A Brief Review of a Common Clinical Question: Intravenous Diltiazem or Metoprolol for Atrial Fibrillation with Rapid Ventricular Response?

Two classes of rate controlling medications—beta blockers (BBs) and non- dihydropyridine calcium channel blockers (CCBs)—are given to patients who present with atrial fibrillation (AF) with rapid ventricular response (RVR). Both are Class I recommendations from the American Heart Association (AHA), American College of Cardiology (ACC), and Heart Rhythm Society (HRS) for the management of AF with RVR. Multiple studies support the view that diltiazem is more effective than metoprolol, even though data from the AFFIRM trial suggests BBs are more frequently used. CCBs are generally avoided in AF with RVR patients who have concomitant heart failure with reduced ejection fraction (HFrEF) for concern of triggering decompensation. However, some recent studies indicate this idea may be unfounded. The aim of this article is to compare the efficacy of diltiazem and metoprolol for rate control in AF with RVR and examine the use of diltiazem in patients with both AF with RVR and HFrEF.

Quantitative analysis of 3-isopropylamino-1,2-propanediol as a degradation product of metoprolol in pharmaceutical dosage forms by HILIC-CAD

Aryloxypropanolamine is an essential structural scaffold for a variety of b-adrenergic receptor antagonists such as metoprolol.Molecules with such a structural motif tend to degrade into α,β ehydroxypropanolamine impurities via a radicaleinitiated oxidation pathway.These impurities are typically polar and nonchromophoric,and are thus often overlooked using traditional reversed phase chromatography and UV detection.In this work,stress testing of metoprolol confirmed the generation of 3-isopropylamino-1,2-propanediol as a degradation product,which is a specified impurity of metoprolol in the European Pharmacopoeia(impurity N).To ensure the safety and quality of metoprolol drug products,hydrophilic interaction chromatography(HILIC)methods using Halo Penta HILIC column(150mm×4.6 mm,5 μm)coupled with charged aerosol detection(CAD)were developed and optimized for the separation and quantitation of metoprolol impurity N in metoprolol drug products including metoprolol tartrate injection,metoprolol tartrate tablets,and metoprolol succinate extended-release tablets.These HILIC-CAD methods were validated per USP validation guidelines with respect to specificity,linearity,accuracy,and precision,and have been successfully applied to determine impurity N in metoprolol drug products.

运用PEG相转移催化剂合成β受体阻滞剂Metoprolol酒石酸盐

提供了一种具有应用前景的合成M etoprolol酒石酸盐新工艺.产品以对甲氧乙基苯酚和环氧氯丙烷为原料,在相转移催化剂聚乙二醇400的作用下发生缩合反应合成2-[4-(2-甲氧基乙基)苯氧基]环氧乙烷中间体,中间体再经过胺化反应合成M etoprolol,M etoprolol与酒石酸成盐生成了M etoprolol酒石酸盐.产物由红外光谱(IR)、核磁光谱(1HNMR)、物理及化学分析等方法证实与目标产物基本一致,总收率达50%.

Development of a sensitive and rapid method for quantitation of (S)-(-)- and (R)-(+)-metoprolol in human plasma by chiral LC–ESI–MS/MS

A selective, sensitive and high throughput liquid chromatography-tandem mass spectro-metry （LC-ESI-MS/MS） method has been developed for separation and quantification of metoprolol enantiomers on a chiral Lux Amylose-2 （250 mm＆#215;4.6 mm, 5 mm） column. Solid phase extraction of （S）-（-）- and （R）-（t）-metoprolol and rac-metoprolol-d6 as an internal standard （IS） was achieved on Lichrosep DVB HL cartridges employing 200 mL human plasma. Both the analytes were chromatographically separated with a resolution factor of 2.24 using 15 mM ammonium acetate in water, pH 5.0 and 0.1% （v/v） diethyl amine in acetonitrile （50：50, v/v） as the mobile phase within 7.0 min. The precursor-product ion transitions for the enantiomers and IS were monitored in the multiple reaction monitoring and positive ionization mode. The method was validated over the concentration range of 0.500-500 ng/mL for both the enantiomers. Matrix effect was assessed by post-column analyte infusion experiment and the mean extraction recovery was greater than 94.0% for both the enantiomers at all quality control levels. The stability of analytes was evaluated in plasma and whole blood under different storage conditions. The method was successfully applied to a clinical study in 14 healthy volunteers after oral administration of 200 mg metoprolol tablet under fasting conditions. The assay reproducibility is shown by reanalysis of 68 incurred samples. The suitability of the developed method was assessed in comparison with＆amp;nbsp;different chromatographic methods developed for stereoselective analysis of metoprolol in biological matrices.

High-frequency Ultrasound Evaluation of Effects of Early Treatment with Metoprolol on Myocardial Inflammatory Cytokine Expression in Rats with Acute Myocardial Infarction

This study evaluated the effects of early treatment with β-adrenergic blocker metoprolol on ventricular remodeling and function after acute myocardial infarction (AMI) by using high frequency ultrasound.The relationship between the efficacy and the expression level of cardiac myocardial inflammatory cytokine was examined in rats.The rat model of AMI was induced by ligating the left ante-rior descending artery.The surviving rats were randomly assigned to two experimental groups:MI control (MI) group and MI metoprolol (MI-B) group,with the rats undergoing sham operation serving as normal control (Sham).MI-B group was given metoprolol for 4 weeks (refer to the CCS-2 protocol) and the other two groups received equal volume of saline via intragastric (i.g.) administation.The ventricular remodeling and function were evaluated by high frequency ultrasound 4 weeks after the treatment.Then all rats were sacrificed for pathological examination and immunohistochemistrical detection of inflammatory cytokines,including IL-1β,IL-6,IL-10 and TNF-α.Compared with the MI group,the left ventricular end-systolic dimension,end-diastolic dimension,end-systolic volume and end-diastolic volume of the MI-B group were significantly decreased (P<0.01),while the left ventricular anterior wall end-diastolic thickness,ejection fraction and fractional shortening were obviously increased (P<0.01).The conspicuous improvement in the left ventricular morphology and function was coincident with the markedly reduced TNF-α and IL-1β expression and the increased IL-10 expression.We are led to conclude that early metoprolol treatment for AMI can regulate myocardial inflammatory cytokine expression to improve cardiac function and the underlying mechanism might be that it decreases the level of pro-inflammatory cytokines and increases the level of its anti-inflammatory counterparts in cardiac myocytes.Our study also showed that echocardiography is a useful technique for the structural and functional assessment of left ventricle after acute myocardial infarction.

Advancing USP compendial methods for fixed dose combinations: A case study of metoprolol tartrate and hydrochlorothiazide tablets

The current United States Pharmacopeia–National Formulary(USP–NF) includes more than 250 monographs of fixed dose combinations(FDCs), and some of them need to be updated due to incompleteness of impurity profiles and obsolescence of analytical methodologies. A case study of metoprolol tartrate and hydrochlorothiazide tablets is presented to summarize challenges encountered during the USP monograph modernization initiative of FDCs and to highlight an "adoption and adaptation" approach employed for method development. To this end, a single stability-indicating HPLC method was developed to separate the two drug substances and eight related compounds with resolution 2.0 or higher between all critical pairs. Chromatographic separations were achieved on a Symmetry column(C18,100 mm*4.6 mm, 3.5 mm) using sodium phosphate buffer(pH 3.0; 34 mM) and acetonitrile as mobile phase in a gradient elution mode. The stability-indicating capability of this method has been demonstrated by analyzing stressed samples of the two drug substances. The developed HPLC method was validated for simultaneous determination of metoprolol tartrate and hydrochlorothiazide and relevant impurities in the tablets. Moreover, the developed method was successfully applied to the analysis of commercial tablet dosage forms and proved to be suitable for routine quality control use. The case study could be used to streamline USP's monograph modernization process of FDCs and strengthen compendial procedures.

Effect of metoprolol on myocardial apoptosis after coronary microembolization in rats

BACKGROUND:Coronary microembolization(CME) is a serious complication following percutaneous coronary intervention(PCI) in patients with acute coronary syndromes.The use of metoprolol before PCI can significantly protect ischemic myocardium from myocardial damage,but the function of metoprolol in the treatment of CME is not entirely clear.This study was to explore the effect and significance of metoprolol on myocardial apoptosis and caspase-3 activation after CME in rats.METHODS:Thirty rats were randomly divided into three groups including sham-operation(control group),CME plus saline(CME group),CME plus metoprolol(metoprolol group),10 rats for each group.The CME group was induced by injecting 3 000 polyethylene microspheres(42 urn)into the left ventricle during a 10-second occlusion of the ascending aorta;the control group was injected with physiological saline instead of microembolization ball;the metoprolol or saline group was given three intravenous bolus injections before CME.Echocardiography,TUNEL staining,and Western blotting were used to evaluate cardiac function,proportion of apoptotic cells and activation of caspase-3 respectively at 6 hours after operation.RESULTS:Echocardiography parameters displayed that the metoprolol group improved cardiac function significantly compared with the CME group(PO.05).The myocardial apoptotic rate of the CME group as well as the contents of activated caspase-3 increased significantly(P<0.05),both of which were ameliorated significantly by metoprolol treatment(P<0.05).CONCLUSIONS:This study demonstrates that metoprolol can protect the myocardium during CME in rats by inhibiting apoptosis and improving cardiac function.These results suggest that the inhibition of apoptosis can be a potential therapeutic strategy for the treatment of CME.

Carvedilol vs. metoprolol: A comparison of effects on endothelial function and oxidative stress in response to acute hyperglycemia in patients with type 2 diabetes and hypertension

Introduction: The GEMINI trial compared the effects of treatment with metoprolol versus carvedilol in patients with type 2 diabetes. Carvedilol demonstrated a more favorable effect on factors associated with the metabolic syndrome than metoprolol. We hypothesize that carvedilol will have additional beneficial effects on markers of inflammation, oxidative stress, and endothelial function than metoprolol. Methods: Twenty subjects were randomized to either carvedilol or metoprolol. Study procedures including assessment of metabolic parameters and endothelial function, while fasting and after a 75 g oral glucose tolerance were conducted at baseline and following 5 months of treatment. Results: Following 5 months of treatment, PAI-1 increased significantly from baseline in the metoprolol group. There were no changes in PAI-1 in the carvedilol group. While not reaching statistical significance, there was a trend toward worsening insulin resistance with metoprolol treatment compared to carvedilol treatment. Flow mediated vasodilation increased in both groups following the 2-hr OGGT during the baseline study. After five months of treatment, there was a non-significant increase in flow-mediated vasodilation under both fasting and post OGTT conditions in the carvedilol group compared to baseline. Conversely, there was no change in fasting flow mediated vasodilation in the metoprolol group. Additionally, metoprolol treatment blunted the increase in flow mediated vasodilation following OGGT compared to baseline (p < 0.05). Conclusion: Treatment with metoprolol was associated with adverse metabolic effects including increases in PAI-1 and trends toward worsening insulin resistance and endothelial function compared to treatment with carvedilol.

Effects of Isoproterenol and Metoprolol on the Suppression of Propafenone on with Supraventricular Tachycardia

This study was to determine whether isoproterenol (Iso) reverses the effects of propafenone(Pro) on the induction of supraventricular tarhycardia and whether the revergal during electrophysiologicstudy (EPS) is predictive of clinical recurrences of SVT during long-term treatment with Pro.Thirtypatients with inducible sustained SVT at baseline state were studied. Iso infusion at a rate necessary toachieve a 20%-40% increase in heart rate completely (16/28 cases,57%) or partially (5/28 case, 18%)revereed Pro's suppressant effects on the induction of SVT.There were clinical recurrcnces of SVT in fiveof 16 patients (31%) treated on a long-term basis (mean 4.5±3.6 months) with Pro,Iso completelyreveroed Pro's supprosant effect on the induction of SVT in four of these five patients (80%).These fivepatients then were treated with Pro and metoprolol and no further clincal recnrrences of SVT.These resultssuggested that reveroal by Iso ofpro's suppresaant effects on the induction of SVT may identify patients whoare likely to experience clinical recurrence of SVT and these patients may benefit from treatment with aB-blocker during longterm therapy with Pro.

Efficacy of Metoprolol Succinate Sustained Release Tablets Combined with Wenxin Granules in the Treatment of Coronary Heart Disease Arrhythmia

Objective:To explore the effect of metoprolol succinate sustained-release tablets combined with Wenxin Granules in the treatment of coronary heart disease patients with arrhythmia.Methods:The research objects were 50 patients with arrhythmia who were treated in our hospital from September 2019 to September 2020.According to different treatment methods,they were divided into observation group(Wenxin Granule+metoprolol succinate treatment)and control group(metoprolol succinate treatment),25 cases in each group.The curative effects of the two groups were compared.Results:After treatment,there was no significant difference in rnn50,RMSSD,sdnni and SDANN between the two groups(P>0.05).Compared with the control group,the SDNN in the observation group was higher than that in the control group(P<0.05);Before treatment,there was no significant difference in the above indexes between the two groups(P>0.05);The effective rates of the observation group and the control group were 92.00%and 68.00%respectively,and the curative effect of the observation group was higher than that of the control group(P<0.05);There was no significant difference in the incidence of adverse reactions between the two groups(P>0.05).Conclusion:In the treatment of patients with coronary heart disease and arrhythmia,Wenxin Granule Combined with metoprolol succinate sustained-release tablets has significant effect,which can effectively improve the dynamic electrocardiogram indexes of patients,improve the clinical efficacy,and has high safety.

Stereoselective Matabolism of Metoprolol in Isolated Rat Liver

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Stress Degradation Behavior of a Polypill and Development of Stability Indicating UHPLC Method for the Simultaneous Estimation of Aspirin, Atorvastatin, Ramipril and Metoprolol Succinate

A novel, sensitive and precise UHPLC method has been developed and validated for the simultaneous determination of the all the active components of a Polypill viz Zycad, i.e., Aspirin (ASP) Atorvastatin (ATV), Ramipril (RMP) and Metoprolol (MTP) in Zycad tablet dosage form in the presence of degradation products. Forced degradation of individual as well as combination of all the drug substances components of Polypill was conducted in accordance with ICH guidelines. Acidic, basic, neutral, and oxidative hydrolysis, thermal stress, and photolytic degradation were used to assess the stability-indicating power of the method. Use of 100 × 2.1 mm, 1.7 μm stationary phases with simple mobile phase combination buffer consisting of 0.1% Perchloric acid (adjusted to pH 2.5) and Acetonitrile, delivered in a gradient mode and quantitation was carried out using ultraviolet detection at 215 nm with a flow rate of 0.6 mL?min–1. The method was optimized using samples generated by forced degradation studies. The method was validated for linearity, accuracy (recovery), precision, Specificity and robustness. The method was linear in the range of 37.5 to 150.0 μg?mL–1 for ASP, 5.0 to 20.0 μg?mL–1 for ATV and 2.5 to 10.0 μg?mL–1 for RMP and 25.0 to 100.0 μg?mL–1 for MTP.

Comparison of Clonidine and Metoprolol Effectiveness on the Control of Post-Operative Blood Pressure in Otorhinolaryngology-Head and Neck Surgeries: A Clinical Trial

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.

Sinus Bradycardia and Multiple Episodes of Sinus Arrest With Lasting Period of More Than 14 Seconds Following Administration of Metoprolol: A Case Report

An aged male patient with coronary heart disease which had been treated with coronary artery bypass grafts （CABG） and administration of metoprolol, presented paroxysmal vertigo in the previous three weeks. The 24 hours synchronic 12- lead dynamic electrocardiography （DCG） revealed many episodes of sinus arrest which mostly were followed by A-V junctional or ventficular escape rhythm, the longest sinus pause lasting more than 14. 5 seconds with no symptom. After withdrawal of metoprolol, the DCG revealed much less episodes of sinus arrest than on-admission, but still some A-V junctional and ventricular escape beats. Sick sinus syndromes was then diagnosed, and a synchronous dual-chamber pacemaker （DDDR） was implanted two weeks after admission.

Clinical Efficacy of Metoprolol Succinic Acid Sustained Release Tablets Combined with Trimetazidine in the Treatment of Gastrointestinal Tumors with Angina Pectoris

Objective:To investigate the clinical efficacy of metoprolol succinate sustained-release tablets combined with trimetazidine in the treatment of gastrointestinal tumors with angina pectoris.Methods:We enrolled the 58 patients with digestive tract tumor merger angina in November 2017-October 2019 and analysis the hospital clinical data by retrospective method.We included patients with routine treatment in control group(n=31 cases)and the subjects treated with increased dose of succinic acid metoprololzyban joint with trimetazidineinobservation group(n=27 cases)according to the different treatment group.Results:The effective rate of angina pectoris treatment in the observation group was higher than that in the control group.Furthermore,the incidence of adverse reactions was lower than that in the control group and the difference was statistically significant(P<0.05).Conclusion:Metoprolol succinic acid sustained release tablets combined with trimetazidine in the treatment of gastrointestinal tumors with angina pectoris can improve the efficacy of angina pectoris.The drug use is safe and worthy of clinical use.

Effect of Metoprolol on Cardiac Function and Prognosis in Patients with Dilated Cardiomyopathy

Objective:To investigate the effect of metoprolol on cardiac function and prognosis in patients with dilated cardiomyopathy.Methods:100 patients with dilated cardiomyopathy treated in our hospital from January 2018 to December 2019 were randomly divided into control group(n=50)and observation group(n=50).The control group was treated with conventional methods,and the observation group was treated with conventional methods and metoprolol for 6 months.The cardiac function[left ventricular ejection fraction(LVEF),stroke volume(SV),cardiac output(CO)]and prognosis[Glasgow Outcome Scale(GOS)score]of the two groups before and at the end of 6 months of intervention were compared,and the incidence of adverse reactions of the two groups were compared.Results:After 6 months of treatment,the levels of LVEF,SV and CO in the two groups were higher than before treatment,and the comparison level between the observation group and the control group was higher,the difference was statistically significant(P<0.05);After 6 months of treatment,the GOS score of the observation group was higher than that of the control group,and the difference was statistically significant(P<0.05);There was no significant difference in the total incidence of adverse reactions between the two groups(P>0.05).Conclusion:Metoprolol can improve the cardiac function and prognosis of patients with dilated cardiomyopathy,without increasing the incidence of adverse reactions.

A predictive model of response to metoprolol in children and adolescents with postural tachycardia syndrome

Background The present work was designed to explore whether electrocardiogram(ECG)index-based models could predict the effectiveness of metoprolol therapy in pediatric patients with postural tachycardia syndrome(POTS).Methods This study consisted of a training set and an external validation set.Children and adolescents with POTS who were given metoprolol treatment were enrolled,and after follow-up,they were grouped into non-responders and responders depending on the efficacy of metoprolol.The difference in pre-treatment baseline ECG indicators was analyzed between the two groups in the training set.Binary logistic regression analysis was further conducted on the association between significantly different baseline variables and therapeutic efficacy.Nomogram models were established to predict therapeutic response to metoprolol.The receiver-operating characteristic curve(ROC),calibration,and internal validation were used to evaluate the prediction model.The predictive ability of the model was validated in the external validation set.Results Of the 95 enrolled patients,65 responded to metoprolol treatment,and 30 failed to respond.In the responders,the maximum value of the P wave after correction(Pcmax),P wave dispersion(Pd),Pd after correction(Pcd),QT interval dis-persion(QTd),QTd after correction(QTcd),maximum T-peak-to-T-end interval(Tpemax),and T-peak-to-T-end interval dispersion(Tped)were prolonged(all P<0.01),and the P wave amplitude was increased(P<0.05)compared with those of the non-responders.In contrast,the minimum value of the P wave duration after correction(Pcmin),the minimum value of the QT interval after correction(QTcmin),and the minimum T-peak-to-T-end interval(Tpemin)in the responders were shorter(P<0.01,<0.01 and<0.01,respectively)than those in the non-responders.The above indicators were screened based on the clinical significance and multicollinearity analysis to construct a binary logistic regression.As a result,pre-treatment Pcmax,QTcmin,and Tped were identified as significantly associated factors that could be combined to provide an accurate prediction of the therapeutic response to metoprolol among the study subjects,yielding good discrimination[area under curve(AUC)=0.970,95%confidence interval(CI)0.942-0.998]with a predictive sensitivity of 93.8%,specificity of 90.0%,good calibration,and corrected C-index of 0.961.In addition,the calibration curve and standard curve had a good fit.The accuracy of internal validation with bootstrap repeated sampling was 0.902.In contrast,the kappa value was 0.769,indicating satisfactory agreement between the predictive model and the results from the actual observations.In the external validation set,the AUC for the prediction model was 0.895,and the sensitivity and specificity were 90.9%and 95.0%,respectively.Conclusions A high-precision predictive model was successfully developed and externally validated.It had an excellent predictive value of the therapeutic effect of metoprolol on POTS among children and adolescents.