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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.

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.

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.

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.

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.

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

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

Adrenergic β-blockers are used to treat many conditions, including hypertension, cardiac arrhythmias, heart failure, angina pectoris, migraine, and tremors. The majority of the β-blockers including Propranolol, Metoprolol, Acebutolol, Alprenolol, Betaxolol, Carvedilol, Nebivolol and Oxprenolol are metabolised majorly by CYP2D6, and Bisoprolol is primarily metabolised by CYP3A4 enzymes. The drugs inhibiting or inducing them may alter the pharmacokinetics of those β-blockers. The plasma concentrations of Propranolol might be elevated by the concomitant use of drugs, such as SSRIs (Fluoxetine, Paroxetine), SNRIs (Duloxetine) and Cimetidine, while the plasma concentrations of Metoprolol increased by the concurrent use of SSRIs (Fluoxetine, Paroxetine), Amiodarone, Celecoxib, Cimetidine, Terbinafine, and Diphenhydramine. β-blockers can also interact pharmacodynamically with drugs, including fluoroquinolones, antidiabetic agents and NSAIDs. In addition, β-blockers may interact with herbs, such as curcumin, Ginkgo biloba, Schisandra chinensis, green tea, guggul, hawthorn, St. John’s wort and Yohimbine. This article focuses on clinically relevant drug interactions of β-blockers with commonly prescribed medications. In addition to Pharmacokinetics and Pharmacodynamics of the drug interactions, recommendations for clinical practice are highlighted. The prescribers and the pharmacists are needed to be aware of the drugs interacting with β-blockers to prevent possible adverse drug interactions.

Short bowel syndrome is a clinical condition defined by malabsorption of nutrients and micronutrients, most commonly following extensive intestinal resection. Due to a loss of absorptive surfaces, the absorption of orally administered drugs is also often affected. The purpose of this study was to systematically review the published literature and examine the effects of short bowel syndrome on drug pharmacokinetics and clinical outcomes. Studies were identified through searches of databases MEDLINE, EMBASE, Web of Science, and SCOPUS, in addition to hand searches of studies’ reference lists. Two reviewers independently assessed studies for inclusion, yielding 50 studies involving 37 different drugs in patients with short bowel syndrome. Evidence of decreased drug absorption was observed in 29 out of 37 drugs, 6 of which lost therapeutic effect, and 14 of which continued to demonstrate clinical benefit through drug monitoring. The influence of short bowel syndrome on drug absorption appears to be drug-specific and dependent on the location and extent of resection. The presence of a colon in continuity may also influence drug bioavailability as it can contribute significantly to the absorption of drugs (e.g., metoprolol); likewise, drugs that have a wide absorption window or are known to be absorbed in the colon are least likely to be malabsorbed. Individualized dosing may be necessary to achieve therapeutic efficacy, and therapeutic drug monitoring, where available, should be considered in short bowel syndrome patients, especially for drugs with narrow therapeutic indices.

Congenital long QT syndrome is a pathology that requires special attention and knowledge about the safety and effectiveness of various medications. Prolongation of the QT interval due to congenital or acquired causes is an important factor in the development of an unfavorable life forecast with the formation of an elongated QT syndrome. With an unfavorable course, patients suffer from loss of consciousness, episodes of tachycardia. Often, stable polymorphic ventricular tachycardia develops. The risk of sudden cardiac death in this pathology can vary from 0.33% to 5%. In people who have suffered an episode of cardiac arrest, and do not have a permanent prescribed antiarrhythmic therapy, the mortality rate reaches 50% within 15 years. Preventive administration of antiarrhythmic drugs is not always effective. A positive result of treatment depends on the severity of long QT syndrome and its genotype. Beta-blockers are often prescribed to patients of different ages with various cardiac pathologies, including for the prevention of arrhythmia in long QT syndrome. Beta-blockers differ in various pharmacokinetic and pharmacodynamic parameters (lipophilicity/hydrophilicity, selectivity, presence/absence of internal sympathomimetic activity), which, along with the variant of the disease genotype, can affect their effectiveness and safety in the considered pathology. This review article presents the results of major studies on the safety and effectiveness of different groups of beta blockers in various variants of long QT syndrome. The preferred beta-blockers for various genotypes of the syndrome were determined, and a comparative characteristic of beta-blockers for their safety and preventive effectiveness was given.

Areca catechu is an important ancient drug commonly known as Supari in ayurvedic system of medicine. A lot of research work has been done on Areca catechu regarding various cardiovascular disorders such as Hypertension, Arrhythmia but no work has been done to find out its cardioprotective activity. Experimental procedures done on Wistar Albino rats as Normal control group (NC) received 0.5ml of normal saline throughout the study and served as control. Isoprenaline group (ISO) received 0.5ml of normal saline throughout the experimental phase and received Isoprenaline (85mg/kg, s.c.) on 14th and 15th day at a time lapse of 24 hours. Standard group (STD) received Metoprolol (pure) (10mg/kg/day, p.o.) for 13 days and received Isoprenaline (85mg/kg, s.c.) on 14th and 15th day. Test group received Areca catechu extract (100mg/kg/day, p.o.) and (200 mg/kg/day, p.o.) respectively for 13 days and Isoprenaline (85mg/kg, s.c.) on 14th and 15th day. On 16thday animals were sacrificed. The level of marker enzyme in serum as AST, ALT, CK, LDH, Troponin-I have shown significant decrease (P

Exercise oscillatory ventilation (EOV) is a form of periodic breathing that is associated with a poor prognosis in heart failure patients, but little is known about EOV in other populations. We sought to provide insights into the phenomenon of EOV after it was observed in young healthy subjects, including athletes, after the administration of dual autonomic blockade (DAB). From 29 participants who completed cardiopulmonary exercise testing (CPET) with and without DAB (0.04 mg/kg atropine and 0.2 mg/kg metoprolol), 5 subjects developed EOV (age = 29 ± 5 years; 3/5 were athletes) according to American Heart Association criteria. For each case, we identified 2 non-EOV healthy controls (age = 34.2 ± 8.3; 7/10 were athletes) that were subsequently age- and sex-matched. No participants had EOV during exercise without DAB. The 5 participants (4 male, 1 female) who demonstrated EOV with DAB had lower mean tidal volume (1.7 ± 0.5 L/min vs. 1.8 ± 0.5 L/min; p = 0.04) compared to participants in the non-EOV group and a decrease in peak tidal volume (2.9 ± 0.6 L/min to 2.2 ± 0.7 L/min; p = 0.004) with DAB. There were few other differences in CPET measures between EOV and non-EOV participants, although the PETCO2 tended to be higher in the EOV group (p = 0.07). EOV can be elucidated in young healthy subjects, including athletes, during cardiopulmonary exercise testing, suggesting that it may not be an ominous sign in all populations.

Coronary CT angiography (CCTA) is increasing seen as a first line investigation in patients with suspected coronary artery disease. Heart-rate control improves the image quality and diagnostic accuracy of CCTA. Typically, beta-blockers are administered to induce sinus bradycardia. Sinus bradycardia may also be induced by ivabradine. We hypothesized that in a real-world population ivabradine would be an effective alternative to metoprolol at heart rate lowering for CCTA.This was a retrospective analysis of consecutive patients who were exposed to an ivabradine-based (IB) versus a metoprolol-only (MO) protocol to achieve a target heart rate/ = 65bpm. Hemodynamic responses to both strategies were compared along with differences in cost and the time expired from medication administration to CCTA.5955 consecutive patients were included in the analysis: 3211 were imaged during an era of a metoprolol only strategy (MO) and 2744 CCTA following an ivabradine based (IB) strategy. 2676 patients had heart rates65 and received heart-rate lowering medication: 1958 patients had MO, and 718 received IB protocol. Target heart rate of/ = 65bpm was achieved in 77% of MO and 89% of IB patients (p 0.01). The time from initial medication administration to CCTA was longer in the IB versus MO patients (77 versus 48 min, p 0.01).Introduction of a novel single dose ivabradine-based protocol to control heart rate for CCTA was more successful in achieving target heart rate than a metoprolol-only strategy. The use of ivabradine however incurred a 1.6-fold increase in the time delay from medication administration and imaging compared to a metoprolol only protocol.

Rational & Objective Beta-blockers are recommended for patients with heart failure (HF) but their benefit in the dialysis population is uncertain. Beta-blockers are heterogeneous, including with respect to their removal by hemodialysis. We sought to evaluate whether β-blocker use and their dialyzability characteristics were associated with early mortality among patients with chronic kidney disease with HF who transitioned to dialysis. Study Design Retrospective cohort study. Setting & Participants Adults patients with chronic kidney disease (aged≥18 years) and HF who initiated either hemodialysis or peritoneal dialysis during January 1, 2007, to June 30, 2016, within an integrated health system were included. Exposures Patients were considered treated with β-blockers if they had a quantity of drug dispensed covering the dialysis transition date. Outcomes All-cause mortality within 6 months and 1 year or hospitalization within 6 months after transition to maintenance dialysis. Analytical Approach Inverse probability of treatment weights using propensity scores was used to balance covariates between treatment groups. Cox proportional hazard analysis and logistic regression were used to investigate the association between β-blocker use and study outcomes. Results 3,503 patients were included in the study. There were 2,115 (60.4%) patients using β-blockers at transition. Compared with nonusers, the HR for all-cause mortality within 6 months was 0.79 (95% CI, 0.65-0.94) among users of any β-blocker and 0.68 (95% CI, 0.53-0.88) among users of metoprolol at transition. There were no observed differences in all-cause or cardiovascular-related hospitalization. Limitations The observational nature of our study could not fully account for residual confounding. Conclusions Beta-blockers were associated with a lower rate of mortality among incident hemodialysis patients with HF. Similar associations were not observed for hospitalizations within the first 6 months following transition to dialysis.

Present investigation is based upon a new method development and validation for the simultaneous estimation of drugs comes under the classification of anti-hypertensive and anti-diabetic. For the proposed method metformin, ivabradine, metoprolol and ertugliflozin drugs were selected. The chromatographic separation was achieved by using mobile phase 0.01N potassium dihydrogen ortho phosphate buffer and acetonitrile (50:50) ratio and stationary phase of kromasil C18(250×4.6mm, 5µm) column. The retention times for metformin, ivabradine, metoprolol and ertugliflozin were found to be 2.560min, 3.116 min, 3.473 min and 5.196 min respectively. The developed method shows that all the drugs were clearly separated among each other with the system suitability. The developed method was further validated as per ICH guidelines Q2R1. It was found the method was accurate, presice with good linearity. Hence this method can be used for the routine analysis of these drugs in biological sample.

Choroidal hemangioma is a visual threatening condition for which treatments is neither uniform nor widely available. New management options are necessary. The purpose of this study is to assess the safety and early outcome of intravitreal metoprolol tartrate in five patients with CCH. Five eyes of five patients diagnosed with subfoveal or peripapillary CCH and unsuccessfully treated with intravitreal anti-VEGF agents were enrolled and received off-label intravitreal injections of metoprolol (50μg/0.05 ml). Baseline and follow-up evaluations included best-corrected visual acuity, intraocular pressure measurement, assessment of anterior chamber cellular score/flare and vitritis, retinography, fundus autofluorescence, and ERG. Patients were followed for a period of 30 days. Statistical analysis involved comparison of pre- and post-treatment findings using a paired t-test. There was no significant difference in all ERG parameters regarding a- and b-wave amplitude and implicit time, and oscillatory potentials’ maximal amplitude. There were no significant changes in visual acuity. None of the patients developed clinical signs of intraocular inflammation. The subretinal and/or intraretinal fluid improved in 3 out of 5 patients 4 weeks after the metoprolol injection. Patients with CCH treated with a single injection of 50μg/0.05ml intravitreal metoprolol injections showed no signs of acute ocular toxicity. This pilot study did not assess long-term retinal toxicity, different concentrations, drug resistance, and complications from repeated-intravitreal injections.

Open abdominal surgery is frequently related to excessive inflammation and a compromised intestinal barrier, leading to poor clinical outcomes. The administration of beta-1 blocker has been shown to effectively reduce inflammation and preserve intestinal barrier function in patients with sepsis, shock, or other critical illnesses. The underlying mechanism of these effects may be associated with the autonomic nervous system's activation via cholecystokinin receptors. This study aimed to investigate the effect of beta-1 blocker on systemic and local inflammatory responses and the intestinal barrier function in the context of open abdominal surgery.A rat model of open abdominal surgery was induced through peritoneal air exposure for 3 hours and treated via gavage with the beta-1 blocker, metoprolol, or saline. Cholecystokinin-receptor antagonists were administered before the metoprolol treatment. Peritoneal lavage fluid, serum, and tissues were collected 24 hours after surgery to determine systemic and local inflammation and intestinal integrity.The intervention with metoprolol significantly reduced serum tumor necrosis factor-alpha and interleukin-6 (P.05) and peritoneal interleukin-6 (P.01) compared with those of animals treated with saline. The intestinal myeloperoxidase indicating the influx of neutrophils was also significantly prevented by the administration of metoprolol (P.05). Above all, this intervention resulted in a significant decrease in serum D-lactate and intestinal fatty acid-binding protein, intestinal permeability, bacterial translocation, and Chiu's score for intestinal mucosa injury (P.05). However, the anti-inflammatory and intestinal integrity protective effects of metoprolol were prevented by the blockage of cholecystokinin receptors (P.05).Our data indicate that beta-1 blocker reduces systemic and local inflammatory responses and preserves intestinal barrier function after open abdominal surgery through a mechanism that depends on cholecystokinin receptors. Clinically, these findings imply that perioperative intervention with a beta-1 blocker may be an effective new therapy to enhance recovery after open abdominal surgery.

Males and females may respond differently to medications, yet knowledge about sexual dimorphisms in the effects of polypharmacy remains limited, particularly in aging. This study aimed to assess the effect of high Drug Burden Index (DBI) polypharmacy treatment compared to control on physical function and behavior in young and old, male and female mice. We studied whether age and sex play a role in physical function and behavior following polypharmacy treatment and whether they are paralleled by differences in serum drug levels. Young (2.5 months) and old (21.5 months), C57BL/6 mice were randomized to control or high DBI polypharmacy treatment (simvastatin, metoprolol, oxybutynin, oxycodone, and citalopram; n = 6–8/group) for 4–6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, and total distance), middle zone distance (increased anxiety), and nesting score (reduced activities of daily living) in mice of both ages and sexes (p < .001). Old animals had a greater decline in nesting score (p < .05) and midzone distance (p < .001) than young animals. Grip strength declined more in males than females (p < .05). Drug levels at steady state were not significantly different between polypharmacy-treated animals of both ages and sexes. We observed polypharmacy-induced functional impairment in both age and sex groups, with age and sex interactions in the degree of impairment, which were not explained by serum drug levels. Studies of the pathogenesis of functional impairment from polypharmacy may improve management strategies in both sexes.

Introduction. Hyperviscosity syndrome plays an important role in the pathogenesis of arterial hypertension and its complications associated with impaired microcirculation in target organs. Therefore, along with the use of antihypertensive drugs, it is important to pay attention to the correction of the hyperviscosity syndrome with means of hemorheological agents.The aimis to study the effect of metoprolol and its combined use with dihydroquercetin (DHQ) on the rheological parameters of blood in rats with spontaneous arterial hypertension.Materials and methods. The experiments were carried out on normotensive male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). SHRs of the experimental groups received metoprolol (50 mg/kg) or metoprolol and DHQ (50 mg/kg each) daily intragastrically for 6 weeks in 1 % starch mucus; SHRs of the control group and normotensive rats received 1 % starch mucus according to the same scheme. Systemic blood pressure was registered in awake animals. Blood was sampled from the catheterized right common carotid artery. Blood viscosity, plasma viscosity, hematocrit, erythrocyte aggregation and deformability were studied.Results. Compared with the parameters in normotensive rats, SHRs showed significant increase of blood viscosity, hematocrit, erythrocyte aggregation, and decrease of erythrocyte deformability. The course administration of metoprolol induced to a further increase in blood viscosity at low shear rates (15–45 s–1); plasma viscosity, hematocrit and micro-rheological parameters in rats of this group did not significantly differ from those in the control. With the combined administration of metoprolol and DHQ, blood viscosity at shear rates of 300 and 450 s–1and erythrocyte aggregation were significantly lower than in the control SHRs.Conclusions. The course administration of metoprolol increases the severity of the hyperviscosity syndrome in SHRs. The use of DHQ together with metoprolol partially eliminates adverse effects of the beta blocker on blood rheology parameters.

Sympathetic nervous system plays an important role in secondary injury of diseases. Accumulating evidence has observed association between ischemic stroke and renal dysfunction, but the mechanisms are incompletely clear. In this study, we investigated whether sympathetic hyperactivity can cause the development of renal dysfunction, apoptosis, and fibrogenesis after focal cerebral infarction. To determine the renal consequences of focal cerebral ischemia, we subjected a mice model of transient middle cerebral artery occlusion (tMCAO) and examined systolic blood pressure, heart rate, renal structure and function, serum catecholamine, and cortisol levels, and the expression of active caspase-3 bcl-2, bax, and phosphorylated p38 MAPK after 8 weeks. We also analyzed the relationship between insular cortex infarction and acute kidney injury (AKI) in 172 acute anterior circulation ischemic stroke (ACIS) patients. Transient right middle cerebral artery occlusion induced sympathetic hyperactivity, renal dysfunction, upregulation of apoptosis, and fibrogenesis in kidneys of mice. Metoprolol treatment relieves the development of renal injury. Study in stroke patients demonstrated that insular cortex infarction, especially the right insular cortex infarction, is an independent risk factor of AKI. Focal cerebral ischemia in mice leads to the development of renal injury driven by sympathetic hyperactivity. Right insular cortex infarction is an independent risk factor of AKI in older patients. Understanding the brain-kidney interaction after stroke would have clinical implications for the treatment and overall patient outcome.

Endothelial cell dysfunction in pregnancy, which can be induced by placental factors, is the fundamental component of the pathogenesis of pre-eclampsia. The dysfunctional vascular endothelium disrupts the balance of vasodilatory and vasoconstrictive factors, resulting in increasing blood pressure. There is currently no effective treatment for pre-eclampsia and effective control of hypertension may reduce neonatal morbidity and mortality by prolonging gestation, especially in cases of early onset disease. To date methyldopa, labetalol, nifedipine and metoprolol are recommended for controlling blood pressure in pre-eclampsia. All of these drugs have different mechanisms of action. In this in vitro study we investigated whether different types of anti-hypertensive drugs could have different effects on improving maternal endothelial cell dysfunction. Endothelial cells (HMEC-1) were exposed to phorbol-12-myristate-13-acetate (PMA) or pre-eclamptic sera or extracellular vesicles (EVs) derived from pre-eclamptic placentae, in the presence of each of the studied anti-hypertensive drugs (methyldopa, labetalol, nifedipine and metoprolol) or placebo for 24 h. Endothelial cell-surface adhesion molecule (ICAM-1) and monocyte adhesion were measured. The expression of cell-face ICAM-1 by HMEC-1 cells and THP-1 monocyte adherent to HMEC-1 that were exposed to three separate well-known activators of endothelial cells in the presence of four anti-hypertensive drugs was significantly reduced regardless of the dose. However, the effect on the reduction of ICAM-1 expression and monocyte adhesion was not significantly different between the four medications. Our data suggest that the beneficial effect on improving endothelial cell function by these commonly prescribed anti-hypertensive drugs is seemingly independent of the anti-hypertensive mechanisms of the medication.

Purpose Current guidelines have no sex‐specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population‐based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data. Methods The mean daily starting doses of metoprolol in both sexes were compared with independent‐samples t‐tests and a linear regression analysis was used to adjust in the RS for co‐variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI‐database, adjustment was for age only. Results The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI −7.8, −1.8) and 4.6 mg (95%CI −5.3,‐4.0), respectively. Statistical significance remained after adjustment in both databases. Conclusions Women received lower starting doses of metoprolol than men in two independent data collections despite non‐sex specific cardiovascular guideline recommendations. This example of real‐life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.

Aim: This study aimed to describe the trends in beta-blocker prescribing in the outpatient setting of a public hospital in Al Saih. Methodology: This is a retrospective study that includes patient electronic records revision of outpatients Between 1st July and 31th December 2018. Results: The most commonly prescribed beta-blocker was bisoprolol (79.10%) followed by metoprolol (7.34%) More than half of the patients were less than 60 years old (52.54%). About 55.93% of the patients receiving beta-blockers were male. About 39.55% of the prescribed drugs were prescribed by cardiology department (39.55%) followed by internal medicine department (36.72%). Conclusion: It can be concluded that beta-blockers were prescribed commonly. More studies are needed to find the prescribing patterns of beta-blockers for treating different indications and to prepare stratified guidelines to treat cardiovascular patients based on their characteristics.

International audience; Aims Our objectives were to validate a murine model of chronic cardiotoxicity induced by Doxorubicin (Dox) and Trastuzumab (Trast) and to test the potential cardio-protective effect of metoprolol. Methods and results Male C57Bl6 mice were intraperitoneally injected during 2 weeks with Dox (24 mg/kg) or saline, and then with Trast (10 mg/kg) or saline for two more weeks. Half of the mice received metoprolol (100 mg/kg). Cardiotoxicity was defined by a decline in left ventricular ejection fraction (LVEF) ≥ 10 points. At Day 42, Dox + Trast-treated mice exhibited a 13-points decline in LVEF (74 ± 2.6% vs. 87 ± 0.8% for control mice, P < 0.001) and a severe cardiac atrophy (heart weight: 105 ± 2.7 mg vs. 119 ± 3.9 mg for control mice, P < 0.01). This cardiac atrophy resulted from an excess of cardiac necrosis (assessed by plasma cardiac troponin I level: 3.2 ± 0.4 ng/L vs. 1.3 ± 0.06 ng/L for control mice, P < 0.01), an increase in apoptosis (caspase 3 activity showing a six-fold increase for Dox + Trast-treated mice vs. controls, P < 0.001), and cardiomyocyte atrophy (myocyte size: 0.67 ± 0.08 μm 2 vs. 1.36 ± 0.10 μm 2 for control mice, P < 0.001). In addition, Dox + Trast-treated mice were shown to have an increased cardiac oxidative stress (164 ± 14 dihydroethidine-marked nuclei per area vs. 56 ± 9.5 for control mice, P < 0.01) and increased cardiac fibrosis (the semi-quantitative fibrosis score was threefold higher for Dox + Trast-treated mice as compared with controls, P < 0.01). Metoprolol was not able to prevent either the decrease in LVEF or the severe cardiac atrophy, the cardiac necrosis, and the cardiac remodelling induced by chemotherapies. Conclusion A murine model of chronic cardiotoxicity induced by Dox and Trast was characterized by a decrease in cardiac function, a cardiac apoptosis and necrosis leading to cardiomyocyte atrophy. Metoprolol did not prevent this cardiotoxicity.

Objectives: Adequate control of hemodynamic parameters in patients undergoing otolaryngology-head and neck (OLHN) surgeries is one of the objectives of peri-operative anesthesia management. In this context, we seek to evaluate the effectiveness of metoprolol compared to clonidine in the post-operative control of systolic (SBP) and diastolic (DBP) blood pressures, and heart rate (HR), when these medications are used in the immediate pre-operative period. Method: this is a randomized double-blind clinical trial. Patients over 18 years old, according to the American Society of Anesthesiologists Physical Status Classification (ASA) I or II, who would undergo OLHN surgery, presenting with greater than 140 mmHg (SBP) or 90 mmHg (DBP), upon arrival at the surgical ward, were included in the study. 46 patients were randomized into two groups (C or M) who received clonidine (75 or 150 mcg) or metoprolol (5 or 10 mg), respectively. The averages of SBP, DBP and HR were compared between groups upon arrival at the post anesthesia care unit (PACU) and four hours post-surgery. Results: In group C, SBP (127.7 ± 18.8 vs 137.3 ± 14.1 mmHg, p = 0.03) and DBP (73.1 ± 15.46 vs 82.6 ± 7.9 mmHg, p 0.01) were lower, when compared with group M. No difference was observed in HR immediately upon PACU arrival. In addition, for four hours post-surgery, no change was noted in the SBP, DBP or HR. Conclusion: metoprolol was less effective than clonidine in reducing systolic and diastolic blood pressures in the immediate post-operative period of OLHN surgeries.

A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto–Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin–angiotensin–aldosterone system (RAAS) overactivation.

Context Garden cress (GC), fenugreek (FG), and black seed (BS) are traditional herbal medicine for managing hypertension. Objective The effects of the three herbs on the pharmacodynamics of metoprolol tartrate (MT) in hypertensive rats were investigated. Materials and methods Wistar rats were divided in five groups (n = 6). Group I served as normal control group and Group II (hypertensive control group) had rats treated orally with N-nitro L-arginine methyl ester (L-NAME, 40 mg/kg/day) only. Groups III, IV, and V rats were orally treated with L-NAME (40 mg/kg/day) + GC (300 mg/kg, once daily), L-NAME (40 mg/kg/day) + FG (300 mg/kg, once daily) and L-NAME (40 mg/kg/day) + BS (300 mg/kg, once daily), respectively, for 2 weeks, and on the 14th day, blood pressure and heart rate were recorded using a tail-cuff blood pressure-measuring system. On the 16th day, a single dose of MT (10 mg/kg) was orally administered, and the rats' blood pressure and heart rate were recorded. Results GC, FG, and BS decreased systolic blood pressure (SBP) by 8.7%, 8.5%, and 8.7%, respectively, in hypertensive rats. A greater decrease in SBP by 14.5%, 14.8%, and 16.1% was observed when hypertensive rats were treated with L-NAME + GC + MT, L-NAME + FG + MT, and L-NAME + BS + MT, respectively. Similarly, hypertensive rats treated with the combination of herbs and MT had significantly lower diastolic blood pressure (DBP) than those treated with herbs alone and those treated with L-NAME alone. Conclusions The combination of investigated herbs and MT had a beneficial effect on hypertension. However, the concurrent administration of drugs, particularly those predominantly cleared through CYP450 2D6-catalyzed metabolism, with the three investigated herbs should be considered with caution.

We present an extreme rare case of cristal atrial tachycardia (AT) in a 23-year-old male presenting with recurrent refractory palpitation since last 1 year treated with betablocker metoprolol 50 mg twice daily. We subjected the patient for electrophysiologic study and radiofrequency ablation and A wave in the mid cristal region preceded the surface P-wave by 16 ms. Ablation here terminated the tachycardia but interestingly patient turned up with recurrent palpitation after 1 month. In view of mid cristal AT, we treated the patient with Ivabradine 5 mg twice daily after which the patient was asymptomatic in follow up. Our case is a unique demonstration of sinus node funny current inhibitor Ivabradine being effective to relieve symptoms even in failed cases of radiofrequency ablation with partial modification of mid cristal region in a case of recurrent mid cristal AT. Our take home message from this electrophysiology experience is that even in cases with partial modification of crista terminalis or failed radiofrequency ablation of Cristal atrial tachycardia Ivabradine can serve as an alternative before proceeding to 3D ablation.

This article presents results of a systematic review, which was designed for evaluating the effect of combination treatment with ivabradine and metoprolol on heart rate, frequency of angina attacks, frequency of using short-acting nitrates, and angina severity. The analysis included data from three large observational studies on efficacy of the ivabradine and metoprolol tartrate combination in patients with chronic angina. Results of the analysis supported the efficacy of the metoprolol and ivabradine combination in clinical practice, which provided effective decreases in the heart rate, frequency of angina attacks, requirement for short-acting nitrates, and alleviation of angina severity. The studies demonstrated good tolerability of this treatment.