Analysis of the Efficacy of Low-Dose Betaloc Combined with Amiodarone in Treating Ventricular Arrhythmia

Objective:To explore and analyze the clinical effect of low-dose Betaloc combined with amiodarone in treating ventricular arrhythmia.Methods:70 patients with ventricular arrhythmia who were admitted to the Department of Cardiology of our hospital between August 2022 and August 2023 were selected as research subjects.They were divided into two groups using the coin-tossing method:the combination group(n=35)and the reference group(n=35).The combination group was treated with low-dose Betaloc and amiodarone,and the control group was treated with low-dose Betaloc alone.The treatment efficacy,cardiac function indicators,and related tested indicators of the two groups were compared.Results:The total efficacy of the treatment received by the combination group was much higher than that of the control group(P<0.05).Besides,after treatment,the cardiac function indicators such as left ventricular ejection fraction(LVEF),left ventricular end-systolic volume(LVESV),and cardiac index(CI)of the patients in the combination group were significantly better than those of the reference group(P<0.05).Furthermore,the high-sensitivity C-reactive protein(Hs-CRP),N-terminal prohormone of brain natriuretic peptide(NT-proBNP),adiponectin(APN),and other related test indicators of the patients in the combination group were significantly better than those of the reference group(P<0.05).Conclusion:Low-dose Betaloc combined with amiodarone has a noticeable effect in treating ventricular arrhythmia and deserves to be widely promoted.

Clinical Efficacy of Metoprolol Succinate Extended-Release Tablets in the Treatment of Post-Myocardial Infarction Ventricular Arrhythmias

Objective:To investigate the clinical efficacy of metoprolol succinate extended-release tablets in the treatment of post-myocardial infarction ventricular arrhythmias.Methods:The clinical data of 84 patients with post-myocardial infarction ventricular arrhythmia included in the study were collected and they were divided into Groups A and B with 42 cases each using the randomization method.Group A was treated with oral glucosamine hydrochloride,while Group B was administered oral metoprolol succinate extended-release tablets.Combined indicators were used to evaluate the improvement of clinical indicators,therapeutic effects,and the incidence of adverse reactions in the two groups.Results:The baseline data of the two groups of patients were not statistically significant(Pall>0.05);after treatment,the QT dispersion,corrected QT dispersion,and heart rate of Group B were lower than that of Group A(Pall=0.000<0.001);the 2 total clinical effectiveness of Group B was 95.24%,which was significantly higher than 80.95%in Group A(χ=4.087,P=0.043<0.05);the total incidence of adverse reactions in Group B was 4.76%,which was significantly lower than 219.04%in Group A(χ=4.087,P=0.043<0.05).Conclusion:In the treatment of post-myocardial infarction ventricular arrhythmia,the use of metoprolol succinate extended-release tablets can effectively correct the QT dispersion of patients,improve their heart rate,increase clinical effectiveness,and reduce the incidence of adverse reactions.

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.

Adverse reactions of Amiodarone

Adverse drug reaction is defined by the World Health Organization as any response to a drug that is noxious and unintended and occurs at a dose normally used in man.Older people are at elevated risk of adverse drug reactions—because of changes in pharmacodynamics,concurrent use of multiple medications and the related drug interactions.However,adverse drug reactions are significantly underestimated in the elderly population that is also exposed to inappropriate drugs.Amiodarone is an antiarrhythmic drug used commonly for the treatment of atrial fibrillation and is increasingly prescribed in older people.While amiodarone is an efficient drug for rhythm control,it’s a carrier of different adverse reactions,and pro and cons must be carefully evaluated before its use especially in older people.

Effect of Lidocaine and Amiodarone on Transmural Heterogeneity of Ventricular Repolarization in Isolated Rabbit Hearts Model of Sustained Global Ischemia

Summary： To study the effect of of lidocaine and amiodarone on the transmural heterogeneity of ventricular repolarization in isolated rabbit hearts model of sustained global ischemia and to explore the mechanisms underlying the antiarrhythmic activity of lidocaine and amiodarone, rabbits were randomly divided into 4 groups： control group, ischemia group, lidocaine group and amiodarone group. By the monophasic action potential （MAP） recording technique, MAPs of epicardium, midmyocardium and endocardium were simultaneously recorded across the left ventricular free wall in rabbit hearts perfused by low-flow ischemia （2. 5 mL/min） in Langendorff method to study the transmural dispcrsion of repolarization （TDR） and arrhythmic induced by ischemia.Our results showed that TDR of three myocardial layers in ischemia group were significantly lengthened after ischemia. TDR was increased from 17.5±3.9 ms to 31.2±4.6 ms at the time that concided with the onset of sustained ventricle arrhythmic. Amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia, and no significant difference was found at other ischemia time points. 5 cases had ventriclar arrhythmia in ischemia group （62. 5%）, but no case in lidocaine group （P〈0.01） and only 1 case in amiodarone group had ventrilar arrhythmia （P〈 0.01）. No significant difference was found between amiodarone group and lidocaine group. It is concluded that TDR of of three myocardial layers increases significantly at ischemia and it is closely associated with development of ventricular arrhythmia, and amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia and has no effects at other ischemia time points.

N-acetylcysteine treats intravenous amiodarone induced liver injury

We report a case of intravenous(IV) amiodarone drug induced liver injury(DILI).The patient received IV N-acetylcysteine(NAC) which resulted in a rapid improvement in liver enzymes.While the specific mechanisms for the pathogenesis of IV amiodaroneDILI and the therapeutic action of IV NAC are both unknown, this case strongly implies at least some commonality.Because IV amiodarone is indicated for the treatment of serious cardiac arrhythmias in an intensive care unit setting, some degree of ischemic hepatitis is likely a cofactor in most cases.

Acute hepatitis secondary to parenteral amiodarone does not preclude subsequent oral therapy

Amiodarone chlorhydrate is a diiodated benzofuran derivative used to treat cardiac rhythm abnormalities. Hepatotoxicity is a relatively uncommon side effect of amiodarone and symptomatic hepatic dysfunction occurs in less than 1% to 3% of patients taking amiodarone. We report here on an unusual case of amiodarone-induced hepatotoxicity. A 29 year old woman with normal liver function was given amiodarone intravenously to treat her atrial fibrillation. She developed acute toxic hepatitis after 24 h. The intravenous form of amiodarone was immediately avoided and replaced by the oral form, using conventional loading doses as soon as the deranged liver function tests had normalized, without recurrence of the hepatitis. These observations show that the occurrence of acute hepatic impairment with intravenous amiodarone does not necessarily preclude the use of this drug by mouth and the necessity of monitoring the hepatic function of patients treated with amiodarone.

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.

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.

Ameliorative effect of grapefruit juice on amiodarone-induced cytogenetic and testicular damage in albino rats

Objective:To evaluate the ameliorative role of grapefruit juice on the cytogenetic and testicular damage induced by the antiarrythmic drug amiodarone in albino rats.Methods:Animals were divided into four groups.Group I was considered as control.Group II was given grapefruit juice at a dose level of 27 mL/kg body weight.Group III was orally administered amiodarone(18 mg/kg body weight)daily for 5 weeks.Animals were sacrificed after 5 weeks of treatment.Bone marrow was collected from the femurs for analysis of chromosomal aberrations and mitotic indices.Testes were removed and stained with H&E for histological examination.Sperms were collected from epidedymis for detection of sperm head abnormalities.Comet assay was used to detect DNA damage.Results:Amiodarone treatment caused a significant increase in the percentage of chromosomal aberrations,decreased the mitotic index and increased DNA damage.The testis showed many histopathological alterations,inhibition of spermatogenesis and morphometric changes.The number of sperm head abnormalities was increased.Treating animals with amiodarone and grapefruit juice caused a reduction in chromosomal aberrations,mitotic index,DNA damage and testicular alterations caused by amiodarone.Conclusions:The results of this study indicated that grapefruit juice ameliorates the cytotoxicty and testicular alterations induced by amiodarone in albino rats and this is may be due to the potent antioxidant effects of its components.

Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: A case report

The anti-arrhythmic agent amiodarone （AD） is associated with numerous adverse effects, but serious liver disease is rare. The improved safety of administration of daily low doses of AD has already been established and this regimen is used for long-term medication. Nevertheless, asymptomatic continuous liver injury by AD may increase the risk of step-wise progression of non-alcoholic fatty liver disease. We present an autopsy case of AD-induced liver cirrhosis in a patient who had been treated with a low dose of AD （200 rag/d） daily for 84 too. The patient was a 85-year-old male with a history of ischemic heart disease. Seven years after initiation of treatment with AD, he was admitted with cardiac congestion. The total dose of AD was 528 g. Mild elevation of serum aminotransferase and hepatomegaly were present. Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were observed. Initially, withdrawal of AD led to a slight improvement of serum aminotransferase levels, but unfortunately his general condition deteriorated and he died from complications of pneumonia and renal failure. Long-term administration of daily low doses of AD carries the risk of progression to irreversible liver injury. Therefore, periodic examination of liver function and/or liver biopsy is required for the management of patients receiving long-term treatment with AD.

Acute pancreatitis and amiodarone:A case report

Amiodarone, a class Ⅲ antiarrhythmic drug, is one of the most effective drugs used in the treatment of ventricular and paroxysmal supraventricular tachyarrhythmia. Adverse effects of amiodarone including pulmonary toxicity, hepatotoxicity, aggravation of arrhythmia, and thyroid diseases are well understood. A 66-year old woman with acute pancreatitis was admitted to our hospital with the complaint of epigastralgia radiating to both flanks for two months. Her symptoms and elevation of pancreatic enzymes did not respond to conventional medical treatment of pancreatitis for 18 d. No known causal factors for pancreatitis such as biliary tract stone, hypertriglyceridemia and alcohol consumption could be identified. Under the suspicion of amiodarone-induced acute pancreatitis, amiodarone was substituted by propafenone. Her symptoms soon alleviated and serum lipase level declined. Three months after hospital discharge, the abdominal pain did not recur. Amiodarone was approved to treat recurrent ventricular fibrillation or sustained ventricular tachyarrhythmia that has been resistant to other medications since 1986. Pancreatitis is a very rare adverse effect associated with the use of amiodarone, and only four cases of amiodarone-induced pancreatitis have been reported in literature. We report a patient who developed acute pancreatitis during amiodarone therapy.

Amiodarone hepatotoxicity complicating obstructive jaundice due to ampullary cancer

BACKGROUND:The presence of dual pathology can cause diagnostic dilemmas. We present a case of adenocarcinoma of the ampulla of Vater with concurrent amiodarone hepatotoxicity. METHODS:Painless jaundice associated with a palpable gallbladder was investigated clinically,radiologically endoscopically and via liver biopsy. RESULTS:Liver biopsy showed amiodarone hepatotoxicity Endoscopic biopsy identified an ampullary adenoma However,the endoscopic ultrasound and intra-operative findings suggested a malignancy,which was confirmed postoperatively. CONCLUSIONS:While the classic findings of Courvoisier’s Law are borne out in this case,the etiology of jaundice is twofold. Although dual pathology is uncommon it should always be considered.

Spatiotemporal pharmacometabolomics based on ambient mass spectrometry imaging to evaluate the metabolism and hepatotoxicity of amiodarone in HepG2 spheroids

Three-dimensional(3D)cell spheroid models combined with mass spectrometry imaging(MSI)enables innovative investigation of in vivo-like biological processes under different physiological and pathological conditions.Herein,airflow-assisted desorption electrospray ionization-MSI(AFADESI-MSI)was coupled with 3D HepG2 spheroids to assess the metabolism and hepatotoxicity of amiodarone(AMI).High-coverage imaging of>1100 endogenous metabolites in hepatocyte spheroids was achieved using AFADESI-MSI.Following AMI treatment at different times,15 metabolites of AMI involved in Ndesethylation,hydroxylation,deiodination,and desaturation metabolic reactions were identified,and according to their spatiotemporal dynamics features,the metabolic pathways of AMI were proposed.Subsequently,the temporal and spatial changes in metabolic disturbance within spheroids caused by drug exposure were obtained via metabolomic analysis.The main dysregulated metabolic pathways included arachidonic acid and glycerophospholipid metabolism,providing considerable evidence for the mechanism of AMI hepatotoxicity.In addition,a biomarker group of eight fatty acids was selected that provided improved indication of cell viability and could characterize the hepatotoxicity of AMI.The combination of AFADESI-MSI and HepG2 spheroids can simultaneously obtain spatiotemporal information for drugs,drug metabolites,and endogenous metabolites after AMI treatment,providing an effective tool for in vitro drug hepatotoxicity evaluation.

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.

Amiodarone Therapy for Cardiac Arrhythmias: Is It Associated with the Development of Cancers?

Amiodarone is used worldwide to treat cardiac arrhythmias, as well as highly symptomatic cases of atrial fibrillation. With this expanded use, especially following its 1985 United States Food and Drug Administration approval, and its use as a long-term therapy in common practice, reports of cancers temporarily related to amiodarone have begun to increase. Animal studies, several clinical trials, numerous case reports, and a population-based cohort study have suggested that cancers may be associated with amiodarone use. This review focuses on the ever increasing evidence in the literature that suggests amiodarone therapy, especially with long-term use, may increase the potential risk of cancer development. It also expresses the need for more definitive studies to be conducted to provide clinicians with a clear answer to this important question.

Amiodarone Modulation of Intracellular Transport of Calcium Ions in Cardiomyocites

The influence of amiodarone on intracellular transport of calcium ion in cardiomyocytes of rat was investigated. The experiments were performed on isolated papillary muscles of Wistar rats. Force-frequency dependence (0.7, 1, 2, 3, 4 Hz), extrasystolic and postextrasystolic contractions and post-rest (4-60 s) reactions of rat myocardium after amiodarone treatment (1 μM) were investigated. Decay potentiation coefficient of contraction force was estimated. Results. The analyses of force-frequency dependence has shown that amiodarone prevent the decreasing of the force contraction at increasing of the stimulation frequency. Amiodarone promotes increase of the time constant t1(T50), that indicate the drug promotes acceleration of Са2+ transport inside the SR resulting increase of Са2+ in the places of its release from the sarcoplasmic reticulum (SR). Treatment of papillary muscle with amiodarone decreased amplitude of extrasystolic contractions. As known, postextrasystolic and post-rest reactions of myocardium characterize the SR function. We have found amiodarone increased potentiation of postextrasystolic and post-rest contractions. Preliminary caffeine perfusion of muscles preparations cancelled the amiodarone-induced increasing postextrasystolic and post-rest potentiation. However, potentiation decay coefficient before and after treatment with amiodarone didn’t have difference. Conclusions, amiodarone influences on intracellular calcium ions homeostasis by modulation SR functions related with most likely are stipulated either by activation of Са2+ transport from uptake sites to release sites or by prevent of Са2+ leakage from the SR.

Amiodarone-induced hepatotoxicity-quantitative measurement of iodine density in the liver using dual-energy computed tomography:Three case reports

BACKGROUND Amiodarone is the drug most commonly used to manage arrhythmias.Long-term amiodarone administration causes hepatotoxicity due to iodine accumulation in the liver.Here,we present three cases of amiodarone-induced hepatotoxicity in patients on long-term oral amiodarone therapy who underwent dual-energy computed tomography(DECT).CASE SUMMARY We report the clinical and iodine density in the liver using DECT in three patients with amiodarone-induced hepatotoxicity.Liver enzymes were increased in these three patients,and abdominal DECT without contrast medium showed highly increased attenuation in the liver.Furthermore,the iodine concentration in the liver was increased.The first patient with amiodarone-induced reversible hepatotoxicity,showed a reversible course of liver function and a decrease in CT values after discontinuation of amiodarone.The second patient on long-term oral amiodarone had increased iodine concentration in the liver and liver damage,the patient eventually developed rapidly progressive pneumonia and died of multiple organ failure.The third patient,showed an increased iodine concentration in the liver and elevated liver enzymes.However,the patient refused radiofrequency ablation for atrial fibrillation and continued oral amiodarone to control atrial fibrillation,and routine liver function tests were required every 3-6 mo in this patient.CONCLUSION DECT is a potentially noninvasive diagnostic tool for quantifying iodine concentration in the liver and monitoring adverse reactions due to amiodarone.