Search

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.

Atrial fibrillation (Afib) with rapid ventricular response (RVR) is acutely treated with intravenous push (IVP) metoprolol (MET) or diltiazem (DIL). In heart failure (HF) patients, diltiazem is not recommended due to negative inotropic effects. Studies comparing the treatment of atrial fibrillation often exclude HF. Hirschy et al. evaluated HF patients with concomitant Afib with RVR who received IVP metoprolol or diltiazem to determine their effectiveness and safety. They found similar safety and effectiveness outcomes between the two groups.This retrospective, IRB-approved study evaluated patients presenting to the emergency center (EC) with Afib with RVR and HF from January 1, 2018 to July 31, 2021. Included patients were 18 years of age or older, received IVP metoprolol or diltiazem in the EC, and had a recorded baseline ejection fraction (EF). The primary effectiveness outcome was successful heart rate (HR) control 30 min after treatment with either IVP metoprolol or diltiazem, which was defined as HR100 beats per minute (bpm). Secondary effectiveness outcomes included HR control 60 min post-IVP and at EC discharge or transfer and HR reduction20% at 30 min after IVP, 60 min after IVP, and at time of discharge or transfer. Other secondary outcomes included the time to adequate HR control, the total dose of IVP metoprolol or diltiazem given, any additional rate-controlling agents given, and crossover between metoprolol and diltiazem. Safety outcomes included bradycardia, hypotension, shortness of breath, increased oxygen requirements, change in EF, acute kidney injury or renal replacement therapy.Of 2580 evaluated, 193 patients were included (134 DIL vs. 59 MET) with age 73.3 ± 12.2 years, 63% female. The average EF was 48.2 ± 14.2% and 30% of patients had heart failure with reduced ejection fraction (HFrEF) while 64% had heart failure with preserved ejection fraction (HFpEF). Effective heart rate control 30 min post-IVP was not different between the two groups (55% DIL vs. 41% MET, p = 0.063). DIL effectively controlled HR quicker than MET (13 [9, 125] DIL vs. 27 [5, 50] MET, min, p = 0.009). DIL resulted in greater HR reductions at 30 min (33.2 ± 25.4 DIL vs. 19.7 ± 19.7 MET, bpm, p0.001) and at 60 min (31 ± 23.5 DIL vs. 19.6 ± 19.1 MET, bpm, p = 0.002). DIL also more frequently resulted in a HR reduction of 20% or greater at 30 min (63% DIL vs. 27% MET, p0.001), 60 min post-IVP (59% DIL vs. 41% MET, p = 0.019), and at time of patient discharge or transfer from the EC (70% DIL vs. 49% MET, p = 0.005). No differences in safety outcomes were identified.Acute management of patients with Afib with RVR and HF is challenging. While successful rate control at 30 min was not significantly different between diltiazem and metoprolol, IVP diltiazem reduced HR more quickly and reduced HR by 20% or greater more frequently than IVP metoprolol with no safety outcome differences. Further studies are needed to evaluate diltiazem's safety in patients with Afib and HF.

Beta-adrenergic receptor antagonists potentially risk causing fatal poisoning when taken over the daily recommended doses. The aim of this study is to investigate the differences and potential dose-related effects of propranolol and metoprolol toxicity depending on their selectivity. This 7-year-long retrospective cohort study was conducted among on 43 adult patients who received overdose propranolol (n= 22) and metoprolol (n= 21). Patients were divided into groups, with a daily overdose ≥ 240 mg/day for propranolol, ≥ 200 mg/day for metoprolol, and toxic dose ≥ 400 mg/day for both drugs. The groups were compared in terms of admission symptoms, heart rate, blood pressure, electrocardiography findings, cardiovascular effects, toxicity severity scores, treatment, follow-up times, and outcomes. Thirty-four (79.1%) of the patients who exceeded the daily dose were female, and there were no statistically significant differences between the groups in terms of gender (p= 0,281). The mean age was 29 (18-72) years, and there were no statistically significant differences between groups in terms of mean age (p= 0,192). When the vitals of the patients who exceeded the daily dose was examined, it was found that 23 (54.8%) patients had bradycardia, and 20 (46.5%) patients had hypotension. 65.2% of the bradycardia patients and 70% of the hypotensive patients were in the propranolol overdose group (p= 0,030 p= 0,021, respectively). Mean dose of symptomatic propranolol overdose patients (n= 12) was found as 1256 (280-2000) mg, mean dose of symptomatic metoprolol overdose patients (n= 11) was found as 559 (250-1000) mg. When toxic dose (≥ 400 mg) intakes were compared, more cardiovascular effects were observed in the propranolol group (p= 0,014). As a result, it was determined that Propranolol overdose has more cardiovascular effects than metoprolol overdose and there is a linear dose-symptom relationship for Propranolol.

In shallow, open-water engineered wetlands, design parameters select for a photosynthetic microbial biomat capable of robust pharmaceutical biotransformation, yet the contributions of specific microbial processes remain unclear. Here, we combined genome-resolved metatranscriptomics and oxygen profiling of a field-scale biomat to inform laboratory inhibition microcosms amended with a suite of pharmaceuticals. Our analyses revealed a dynamic surficial layer harboring oxic-anoxic cycling and simultaneous photosynthetic, nitrifying, and denitrifying microbial transcription spanning nine bacterial phyla, with unbinned eukaryotic scaffolds suggesting a dominance of diatoms. In the laboratory, photosynthesis, nitrification, and denitrification were broadly decoupled by incubating oxic and anoxic microcosms in the presence and absence of light and nitrogen cycling enzyme inhibitors. Through combining microcosm inhibition data with field-scale metagenomics, we inferred microbial clades responsible for biotransformation associated with membrane-bound nitrate reductase activity (emtricitabine, trimethoprim, and atenolol), nitrous oxide reduction (trimethoprim), ammonium oxidation (trimethoprim and emtricitabine), and photosynthesis (metoprolol). Monitoring of transformation products of atenolol and emtricitabine confirmed that inhibition was specific to biotransformation and highlighted the value of oscillating redox environments for the further transformation of atenolol acid. Our findings shed light on microbial processes contributing to pharmaceutical biotransformation in open-water wetlands with implications for similar nature-based treatment systems.

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.

© 2022Introduction: Both hypertension and β-blocker drugs used for treating hypertension (HT) can cause erectile dysfunction (ED). Nebivolol, unlike other β-blockers, may not cause impotence since it increases the release of Nitric Oxide (NO), which is the main mediator of erection. This study investigated the effect of Nebivolol and Metoprolol on erectile functions in hypertensive men. Materials and methods: Married men whose blood pressure were >140/90 mmHg were included in the study. All patients were assessed for ED, and the cause of ED was then investigated. Nebivolol or Metoprolol was started for one month in all patients. After one-month drugless period, the β-blockers were switched. Blood pressures, pulses and sexual function tests were evaluated, and plasma NO levels were measured at the end of the treatments and during the drugless period. Results: There was no difference in antihypertensive efficacy between the two drugs (p = 0.828;0.194 for systolic and diastolic BP). Metoprolol caused a significant decrease in IIEF-5 score, whereas Nebivolol did not cause a decrease in IIEF-5 score on patients with psychogenic, arteriogenic, and venous failure related ED (respectively, p

Atrial fibrillation (AF) is a common dysrhythmia associated with significant morbidity and mortality. Although many patients have stable AF, some patients can present with a rapid ventricular response (RVR). In these patients, it is important to lower their heart rate. However, there are several options available for rate control in the emergency department setting.What is the most effective agent for rate control for the patient with AF in RVR?Studies retrieved included two prospective, randomized, double-blind studies and six retrospective cohort studies. These studies provide estimates of the efficacy and safety of calcium channel blockers and β-blockers for rate control in those with AF with RVR.Based upon the available literature, diltiazem likely achieves rate control faster than metoprolol, though both agents seem safe and effective. Clinicians must consider the individual patient, clinical situation, and comorbidities when selecting a medication for rate control.

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.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.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).A significant decrease in myocardial infarction and increase in LVEF (%) was linked to receiving Metoprolol at 1 week and 6-month follow-up.

Acute heart rate control for atrial fibrillation (AF) with rapid ventricular response (RVR) in the emergency department (ED) is often achieved utilizing intravenous (IV) non-dihydropyridine calcium channel blockers (CCB) or beta blockers (BB). For patients with concomitant heart failure with a reduced ejection fraction (HFrEF), the American Heart Association and other clinical groups note that CCB should be avoided due to their potential negative inotropic effects. However, minimal evidence exists to guide this current recommendation. The primary objective of this study was to compare the incidence of adverse effects in the HFrEF patient population whose AF with RVR was treated with IV diltiazem or metoprolol in the ED.This single center, retrospective review included patients ≥18 years old with HFrEF who presented in AF with RVR and received IV diltiazem or metoprolol in the ED. The primary outcome was adverse effects of therapy defined as: 1) hypotension (systolic blood pressure90 mmHg requiring fluid bolus or vasopressors) or bradycardia (heart rate60 beats/min) within 60 min of medication administration 2) worsening heart failure symptoms defined as increased oxygen requirements within four hours or inotropic support within 48 h. Secondary outcomes included the incidence of rate control failure, patient disposition, ED length of stay, hospital length of stay, and in-hospital mortality.One hundred and twenty-five patients met inclusion criteria, with 57 receiving diltiazem and 68 receiving metoprolol. Overall adverse effects for diltiazem and metoprolol were similar (32% vs. 21%, P = 0.217). However, there was a significantly higher incidence of worsening heart failure symptoms within the diltiazem group (33% vs 15%, P = 0.019). Rate control failure at 60 min did not differ significantly between diltiazem and metoprolol (51% vs 62%, P = 0.277).In HFrEF patients with AF, there was no difference in total adverse events in patients treated with IV diltiazem compared to metoprolol. However, the diltiazem group had a higher incidence of worsening CHF symptoms defined as increased oxygen requirement within four hours or initiation of inotropic support within 48 h.

Adherence to therapy is the key to a successful therapeutic intervention, especially in cardiovascular diseases in which a lack of adherence may have serious consequences in terms morbidity and/or mortality. In this context, hair analysis can be an excellent tool to monitor adherence to therapy. Indeed, drugs present in blood are incorporated into the hair matrix, where drugs and metabolites can stay unaltered for a long time protected from metabolism and degradation. In the present study, a simple, specific, and sensitive ultra-high performance liquid-chromatography-tandem mass spectrometry (UHPLC-MS/MS) method set up to determine in human hair seven beta-blockers (viz., metoprolol, sotalol, labetalol, atenolol, nebivolol, bisoprolol, and nadolol) and two calcium-channel blockers (lercanidipine and amlodipine), which are widely prescribed to treat medium-to-severe hypertensive conditions. The optimized method was successfully validated in terms of accuracy, repeatability, reproducibility, matrix effect and extraction recovery. Moreover, the applicability of the method was evaluated by analyzing 34 real samples of hair obtained from patients under long-term therapy with calcium channel blockers and beta-blockers.

Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states.In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting.The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed.The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol.Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.

Metoprolol, a selective β

As a selective β

The histidine-modified zeolitic imidazolate framework [His-ZIF-67] was prepared with the histidine, 2-methylimidazole, and Co

Depression is common among people with cardiovascular diseases. Therefore, the combined use of antidepressants and cardiovascular drugs is very common, which increases the possibility of drug interaction. Simultaneously compare the effects of duloxetine and fluoxetine on metoprolol metabolism, and provide evidence-based guidance for medication safety. Sprague-Dawley rats were randomly divided into three groups: group A (10.3 mg/kg metoprolol alone), group B (10.3 mg/kg metoprolol + 6.2 mg/kg fluoxetine), and group C (10.3 mg/kg metoprolol + 6.2 mg/kg duloxetine). Tail vein blood was collected and subjected to the ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) detection. Moreover, in vitro inhibition of fluoxetine and duloxetine were assessed by incubating liver microsomes and CYP2D6.1 with metoprolol. In in vivo study, the administration of fluoxetine or duloxetine significantly increased the AUC

BACKGROUND Beta-blockers have become the cornerstone for medical management in patients with chronic type B aortic dissection (TBAD). However, the effect of being on and/or receiving intravenous beta-blockers during hospitalization on outcomes of surgical repair of TBAD is not fully described. We sought to investigate this association during open surgical repair (OSR) and endovascular (Endo) intervention for nontraumatic TBAD. METHODS The Premier Healthcare Database was inquired (June/2009-March/2015). Patients with nontraumatic isolated TBAD were identified via ICD-9-CM diagnosis and procedural codes. Patients with codes that indicated TAAD were excluded. In-hospital mortality, cardiac complications (CHF, MI, arrythmia) and stroke were evaluated. Log binomial regression analyses with bootstrapping were performed to assess the relative risk of adverse outcomes. RESULTS A total of 1,752 were admitted for OSR (54.3%) and Endo (45.7%) TBAD repair. Use of oral beta blocker (BB) was 16.0% in OSR and 56.4% in Endo groups. In each arm, patients on BB were more likely to be diabetic, on aspirin or statin and more likely to receive additional IV BB than nonBB patients. There was no significant difference in age, sex, race, or prior history of CHF between BB and nonBB groups. Mortality was proportionally lower in patients on BB in OSR group (7.9% vs. 16.7%; P = 0.006) and Endo (3.3% vs. 9.2%; P < 0.001). The adjusted relative risk for mortality and stroke were significantly lower in oral BB recipients compared with none [aRR (95% CI): 0.53 (0.32-0.90) and 0.46 (0.25-0.87); both P ≤ 0.02]. IV metoprolol was the only IV BB that reduced mortality [aRR (95% CI): 0.62 (0.46-0.85); P = 0.003]. A dose of ≤10 mg was associated with significant mortality reduction: 6.3% (3.0-9.5%) compared with 8.1% (4.6-11.6%) in no IV BB group. Cardiac complications were not affected by BB use. CONCLUSIONS For patients with nontraumatic TBAD, use of oral BB was associated with significant protection against in-hospital mortality and stroke following repair. Metoprolol was the only Intravenous BB type associated with improved survival. Further research is warranted to elucidate the effect of beta-blockers on the long-term surgical outcomes of TBAD.

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

Background: Heart failure (HF) patients with atrial fibrillation (AF) often have conduction system disorders, which may be worsened by β-blocker therapy.Objective: In a post hoc analysis we examined the prevalence of bradycardia and its association with adverse events (AEs) and failure to achieve target dose in the GENETIC-AF trial.Methods: Patients randomized to metoprolol (n = 125) or bucindolol (n = 131) entering 24-week efficacy follow-up and receiving study medication were evaluated. Bradycardia was defined as an electrocardiogram (ECG) heart rate (HR) Results: Mean HR in sinus rhythm (SR) was 62.6 ± 12.5 bpm for metoprolol and 68.3 ± 11.1 bpm for bucindolol (P < .0001), but in AF HRs were not different (87.5 bpm vs 89.7 bpm, respectively). Episodes per patient for bucindolol vs metoprolol were 0.82 vs 2.08 (P < .001) for bradycardia and 0.24 vs 0.57 for severe bradycardia (P < .001), with 98.9% of the episodes occurring in SR. Patients experiencing bradycardia had a 4.15-fold higher prevalence of study medication dose reduction (P Conclusion: In AF-prone HF patients bradycardia may limit the effectiveness of β blockers, and this property is agent-dependent.

To determine the effect of prolonged (2 years) antiarrhythmic therapy on cognitive functions of patients with atrial fibrillation, we have examined 117 patients. The condition of patients was evaluated on a number of accepted scales (Mini-Mental State Examination, Global Deterioration Scale, Clinical Dementia Rating) and a battery of neuropsychological tests. In addition, we have determined the genotype of the apolipoprotein E (ApoЕ). The patients were divided into 2 comparable groups in accordance with the characteristics of treatment: 61 individuals treated with beta-blockers (bisoprolol or metoprolol) and 56 — by amiodarone. The findings evidence the benefits of therapy using beta-blockers compared with amiodarone in terms of slowing the progression of cognitive deficit and preventing its transition into the diagnostic category of dementia. The feature of action of beta-blockers was their higher efficiency in patients with cognitive dysfunction with genotype ApoE(4+), i.e. in those, who are at high risk for Alzheimer’s disease.

Background. The evaluation of the effect of prolonged-effect metoprolol therapy on morning blood pressure elevation with ambulatory blood pressure monitoring (ABPM) in patients with mild to moderate arterial hypertension was the purpose of our study. Materials and methods. 118 patients were included in the study. We have evaluated systolic (SBP) and diastolic blood pressure (DBP), heart rate, patient’s compliance, adverse reactions, efficacy of therapy at baseline and on weeks 2, 4, 8 of treatment. Ambulatory blood pressure monitoring was performed in all patients before and on 2 nd month of therapy. Metoprolol was administered in initial daily dose 25 mg per day, and then the dose was up titrated every 10 days to 300 mg daily. If monotherapy was ineffective, hydrochlorothiazide was added (25 mg per day). Data of ABPM were obtained in 118 patients. In addition to the 24-hour active and passive periods, average parameters for a special period (6:00–12:00) were calculated, as well as indicators of the level of SBP increase in the morning hours and the rate of maximum SBP increase in the mor-ning hours. The level of the maximum SBP surge in the mor-ning was determined. The mean age of patients was 56.20 ± 0.76 years, the body mass index — 28.90 ± 0.35 kg/m 2 . The baseline level of office mean SBP and DBP as a whole for the group was 164.2 ± 0.9 mmHg and 96.8 ± 0.7 mmHg, respectively. Results. It was established that in mild and moderate hypertensive patients, metoprolol retard (alone or in combination with hydrochlorothiazide) decreased the office SBP and DBP by 32 and 18 mmHg, respectively, heart rate — by 18 beats per min (p < 0.001). Also, average daily SBP and DBP decreased by 21 and 13 mmHg (p < 0.05), average daytime SBP and DBP — by 23 and 12 mmHg (p < 0.05), and nighttime SBP and DBP — by 21 and 12 mmHg (p < 0.05). The average daily heart rate reduced by 7 bpm (p < 0.05), the average daytime heart rate — by 7.4 (p < 0.05), and nighttime — by 5.5 beats per minute (p < 0.05), respectively. Target BP according to ABPM (< 125/80 mmHg) was achieved in 64.4 % of patients. The target office blood pressure (< 140/90 mmHg) was reached in 93.6 % of patients. There was a significant decrease in mean SBP, DBP, pulse pressure for a special period by 20, 11 and 8 mmHg, respectively, a decrease in the temporal index for SBP and DBP (from 85.10 ± ± 1.35 and 67.1 ± 2.2 % to 56.80 ± 2.84 % and 43.10 ± 2.72 %, p < 0.05) and pressure load index for SBP and DBP (from 499.5 ± 28.4 and 243.10 ± 17.27 mmHg to 247.30 ± 24.01 and 103.10 ± 10.53 mmHg, p < 0.05). The mean decrease of the maximum SBP in the morning was 29 mmHg (р < 0.001). The level of SBP surge in the morning hours significantly decreased from 60.9 ± 1.9 to 50.5 ± 1.7 mmHg (p < 0.05). The dyna-mics of the decrease in the rate of the maximum SBP increase in the morning hours was not significant. We did not register any negative biochemical changes. Only 16 (12.1 %) adverse events were noted. Conclusions. In patients with mild to mode-rate arterial hypertension, taking metoprolol retard at a dose of 100–300 mg once a day contributed to a significant decrease in the maximum level of systolic blood pressure and the degree of its increase in the morning.

Combining solid phase microextraction (SPME) and mass spectrometry (MS) analysis has become increasingly important to many bioanalytical, environmental, and forensic applications due to its simplicity, rapid analysis, and capability of reducing matrix effects for complex samples. To further promote the adoption of SPME-MS based analysis and expand its application scope calls for efficient and convenient interfaces that couple the SPME sample handling with the efficient analyte ionization for MS. Here we report a novel interface that integrates both the desorption and the ionization steps in one device based on the capillary vibrating sharp-edge spray ionization (cVSSI) method. We demonstrated that the cVSSI is capable of nebulizing liquid samples in a pulled-tip glass capillary with a battery powered function generator. The cVSSI device allows the insertion of a SPME probe into the spray capillary for desorption, and then direct nebulization of the desorption solvent in situ. With the integrated interface, we have demonstrated rapid MS analysis of drug compounds from serum samples. Quantitative determination of various drug compounds including metoprolol, pindolol, acebutolol, oxprenolol, capecitabine and irinotecan was achieved with good linearity (R(2) = 0.97–0.99) and limit of detection ranging from 0.25 to 0.59 ng/mL without using a high voltage source. Only 3.5 μL of desorption solvent and 3 min desorption time were needed for the present method. Overall, we demonstrated a portable SPME-MS interface featuring high sensitivity, short analysis time, small footprint, and low cost, which makes it an attractive method for many applications requiring sample cleanup including drug compound monitoring, environmental sample analysis, and forensic sample analysis.

Background/purpose To describe a patient with visually symptomatic circumscribed choroidal hemangioma (CCH) treated successfully with intravitreal beta-blocker. Methods This is an interventional single case report of a 63 year-old man with a juxtafoveal CCH and extensive subretinal fluid (SRF) unsuccessfully treated with intravitreal anti-VEGF. Off-label intravitreal use of metoprolol (50μg/0.05 ml) was then performed. Main outcome measures were resolution or decreased subretinal fluid on OCT, visual stability or improvement, lack of retinal/ocular toxicity. Results Following 2 intravitreal injections of metoprolol (1 month apart), significant response was observed with decrease of SRF and visual improvement to 20/400 during a 9-week follow-up after the injections. Conclusion These preliminary findings suggest that intravitreal metoprolol can be a safe alternative treatment for patients with CCH. This off-label therapy could represent another option for patients with this condition.

The present study aimed to characterize and compare β-adrenoceptors in the rat bladder with those in the heart and lungs of SD rats (8–10 weeks old) using subtype-selective agonists and antagonists in a radioligand binding assay with (-)-[125I]cyanopindolol ([125I]CYP), and also to clarify alterations in β-adrenoceptors in the bladder of spontaneously hypertensive rats (SHR) at 14 weeks old, from those of Wistar-Kyoto rats (WKY) and Wistar rats at the same age. A radioligand binding assay with [125I]CYP was used to measure β-adrenoceptor binding activity in rat tissues. Metoprolol exhibited the highest affinity to specific binding sites of [125I]CYP in the rat heart, indicating the dominance of β1-adrenoceptors. β3-selective agonists (BRL37344 and CL316243) and antagonist (SR59230A) exhibited higher affinity to specific binding sites of [125I]CYP in the bladder than in the heart and lungs. Furthermore, the binding affinity of the β2-selective antagonist, ICI118551 was the highest in the bladder. The Bmax of specific [125]CYP binding in the bladder was significantly lower in WKY and SHR than in Wistar rats. The present study provides further evidence for the coexistence of β2-and β3-adrenoceptors in the rat bladder, and indicates that β-adrenoceptor density is lower in the bladders of WKY and SHR.

Due to the inability of conventional wastewater treatment procedures to remove organic pharmaceutical pollutants, active pharmaceutical components remain in wastewater and even reach tap water. In terms of pharmaceutical pollutants, the scientific community focuses on β-blockers due to their extensive (over)usage and moderately high solubility. In this study, the photocatalytic activity of V2O5 was investigated through the degradation of nadolol (NAD), pindolol (PIN), metoprolol (MET), and their mixture under ultraviolet (UV) irradiation in water. For the preparation of V2O5, facile hydrothermal synthesis was used. The structural, morphological, and surface properties and purity of synthesized V2O5 powder were investigated by scanning electron microscopy (SEM), X-ray, and Raman spectroscopy. SEM micrographs showed hexagonal-shaped platelets with well-defined morphology of materials with diameters in the range of 10–65 µm and thickness of around a few microns. X-ray diffraction identified only one crystalline phase in the sample. The Raman scattering measurements taken on the catalyst confirmed the result of XRPD. Degradation kinetics were monitored by ultra-fast liquid chromatography with diode array detection. The results showed that in individual solutions, photocatalytic degradation of MET and NAD was relatively insignificant (

The Cocktail probe drug method was used to evaluate the effect of Laportea bulbifera extract on the different subtypes of CYP450 enzyme activities in rats, and to provide references for its clinical rational drug use. The rats were randomly divided into a high-dose L. bulbifera group(0.45 g·kg~(-1)·d~(-1)) and a low-dose L. bulbifera group(0.09 g·kg~(-1)·d~(-1)). After continuous gavage for 7 and 14 days, the Cocktail probe mixing solution, including caffeine, midazolam, tolbutamide, omeprazole, metoprolol, and chlorzoxazone, was injected into the tail vein, and the blood sample was obtained from the tail vein at different time points. Ultra-high performance liquid chromatography-mass spectrometry(UPLC-MS) was established to determine the concentration of six probe drugs in rat plasma. DAS 2.0 was used to calculate its pharmacokinetic parameters, and the effect of L. bulbifera extract on CYP1 A2, CYP2 C9, CYP2 C19, CYP2 D6, CYP2 E1, and CYP3 A4 in rats was investigated. As compared with the blank control group, under the omeprazole index, the AUC_(0-t) and AUC_(0-∞) of the 7-day administration groups and the 14-day high-dose group were significantly decreased, and the CLz and Vz were significantly increased. Under the midazolam index, the AUC_(0-t) and AUC_(0-∞) of the 7-day low-dose group and the 14-day administration group were significantly decreased, and the CLz was significantly increased. In addition, the AUC_(0-∞) of the 7-day high-dose group was also significantly decreased. Under the index of metoprolol, the AUC_(0-t) and AUC_(0-∞) of each experimental group were decreased significantly, and the CLz and Vz of the 7-day low-dose group and the 14-day low-dose group were increased significantly. Under the caffeine index, the AUC_(0-t) and AUC_(0-∞) of the 7-day administration groups were increased significantly, the CLz was decreased significantly, and the t_(1/2 z) of the 14-day high-dose group was increased significantly. Under the chlorzoxazone index, the AUC_(0-t) and AUC_(0-∞) of the 7-day low-dose group were increased significantly, and the CLz was decreased significantly. Under the tolbutamide index, there was no statistical difference in the pharmacokinetic parameters. In conclusion, L. bulbifera extract induces the activities of CYP2 C19, CYP3 A4, and CYP2 D6, inhibits the activities of CYP1 A2 and CYP2 E1, and does not affect the activity of CYP2 C9.

Herein, we examined the protective effect of metoprolol combined with atractylenolide I (Atr I) in acute myocardial infarction (AMI) by regulating the SIRT3 (silent information regulator 3)/β-catenin/peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway. Briefly, 50 rats were randomly divided into the sham operation, model, metoprolol, Atr I, and combination metoprolol with Atr I groups (combined treatment group). The AMI model was established by ligating the left anterior descending coronary artery. After treatment, infarct size, histopathological changes, and cell apoptosis were examined using 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, and the TUNEL assay. The left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS), and left ventricular mass index (LVMI) were detected by echocardiography. Endothelin-1 (ET-1), nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) levels were detected using enzyme-linked immunosorbent assays. Furthermore, we measured lactate dehydrogenase (LDH), creatine kinase (CK) isoenzyme (CK-MB), and CK levels. Western blotting was performed to determine the expression of SIRT3, β-catenin, and PPAR-γ. Herein, the combined treatment group exhibited increased levels of LVEF, LVFS, and NO, whereas LVMI, ET-1, TNF-α, IL-6, LDH, CK-MB, and CK levels were decreased. Importantly, the underlying mechanism may afford protection against AMI by increasing the expression levels of SIRT3, β-catenin, and PPAR-γ.

The aim of the study was to evaluate the efficacy and safety of fixed-dose combination (FDC) of metoprolol, telmisartan, and chlorthalidone in patients with essential hypertension and stable coronary artery disease (CAD) who showed inadequate response to dual therapy.In this phase III, open-label, multicenter study, 254 adults with stable CAD having uncontrolled hypertension despite being treated with FDC of metoprolol (25/50 mg) and telmisartan (40 mg) were included. Patients received either of the following FDC for 24 weeks: metoprolol (25 mg), telmisartan (40 mg), and chlorthalidone (12.5 mg) (FDC1; n = 139) or metoprolol (50 mg), telmisartan (40 mg), and chlorthalidone (12.5 mg) (FDC2; n = 115) tablets once daily. The FDCs were developed using the novel Wrap Matrix™ platform technology. Primary endpoint assessed the mean change in seated diastolic blood pressure (SeDBP) and seated systolic blood pressure (SeSBP) from baseline to 24 weeks. Secondary efficacy endpoints included proportion of patients achieving 90 mmHg SeDBP (SeDBP responder) and 140 mmHg SeSBP (SeSBP responder) at weeks 12, 16, 20, and 24. Safety was assessed throughout the study.A total of 243 (95.70%) patients completed study. The mean change in BP from baseline (FDC1, 155/96 mmHg; FDC2, 165/98 mmHg) to week 24 (FDC1, 128/82 mmHg; FDC2, 131/83 mmHg) was statistically significant (both groups p 0.0001). Within FDC1 and FDC2, the mean change from baseline to week 24 in SeDBP (82.60 mmHg and 83.09 mmHg) and SeSBP (128.07 mmHg and 131.29 mmHg) was statistically significant (both groups p 0.0001). At week 24, in FDC1, 80.15% and 84.73% were SeDBP and SeSBP responders, respectively; in FDC2, 79.46% and 74.11% were SeDBP and SeSBP responders, respectively. No serious adverse events or deaths were reported.Triple FDCs of metoprolol, telmisartan, and chlorthalidone were considered effective and well tolerated in patients with hypertension who respond inadequately to dual therapy.CTRI/2016/11/007491.The increasing prevalence of hypertension in India requires immediate attention. To adequately manage blood pressure and ensure compliance to medications, innovative treatment options involving combination therapy with three or more drugs to treat hypertension need to be explored. Fixed-dose combination (FDC) of three antihypertension drugs, viz., metoprolol, telmisartan, and chlorthalidone, were tested in Indian patients who could not respond adequately to dual treatment. The rationale behind using a combination of three drug types was to take advantage of the complementary actions of each drug class for an enhanced treatment effect. The two variants of FDCs were tested in 254 adults with the most common form of heart disease, i.e., stable coronary artery disease. Changes in seated diastolic and systolic blood pressure (SeDBP and SeSBP) were measured to assess the effectiveness of the FDC. The mean changes in SeDBP and SeSBP were statistically significant by the end of the study, i.e., it determined that results are not explainable by chance alone. A greater proportion of patients (range 74–84%) achieved their target BPs with the FDC used in the study. The FDC variants were well tolerated without any reports of serious adverse events or deaths. Overall, this triple combination therapy option was effective and considered safe to be administered to hypertensive Indian adults with stable coronary artery disease who did not respond adequately to dual antihypertension therapy.

Xue-Hong Feng,1 Yang Wang,1 Lian-Yu Wang,1 Jun-Fei Shen,1 Chun-Yuan You,1 Qiu-Ting Feng2 1Department of Echocardiography, The Second Hospital of Wuxi Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214002, People’s Republic of China; 2Department of Cardiology, The Second Hospital of Wuxi Affiliated to Nanjing Medical University, Wuxi, Jiangsu, 214002, People’s Republic of ChinaCorrespondence: Qiu-Ting FengDepartment of Cardiology, The Second Hospital of Wuxi Affiliated to Nanjing Medical University, No. 68 Zhongshan Road, Wuxi, 214002, Jiangsu Province, People’s Republic of ChinaTel +86-15961823329Email fengbiqu22538573@163.comObjective: To investigate the predictive value of PTEN and echocardiography in the treatment of heart failure with trimetazidine combined with metoprolol.Methods: A total of 100 patients with coronary heart disease and HF who admitted to our hospital from August 2018 to August 2020 were enrolled into research. All patients received routine treatment according to the guidelines and were treated with trimetazidine and metoprolol for a total course of 6 months. Echocardiographic parameters and PTEN levels were measured at baseline and after treatment. The patients were divided into groups according to the quartile of basic PTEN level, and the total effective rates were compared. The echocardiographic parameters of patients with different prognosis were analyzed. Bivariate correlation analysis was used to evaluate the correlation between PTEN, echocardiography and treatment effect.Results: Compared with that before treatment, the level of PTEN increased significantly after treatment (P < 0.01). According to the quartile of basic PTEN level, the total effective rate of patients with different levels of basic PTEN was was statistically different (P < 0.01). There was a linear correlation between the level of basic PTEN and the treatment effect, and the total effective rate of patients with high level of basic PTEN was higher than that of patients with low level of PTEN. Compared with before treatment, LVEF, SV, E/A and lvfs increased significantly after treatment (P < 0.01). There was a correlation between the basic echocardiographic parameters and the treatment effect of patients. The basic echocardiographic parameters of patients with poor prognosis were worse than those with good prognosis. PTEN expression in patients’ serum was only positively correlated with E/A, but not with LVFE, SV and LVFS (P < 0.01).Conclusion: PTEN and echocardiographic parameters serve as a good method to evaluate the short-term therapeutic effect of trimetazidine combined with metoprolol in patients with heart failure.Keywords: PTEN, echocardiographic parameter, heart failure, trimetazidine, metoprolol, efficacy prediction

Background: Over the last few years, considerable interest in endoscopic surgery of the paranasal sinuses has been expressed, which is a minimally invasive technique. Complications related to this technique often arises due to excessive bleeding during surgery. This study compares oral Clonidine (centrally acting a-2 agonist) and oral Metoprolol (cardioselective beta blocker) used as premedication in functional endoscopic sinus surgery to evaluate improvement in operative field. Method: This prospective, randomized, double blind study included 50 ASA Grade I and II patients, aged between 18-60 years, who were equally divided into two groups as Group I (received oral Metoprolol 50 mg) and Group II (received oral Clonidine 3mcg/kg ) 90 min prior to surgery. Pulse Rate and blood pressure were recorded at different time intervals including before starting the drug, before pre medication, after intubation, every 5 minutes thereafter for 30 minutes, every 10 minutes thereafter till the end of surgery and after extubation. Assessment of surgical field was done by using Fromme et al scale adapted by Boezaart et al. Results: Metoprolol was more effective in controlling heart rate intra operatively than Clonidine, whereas Clonidine was more effective than Metoprolol in maintaining better surgical field that too in lower doses as compared to the one used in previous studies. Both the drugs were effective in preventing the haemodynamic response associated laryngoscopy, intubation and surgical stimulus. Conclusion: Clonidine is more effective than Metoprolol in reducing intra operative bleeding and maintaining better surgical field even in low doses of 3 mcg/ kg., http://impactfactor.org/PDF/IJTPR/12/IJTPR,Vol12,Issue12,Article34.pdf

Long QT syndrome with Torsades de Pointes (TdP) is a life-threatening polymorphic ventricular arrhythmia. The corrected QT (QTc) prolongation >500 milliseconds (ms) has been associated with TdP. Hypocalcaemia due to severe vitamin D deficiency is an uncommon cause of acquired long QT. We hereby present a case of a 40-year-old woman with sensorineural deafness and having symptoms of palpitations and presyncope. She had a QTc interval of 556 ms (reference range, QTc 451–470 ms in adult healthy woman) on 24-hour Holter analysis. Genetic analysis for congenital long QT syndrome was negative. She was diagnosed with severe hypocalcaemia secondary to severe vitamin D deficiency. After treatment with intravenous calcium gluconate, followed by oral vitamin D and calcium supplementation, the QTc became normalised and no further episode of palpitations or presyncope occurred. The causes of vitamin D deficiency was due to inadequate exposure to sunlight and a strict vegan diet.

Introduction: Classic coronary artery bypass grafting (CABG) surgery involves diastolic cardiac arrest under cardiopulmonary bypass, while off-pump CABG (OPCABG) has become widespread in recent years. Methods: 174 patients who underwent OPCABG were included in the study. Patients were divided into two groups. Group I (n=90) received ivabradine and Group M (n=84) received metoprolol before surgery until postoperative day 10. Intraoperative arrhythmias and hypotension were recorded. Postoperative atrial fibrillation (AF) and arrhythmia, mortality and morbidity rates were assessed based on the 30-day postoperative follow-up. Results: There were no significant differences in the intraoperative amount of inotropic support and red blood cell transfusion between groups (P=0.87 and P=0.31). However, the rates of intraoperative arrhythmias and hypotension were not significantly higher in Group M (P=0.317 and P=0.47). Ventricular tachycardia/ventricular fibrillation (VT/VF) was observed in 2 patients in both groups. Postoperative AF occurred in 7 patients (7.7%) in Group I and in 10 patients (11.9%) in Group M. Although there was a trend towards a higher prevalence of AF in Group M patients, this did not reach statistical significance. In addition, mortality and morbidity rates were comparable between groups.

Aims The effect of elevated heart rate (HR) on morbidity and mortality is evident in chronic stable heart failure; data in this regard in acute decompensated heart failure (ADHF) setting are scarce. In this single‐centre study, we sought to address the prognostic value of HR and beta‐blocker dosage at discharge on all‐cause mortality among patients with heart failure and reduced ejection fraction and ADHF. Methods and results In this retrospective observational study, 2945 patients were admitted for the first time with the primary diagnosis of ADHF between January 2008 and February 2018. Patients were divided by resting HR at discharge into three groups (HR 90 b.p.m.). Evidence‐based beta‐blockers were defined as metoprolol, bisoprolol, and carvedilol. The doses of prescribed beta‐blockers were calculated into a percentage target dose of each beta‐blocker and divided to four quartiles: 0 75% of the target dose. Cox regression was used to calculate the hazard ratio for various HR categories and adjusting for clinical and laboratory variables. At discharge, 1226 patients had an HR 90 b.p.m. The 30 day mortality rate was 2.2%, 3.7%, and 12.1% (P 90 b.p.m., respectively. The adjusted hazard ratio was significantly increased only in HR above 90 b.p.m. category (hazard ratio, 2.318; 95% confidence interval, 1.794–2.996). Conclusions Patients with ADHF and an HR of

Cardiomyocyte senescence is involved in the pathological mechanism of cardiac diseases. Metoprolol is a β1 receptor blocker used for the treatment of hypertension. Recent studies show that Metoprolol can protect cardiomyocytes against ischemia injury. The present study aims to investigate the protective effects of Metoprolol against arginine vasopressin (AVP)-induced cellular senescence in cultured cardiomyocytes. The cell proliferation assay and cytotoxicity lactate dehydrogenase assay showed that the highest tolerated dosage of Metoprolol in H9C2 cardiomyocytes was optimized as 10 µM. The enzyme-linked immunosorbent assay showed that Metoprolol significantly ameliorated the elevated level of the DNA oxidation product 8-hydroxy-2 deoxyguanosine. Metoprolol also decreased the percentage of senescence-associated β-galactosidase positive cells and improved the telomerase activity under AVP exposure. Moreover, treatment with Metoprolol ameliorated the decreased intracellular nicotinamide phosphoribosyltransferase activity, nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide phosphate (NAD+/NADPH) ratio, and Sirtuin1 activity in cardiomyocytes by AVP. Finally, Metoprolol was able to downregulate the AVP-induced expression of acetylated p53 and p21. Taken together, our data reveal that Metoprolol protected the cardiomyocytes from AVP-induced senescence.

β-Blockers are prescribed by physicians for many medical reasons (hypertension, long-term prophylaxis of angina pectoris, myocardial infarction, stable heart failure treatment, cardiac arrhythmias, etc.). Although cases of β-blocker poisoning have a low rate of 0.9% among all poisoning cases, they have a high mortality rate. In β-blocker poisoning with high lipid solubility; seizures, respiratory depression, coma, resistant bradycardia-hypotension and shock may occur. Metoprolol, a type of β-blocker, is a selective β1-adrenoceptor antagonist with sympathomimetic effect. It is also reported that metoprolol is the 2nd most commonly prescribed β-blocker after bisoprolol all over the world. This article aims to present a case who took high-dose metoprolol for suicidal purposes and to examine metoprolol poisoning and its treatment in the light of current literature.

Background. Arrhythmia after myocardial infarction is the leading cause of death in clinical heart disease. Increasing studies have shown that the response to endoplasmic reticulum (ER) stress (ERS) caused by myocardial infarction is related to prognosis and the development of arrhythmias. The unfolded protein response (UPR) could serve as an important regulatory signaling pathway following myocardial infarction. The traditional Chinese medicine Wenxin Granules improve arrhythmias following myocardial infarction, which may be related to ERS intervention and the activation of the UPR and apoptosis. We aimed to investigate the involvement of Wenxin Granules in the activation of the UPR and apoptosis following myocardial infarction. Left coronary artery ligation was established as a rat model of myocardial infarction. The rats were randomly divided into the model group, low-dose Wenxin Granule group, high-dose Wenxin Granule group, and metoprolol group. Rats with only wire insertion and no ligature were used as the sham group. Small animal ultrasound systems were used to detect changes in heart structure and function, and the electrical stimulation threshold for ventricular fibrillation was detected. The expression of glucose-regulated protein (GRP)78, activating transcription factor (ATF)6, X-box binding protein (XBP)1, protein kinase–like ER kinase (PERK), phosphorylated (p)-PERK, Bax, Bcl2, C/EBP homologous protein (CHOP), caspase 12, caspase 8, and caspase 3 were detected by western blot, and terminal deoxynucleotidyl transferase dUTP Nick end labeling (TUNEL) was used to determine the cardiomyocyte apoptosis index. Compared with the sham group, rats in the model group displayed immediate ST-segment elevation and pathological Q waves after 24 hours. After 2 weeks, the left ventricular (LV) anterior wall thickness (LVAW) became thinner, and the inner diameter (LVID) increased. The end-diastolic LVAW (LVAWd), end-systolic LVAW (LVAWs), ejection fraction (EF), and fractional shortening (FS) were significantly reduced ( P < 0.01 ), whereas the LVIDd, LVIDs, diastolic LV volume (LV Vold), and systolic LV volume (LV Vols) significantly increased ( P < 0.01 ). The ventricular fibrillation threshold decreased significantly ( P < 0.01 ). ERS proteins GRP78, p-PERK, PERK, ATF6, and XBP1 and apoptotic proteins CHOP, Bax, caspase 12, caspase 8, and caspase 3 significantly increased ( P < 0.01 , P < 0.05 ), whereas Bcl-2 expression and the Bcl-2/Bax ratio decreased ( P < 0.01 ). Compared with the sham group, LVAWd, LVAWs, FS, and Bcl-2 protein expression were significantly increased in the low-dose Wenxin Granule group ( P < 0.01 , P < 0.05 ), and p-PERK and ATF6 decreased ( P < 0.01 , P < 0.05 ). Compared with the sham group, LVAWd, LVAWs, EF, FS, and the ventricular fibrillation threshold significantly increased in the high-dose Wenxin Granule and metoprolol groups ( P < 0.01 , P < 0.05 ), whereas LVIDs, LV Vols, and ERS proteins were significantly decreased ( P < 0.01 , P < 0.05 ). CHOP, Bax, caspase 12, caspase 8, and caspase 3 protein expression decreased in the Wenxin Granule group ( P < 0.01 , P < 0.05 ), whereas Bcl-2 and the Bcl-2/Bax ratio increased ( P < 0.01 , P < 0.05 ). LVIDd and Bax decreased in the metoprolol group ( P < 0.01 , P < 0.05 ), and the Bcl-2/Bax ratio increased ( P < 0.05 ). The cardiomyocyte apoptosis index values for the low- and high-dose Wenxin Granule and metoprolol groups were significantly reduced ( P < 0.05 ). This study suggested that the UPR is an essential mechanism underlying pathological injury after myocardial infarction. Wenxin Granule treatment can improve ventricular remodeling and cardiac function and inhibit arrhythmia by preventing excessive ERS from activating the UPR and apoptosis.

Alcohol abuse has become a serious health issue worldwide. Ketamine can reduce addiction risk among patients with alcohol use disorders. This study aimed to determine the effects of alcohol on the pharmacokinetics of ketamine during long-term alcohol exposure.An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determination of ketamine and norketamine was developed and validated. A total of 15 rats were given 40% alcohol for 3 weeks. The pharmacokinetics of ketamine were measured at time zero, 1 week, 2 weeks, and 3 weeks after alcohol exposure. The metabolic capability of liver CYP450 was evaluated using three probe drugs: metoprolol, phenacetin, and tolbutamide.During drinking of 40% alcohol, the AUC(0-t), AUC(0-∞), and Cmax of ketamine and norketamine significantly increased, while V and CL significantly decreased with time (p 0.001). The pharmacokinetic changes of norketamine were highly consistent with ketamine. Additionally, the concentration ratio of norketamine/ketamine in sample time also decreased over time. However, there were no pharmacokinetic changes of three probe drugs, which indicated there was no significant change of liver CYPs activities.Alcohol significantly increases plasma concentration of ketamine and norketamine. The effect of alcohol on pharmacokinetics of ketamine should be considered in clinical therapy.

INTRODUCTION AND OBJECTIVES According to the wavefront phenomenon described in the late 1970s, myocardial infarction triggered by acute coronary occlusion progresses with increasing duration of ischemia as a transmural wavefront from the subendocardium toward the subepicardium. However, whether wavefront progression of necrosis also occurs laterally has been disputed. We aimed to assess the transmural and lateral spread of myocardial damage after acute myocardial infarction in humans and to evaluate the impact of metoprolol on these. METHODS We assessed myocardial infarction in the transmural and lateral dimensions in a cohort of 220 acute ST-segment elevation myocardial infarction (STEMI) patients from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction). The patients underwent cardiac magnetic resonance imaging at 5 to 7 days and 6 months post-STEMI. RESULTS On day 5 to 7 post-STEMI cardiac magnetic resonance, there was a strong linear correlation between the transmural and lateral extent of infarction (delayed gadolinium enhancement) (r=-0.88; P

Purpose: A case of new onset bradycardia and hypotension following betel leaf consumption in combination with verapamil and metoprolol in an atrial fibrillation (AF) patient. Summary: A 66-year-old Nigerian woman presented to the emergency department for evaluation of multiple near syncope episodes with underlying AF and slow ventricular response. After initial evaluation, the patient disclosed she had ingested several betel leaves that morning. She was admitted for observation of severe, progressive hypotension and symptomatic bradycardia. Her past medical history included AF, type 2 diabetes, asthma, obesity, hypertension and hypothyroidism. Her home medications consisted of spironolactone, metoprolol succinate, and verapamil ER. Upon admission, her home medications were held. She received IV fluids and atropine .4 mg IV as needed for symptomatic bradycardia. Approximately 18 h following admission, her vital signs stabilized and her labs returned to baseline. She remained stable and was discharged with a recommendation to continue her home medications at prescribed doses with reduced doses of verapamil and metoprolol and to follow-up with her primary care provider. Conclusion: A patient with a history of AF developed significant hypotension and symptomatic bradycardia after betel leaf consumption resulting in an overnight critical care unit admission. The use of betel leaf is not common in the United States; however, practitioners should be cognizant of the use of complementary and alternative medications like betel leaf and incorporate this knowledge in patient evaluation. Patients consuming betel leaf or betel nut should be evaluated for cardiovascular effects as well as laboratory evaluation for organ damage.

The basic purpose of constructing drug delivery systems is to design when and where the drug will be released. The episode of many biological events is really important for such knowledge. Metoprolol pulsatile drug delivery system was developed for this purpose, which can release the drug when blood pressure needs to be modulated in the early morning. The Cup and core techniques were used to build this system, which included immediate release (IR), sustained-release (SR), and a polycaprolactone plug layer. The formulation of the ingredients was facilitated by various preformulation studies. The IR and SR tablets were bilayered, with polycaprolactone entirely coating the IR layer. The IR and SR tablet release profiles were optimised for the F5 batch, which was then used to construct a pulsatile drug delivery system. Clinical trials were conducted with the prepared tablet, which included the use of BaSO4 tagged tablets for X-ray examinations. All of the findings indicated the optimal drug release of metoprolol, which can be used for individuals who are more prone to blood pressure abnormalities in the morning.

Tramadol is an opioid medication used to treat moderately severe pain. CYP2D6 inhibition could be important for tramadol as it decreases the formation of its pharmacologically active metabolite, O-desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol pharmacokinetics using quinidine and metoprolol as prototypical perpetrator drugs. A physiologically-based pharmacokinetic model for tramadol and O-desmethyltramadol was developed and verified in PK-Sim V8 and linked to respective models of quinidine and metoprolol to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O-desmethyltramadol exposure. Our results show that there is a differentiated impact of CYP2D6 inhibitors on tramadol and O-desmethyltramadol based on their mechanisms of inhibition. Following allosteric inhibition by a single dose of quinidine, the exposure of both tramadol (51% increase) and O-desmethyltramadol (52% decrease) was predicted to be significantly altered after concomitant administration of a single dose of tramadol. Following multiple-dose administration of tramadol and a single-dose or multiple-dose administration of quinidine, the inhibitory effect of quinidine was predicted to be long (∼42h) and to alter exposure of tramadol and O-desmethyltramadol by up to 60%, suggesting that co-administration of quinidine and tramadol should be avoided clinically. In comparison, there is no predicted significant impact of metoprolol on tramadol and O-desmethyltramadol exposure. In fact, tramadol is predicted to act as a CYP2D6 perpetrator and increase metoprolol exposure, which may necessitate the need for dose separation. This article is protected by copyright. All rights reserved.

This work is devoted to the dynamic study of heart rate variability indicators for one year in patients with paroxysmal atrial fibrillation treated with antiarrhythmic drugs metoprolol and cordarone. The study found that patients treated with metoprolol monotherapy had a weakening of parasympathetic effects on the heart, due to a decrease in Mean by 12.9%, Mo by 13%, Amo by 29.4%, SDNN by 28.3% compared to the group of healthy individuals, but they differed in stable indicators of heart rate variability and 33% retained sinus rhythm during the year. With cordarone monotherapy, there was a curative effect of sympathetic and parasympathetic effects on the heart, as indicated by an increase in: Mean by 15.9%, Mo by 15.9%, IVR by 95.5%, Amo by 41.1% and a decrease in SDNN by 37.5%, compared with the group of healthy individuals at the initial stage. A year later, a negative dynamics was revealed - the predominance of sympathetic influences on the heart compared to the groups of healthy individuals and the control due to an increase in: IVR by 363.3% and 238.5%; VPR by 116.7% and 106%; Amo by 111.2% and 72.9; IN by 304% and 246.8%; PAPR by 92% and 79.1%, respectively. During the year, 39% of patients left the study due to the replacement of antiarrhythmic therapy and 16.5% due to the development of a permanent form of atrial fibrillation. In the remaining patients in the study, in comparison with their initial data, there was a predominance of sympathetic effects on the heart due to an increase in IVR by 137%. In combination therapy with metoprolol and cordarone, there were no significant changes in heart rate variability compared to the initial ones. Initially, there was a decrease in overall heart rate variability due to a decrease in SDNN by 28.4% and a decrease in parasympathetic effects on the heart due to an increase in Amo by 45.2% and a decrease in Delta X by 32.9% compared to the group of healthy individuals. After a year, 40% left the study due to the replacement of antiarrhythmic therapy and 30% due to the development of a permanent form of atrial fibrillation. During dynamic observation of patients, it was found that the following indicators have the most important prognostic value in the development of atrial fibrillation: SDNN, Delta X and RMSSD. Therefore, it is very important to register an ECG with the measurement of these indicators at least once every 3 months for timely correction of treatment.

This case report presents a 33-year-old woman with premature ventricular contractions (PVCs). Her genetic testing was positive for KCNJ2 missense mutation at chr17:68171832;NM_000891.2. This mutation was compatible with Andersen-Tawil syndrome. We made an electrophysiological study to determine origin of PVCs however at endocardial mapping there was not any focus of PVC and at epicardial mapping we ablated low voltage areas in the inferior segments of both ventricles. She was discharged with flecainide and metoprolol therapy. After 3 months, her PVC burden was significantly decreased at Holter monitoring. (c) 2021 Elsevier Inc. All rights reserved.

To characterize and compare various medicines for chronic heart failure (CHF), changes in circulatory physiological parameter during pharmacotherapy were investigated by a model‐based meta‐analysis (MBMA) of circulatory physiology. The clinical data from 61 studies mostly in patients with heart failure with reduced ejection fraction (HFrEF), reporting changes in heart rate, blood pressure, or ventricular volumes after treatment with carvedilol, metoprolol, bisoprolol, bucindolol, enalapril, aliskiren, or felodipine, were analyzed. Seven cardiac and vasculature function indices were estimated without invasive measurements using models based on appropriate assumptions, and their correlations with the mortality were assessed. Estimated myocardial oxygen consumption, a cardiac load index, correlated excellently with the mortality at 3, 6, and 12 months after treatment initiation, and it explained differences in mortality across the different medications. The analysis based on the present models were reasonably consistent with the hypothesis that the treatment of HFrEF with various medications is due to effectively reducing the cardiac load. Assessment of circulatory physiological parameters by using MBMA would be insightful for quantitative understanding of CHF treatment.

The main objective was to compare the meaning of soluble angiotensin-converting enzyme-2 (sACE2) plasma levels modulation on the prognosis of two cohorts of heart failure (HF) and acute coronary syndrome (ACS). We conducted an observational clinical study where sACE2 was measured in two cohorts of HF or ACS (102 patients each), matched by age and gender. The primary endpoint (cardiac death) and the secondary endpoints (non-fatal myocardial infarction or HF readmission) were registered during a 5-year follow-up period. Association with pharmacotherapy was studied, and the effects of cardiovascular drugs on ACE isoforms expression were analysed in human umbilical vein endothelial cells (HUVEC) in vitro. The levels of sACE2 were significantly higher in the HF than ACS cohort. sACE2 was inversely related with the leukocytes number and directly with urea levels. In the ACS cohort, sACE2 was associated with age and glycaemic parameters, but in the HF cohort, the association was with N-terminal pro-B-type natriuretic peptide. The levels of sACE2 were related to long-term prognosis and confirmed as a non-independent predictor in the HF cohort. Soluble ACE2 was higher in patients treated with angiotensin receptors blockers and β-blockers, accordingly with losartan and metoprolol upregulation of ACE1 and ACE2 in HUVECs. Plasma levels of sACE2 were higher in HF than in ACS, independently of age and gender, and were related to long-term cardiac death in the HF cohort. Losartan and metoprolol, but not enalapril, upregulated ACE expression in endothelial cells, accordingly with higher levels of sACE2 in patients using these drugs. Supplementary Information The online version contains supplementary material available at 10.1007/s00109-021-02129-4.

Background Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting. Objectives The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19–associated ARDS. Methods A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography. Results Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl [Q1, Q3: 4.63, 265 neutrophils/µl] vs median: 397 neutrophils/µl [Q1, Q3: 222, 1,346 neutrophils/µl] in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 [Q1, Q3: 110, 162] vs median: 267 [Q1, Q3: 199, 298] at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17). Conclusions In this pilot trial, intravenous metoprolol administration to patients with COVID-19–associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19–associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic., Central Illustration

Objective To interrogate the National Veterans Health Administration (VA) database to determine if beta-blocker use at time of initiation of androgen therapy deprivation (ADT) would result in improved oncological outcomes in advanced prostate cancer (PCa). Methods All men diagnosed with high risk PCa (PSA >20) from 2000-2008 who were on ADT ≥ 6 months were identified. Patients receiving ADT concurrently with primary radiation therapy were excluded. Pharmacy data was interrogated for all beta-blockers, but then focused on the selective beta-1 blocker metoprolol. Cox proportional hazards ratios were calculated for overall survival (OS), PCa specific survival (CSS) and skeletal related events (SREs). Results In 39,198 patients with high risk PCa on ADT, use of any beta-blocker was not associated with improvement in OS, CSS, or SREs. Further analyses focusing on metoprolol found that 10,224 (31.9%) had used metoprolol while 21,834 had no beta-blocker use. Multivariable analysis with Inverse Propensity Score Weighting, adjusted for factors including PSA, Gleason score, and duration ADT, found that utilization of metoprolol was not associated with improvement in OS (hazard ratio [HR] 0.97, P = .19), CSS (HR 0.94, P = .23) or SREs (HR 0.98, P = .79). Conclusion In this large cohort, metoprolol use in conjunction with ADT in high risk PCa was not associated with improvement in OS, CSS, or risk of SRE. In contrast to a recent smaller clinical study, our data strongly suggests no cancer specific benefit to beta-blocker use in advanced PCa.

Background There is a paucity of literature on the anesthetic management of pediatric esophageal substitution using the stomach. We did a retrospective analysis of all such cases done at our institution. We analyzed the patient’s demography, indication, and type of surgery, co-morbid conditions, anesthesia techniques, duration of postoperative ventilation, hospital stay, complications, and mortality. The use of beta-blockers and their effect on the incidence of intraoperative and postoperative tachycardia in gastric pull-up patients was also analyzed. Results Thirty-four cases of gastric substitution of the esophagus in children were done over 19-year period; gastric pull-up was done in 28 patients and a gastric tube was made in 6 patients. General anesthesia was given to all; a thoracic epidural for pain was sited in 25 patients. Twenty-eight patients were ventilated postoperatively; the mean duration of ventilation is 54 h. Significant intraoperative tachycardia was observed in 85.7% of patients without beta-blocker as compared to 23.8% patients with beta-blocker (p = 0.004). Postoperatively, tachycardia was absent in patients receiving beta-blocker and present in 71.4% of patients not receiving beta-blockers (p < 0.001). Overall mortality was 8.8% but mortality due to cardiac arrhythmia was 42.9% in the patients not receiving beta-blockers (p = 0.001). Conclusions A thorough preoperative preparation, control of tachyarrhythmias, postoperative ventilation, and pain management is recommended for a favorable outcome. In addition, our paper supports the preoperative use of beta-blockers in reducing the incidence of fatal tachyarrhythmias associated with gastric pull-up surgery without any serious adverse effects. Level of evidence Level III