bleeding, as well as postoperative ecchymosis and edema were reduced when MAP was controlled.
CONCLUSION
Given its intra- and postoperative benefits, permissive hypotension can be leveraged to improve outcomes in rhinoplasty. This study presents an updated comprehensive review of various modalities used to achieve permission hypotension in rhinoplasty. Future studies should explore how comorbidities may impact choice of treatment regimen among patients undergoing rhinoplasty.
LEVEL OF EVIDENCE III
This journal requires that authors assign a level of evidence to each article. 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: Humans; Hemorrhage; Hypotension; Rhinoplasty; Treatment Outcome; Postoperative Complications
PubMed: 36877227
DOI: 10.1007/s00266-023-03298-y -
Turkish Journal of Pharmaceutical... May 2024The iatrogenic triad is a significant global health problem in the elderly population. This study aimed to evaluate the iatrogenic triad in the elderly and identify...
OBJECTIVES
The iatrogenic triad is a significant global health problem in the elderly population. This study aimed to evaluate the iatrogenic triad in the elderly and identify potential preventive measures to mitigate its occurrence.
MATERIALS AND METHODS
A preliminary observational study was conducted on 150 ambulatory elderly patients to assess potentially inappropriate medications (PIMs), polypharmacy, and drug interactions. The AGS Beers Criteria 2019, Polypharmacy, Medication Complexity Regimen Index (MRCI), and Micromedex (a drug information software) were used to assess the harmful triad. Before and after data collection, we observed, identified, and unfolded potential strategies to avoid the harmful triad in the elderly population.
RESULTS
MRCI is 30.49 ± 13.77, suggesting a moderate level of complexity in the drug regimens of elderly patients. Among the PIMs identified by the AGS Beer criteria for 2019, glimepiride (45) and diclofenac (23) were found to be the most frequently prescribed. Moderate-level drug-drug interactions were identified between aspirin and metoprolol (20), metoprolol and metformin (13), and aspirin and enalapril (11). All drug-ethanol and drug-food interactions were rapid and often unknown to patients. Furthermore, the study found that MRCI and polypharmacy were significantly associated with the number of PIMs and drug interactions ( < 0.01). Based on data collection, this study identified three possible ways to prevent the iatrogenic triad in elderly patients: interaction, collaboration, and continuing education.
CONCLUSION
In conclusion, this study sheds light on medication regimen complexity, PIMs, and drug interactions in elderly patients. The study also highlights three possible ways to prevent the iatrogenic triad: interaction, collaboration, and continuing education. By implementing these strategies, healthcare providers can help prevent harm and improve the quality of care for elderly patients.
PubMed: 38742853
DOI: 10.4274/tjps.galenos.2023.89457 -
ACS Omega Aug 2023The evolution in the development of drugs has increased the popularity of physiologically based pharmacokinetic (PBPK) models. This study seeks to assess the PK of...
The evolution in the development of drugs has increased the popularity of physiologically based pharmacokinetic (PBPK) models. This study seeks to assess the PK of metoprolol in populations with healthy, chronic kidney disease (CKD), and acute myocardial infarction (AMI) conditions by developing and evaluating PBPK models. An extensive literature review for identifying and selecting plasma concentration vs time profile data and other drug-related parameters was undergone for their integration into the PK-Sim program followed by the development of intravenous, oral, and diseased models. The developed PBPK model of metoprolol was then evaluated using the visual predictive checks, mean observed/predicted ratios (), and average fold error for all PK parameters, i.e., the area under the curve (AUC), maximal plasma concentration, and clearance. The model evaluation depicted that none of the PK parameters were out of the allowed range (2-fold error) in the case of the mean ratios. The model anticipations were executed to determine the influence of diseases on unbound and total AUC after the application of metoprolol in healthy, moderate, and severe CKD. The dosage reductions were also suggested based on differences in unbound and total AUC in different stages of CKD. The developed PBPK models have successfully elaborated the PK changes of metoprolol occurring in healthy individuals and those with renal and heart diseases (CKD & AMI), which may be fruitful for dose optimization among diseased patients.
PubMed: 37599939
DOI: 10.1021/acsomega.3c02673 -
Clinical Pharmacology and Therapeutics Feb 2024CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals,...
CYP2D6 is involved in the metabolism of many drugs. Its activity is affected by pharmacogenetic variability leading to highly polymorphic phenotypes between individuals, affecting safety and efficacy of drugs. Recently, solanidine, a steroidal alkaloid from potatoes, and its metabolites, has been identified as a dietary-derived activity marker for CYP2D6. The intraday variability in plasma within individuals has not been studied yet in healthy subjects. As part of a CYP phenotyping cocktail study with 20 healthy participants, plasma concentrations of solanidine, 4-OH-solanidine and 3,4-secosolanidine-3,4-dioic acid (SSDA) were determined using a sensitive liquid chromatography-mass spectrometry method in urine and in plasma at timepoints 0, 2.5, 5, 8, and 24 hours after intake of test substances. The participants were phenotyped for CYP2D6 with oral metoprolol (12.5 mg) with 15 plasma sampling points over 24 hours (DRKS00028922). Metabolic ratios (MRs) of metabolite to parent plasma concentrations were formed from single timepoints and the area under the curve (AUC). All participants were genotyped for CYP2D6. The intra-individual variability of the CYP2D6 metabolite SSDA was highly stable with a median SD of 11.62% over 24 hours. MR SSDA/solanidine was more variable (median SD 31.90%) but correlated significantly at all measured timepoints with AUC MR α-OH-metoprolol/metoprolol. The AUC MR SSDA/solanidine showed a significant linear relationship with the genetically predicted CYP2D6 activity score. This study substantiates the MR SSDA/solanidine as CYP2D6 activity marker. The high correlation with metoprolol MR indicates a valid prediction of the CYP2D6 phenotype at any timepoint during the study day.
Topics: Humans; Cytochrome P-450 CYP2D6; Metoprolol; Phenotype; Diosgenin; Genotype
PubMed: 37971251
DOI: 10.1002/cpt.3106 -
Current Problems in Cardiology Feb 2024Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication following cardiac surgery. Current guidelines suggest beta-blockers for the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Postoperative atrial fibrillation (POAF) is the most common arrhythmic complication following cardiac surgery. Current guidelines suggest beta-blockers for the prevention of POAF. In comparing metoprolol succinate with carvedilol, the later has sparked interest in its usage as an important medication for POAF prevention.
METHODS
We considered randomized controlled studies (RCTs) and retrospective studies that evaluated the efficacy of carvedilol versus metoprolol for the prevention of POAF. After literature search, data extraction, and quality evaluation, pooled data were analyzed using either the fixed-effect or random-effect model using Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The incidence of POAF was the primary endpoint, while mortality rate and bradycardia were secondary outcomes.
RESULTS
In meta-analysis 5 RCTs and 2 retrospective studies with a total of 1000 patients were included. The overall effect did not favor the carvedilol over metoprolol groups in terms of mortality rate [risk ratio 0.45, 95 % CI (0.1-1.97), P=0.29] or incidence of bradycardia [risk ratio 0.63, 95 % CI (0.32-1.23), P=0.17]. However, the incidence of POAF was lower in patients who received carvedilol compared to metoprolol [risk ratio 0.54, 95 % CI (0.42-0.71), P < 0.00001].
CONCLUSION
In patients undergoing cardiac surgery, carvedilol may minimize the occurrence of POAF more effectively than metoprolol. To definitively establish the efficacy of carvedilol compared to metoprolol and other beta-blockers in the prevention of POAF, a large-scale, well-designed randomized controlled trials are required.
Topics: Humans; Metoprolol; Carvedilol; Atrial Fibrillation; Bradycardia; Propanolamines; Carbazoles; Adrenergic beta-Antagonists
PubMed: 37989396
DOI: 10.1016/j.cpcardiol.2023.102220