Metoprolol (metoprololium tartaricum)

Am Heart J. 2005 Feb;149(2):370-6.
Effects of metoprolol and carvedilol on cause-specific mortality and morbidity in patients with chronic heart failure--COMET.
Torp-Pedersen C, Poole-Wilson PA, Swedberg K, Cleland JG, Di Lenarda A, Hanrath P, Komajda M, Lutiger B, Metra M, Remme WJ, Scherhag A, Skene A; COMET Investigators.
Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark. ctp@heart.dk

BACKGROUND: Beta-blockers with different receptor bindings reduce mortality in patients with chronic heart failure. We compared the effects of the beta1-blocker metoprolol tartrate and the beta1-, beta2-, and alpha1-blocker carvedilol. METHODS: In a randomized double-blind design, 3029 patients with chronic congestive heart failure requiring diuretic therapy and with left ventricular dysfunction were randomized to treatment with carvedilol (n = 1511) or metoprolol tartrate (n = 1518) and titrated to target doses of 25 mg of carvedilol twice daily or 50 mg of metoprolol tartrate twice daily. The main outcome measures were total mortality and the combination of mortality or hospitalization for any cause. Secondary end points were cardiovascular death, combinations of morbidity and mortality, New York Heart Association class, worsening of heart failure, hospitalizations, and discontinuation of study therapy. RESULTS: A total of 512 and 600 patients in the carvedilol group and metoprolol group, respectively, died (hazard ratio [HR] 0.83, 95% CI 0.74-0.93, P = .0017). Cardiovascular death was reduced by carvedilol (HR 0.80, 95% CI 0.70-0.90, P = .0004). There were fewer sudden deaths and deaths caused by circulatory failure or by stroke in the carvedilol group. There was no difference in all-cause hospitalizations or in worsening heart failure between treatment groups. The incidence of fatal or nonfatal acute myocardial infarction was significantly lower in the carvedilol group (HR 0.71, 95% CI 0.52-0.97, P = .03). Discontinuations of study therapy were similar in the 2 groups. CONCLUSION: Compared with metoprolol tartrate, carvedilol reduced cardiovascular mortality, sudden death, death caused by circulatory failure, death caused by stroke, as well as fatal and nonfatal myocardial infarctions.

Am Heart J. 2005 Jan;149(1):159-67.
Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: experiences from MERIT-HF.
Deedwania PC, Giles TD, Klibaner M, Ghali JK, Herlitz J, Hildebrandt P, Kjekshus J, Spinar J, Vitovec J, Stanbrook H, Wikstrand J; MERIT-HF Study Group.
Department of Veterans Affairs Medical Center, Fresno, Calif, USA. deed@ucsfresno.edu

BACKGROUND: The objective of the current study was to examine the efficacy and tolerability of the beta-blocker metoprolol succinate controlled release/extended release (CR/XL) in patients with diabetes in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). METHODS: The Cox proportional hazards model was used to calculate hazard ratios (HR) for convenience expressed as relative risks (risk reduction = 1-HR), and 95% confidence intervals (CI). RESULTS: The risk of hospitalization for heart failure was 76% higher in diabetics compared to non-diabetics (95% CI 38% to 123%). Metoprolol CR/XL was well tolerated and reduced the risk of hospitalization for heart failure by 37% in the diabetic group (95% CI 53% to 15%), and by 35% in the non-diabetic group (95% CI 48% to 19%). Pooling of mortality data from the Cardiac Insufficiency Bisoprolol Study II (CIBIS II), MERIT-HF, and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) showed similar survival benefits in patients with diabetes (25%; 95% CI 40% to 4%) and without diabetes (36%; 95% CI 44% to 27%); test of diabetes by treatment interaction was non-significant. Adverse events were reported more often on placebo than on metoprolol CR/XL. CONCLUSIONS: Patients with heart failure and diabetes have a much higher risk of hospitalization than patients without diabetes. Regardless of diabetic status, a highly significant reduction in hospitalizations for heart failure was observed with metoprolol CR/XL therapy, which was very well tolerated also by patients with diabetes. Furthermore, the pooled data showed a statistically significant survival benefit in patients with diabetes.

Clin Pharmacol Ther. 2005 Mar;77(3):189-201.
Association between adherence measurements of metoprolol and health care utilization in older patients with heart failure.
Tu W, Morris AB, Li J, Wu J, Young J, Brater DC, Murray MD.

Objective Data from electronic dosing monitors and published pharmacokinetic parameters were used to derive medication adherence measures for immediate-release metoprolol and examine their association with health care utilization of outpatients aged 50 years or older with heart failure. Methods We used a 1-compartment model and published population pharmacokinetic parameters to estimate mean plasma metoprolol concentrations for patients treated for 6 to 12 months. In the absence of directly measured plasma concentrations, we calculated the intended mean plasma concentration (Cp' ave ) under the assumption of perfect adherence to the prescribed dose and frequency of administration. Projected mean plasma concentrations (Cp ave ) were estimated by use of data from recorded dosing times. In addition to taking adherence (percentage of dose taken) and scheduling adherence (percentage of doses taken on schedule), we calculated the deviation from the intended exposure (DeltaCp ave = Cp' ave - Cp ave ) and the proportion of intended exposure achieved by the patient (Cp ave /Cp' ave ). We assessed the association between the adherence measures and the numbers of emergency department visits and hospital admissions experienced by the patients. Results Patients (N = 80) were aged 62 +/- 8 years. Mean DeltaCp ave and Cp ave /Cp' ave were 7.9 ng/mL (SD, 10.7) and 0.6 (SD, 0.3), respectively. Log-linear models adjusted for patient functional status indicated that greater deviation from the intended metoprolol exposure (DeltaCp ave ) was associated with increased numbers of emergency department visits ( P < .0001) and hospital admissions ( P < .0001). A higher proportion of intended exposure (Cp ave /Cp' ave ) corresponded to a reduced number of emergency department visits ( P = .0204) and hospital admissions ( P = .0093). Taking adherence was univariately associated with both emergency department visits and hospital visits ( P < .0001 and P = .0010, respectively). Scheduling adherence was associated with the number of emergency department visits ( P = .0181) but not with the number of hospital admissions ( P = .1602). Model selection procedures consistently chose the proposed measures over taking adherence and scheduling adherence. Conclusion Deviation from the intended exposure and proportion of intended exposure achieved by the patient are valid adherence measures for immediate-release metoprolol and are associated with health care utilization. The potential utility of these measures for other beta-adrenergic antagonists and perhaps other cardiovascular drugs should be investigated.

Eur J Pharm Biopharm. 2004 Nov;58(3):697-703.
Pharmacokinetic evaluation of guar gum-based three-layer matrix tablets for oral controlled delivery of highly soluble metoprolol tartrate as a model drug.
Al-Saidan SM, Krishnaiah YS, Satyanarayana V, Bhaskar P, Karthikeyan RS.
Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, SAFAT, Kuwait.
The objective of the present study is to carry out pharmacokinetic evaluation of oral controlled release formulation (guar gum-based three-layer matrix tablets) containing highly soluble metoprolol tartrate as a model drug. Six healthy volunteers participated in the study, and a two-way crossover design was followed. The plasma concentration of metoprolol tartrate was estimated by reverse-phase HPLC. The pharmacokinetic parameters were calculated from the plasma concentration of metoprolol tartrate versus time data. The delayed [Formula: see text] lower [Formula: see text] decreased [Formula: see text] unaltered bioavailability and prolonged [Formula: see text] indicated a slow and prolonged release of metoprolol tartrate from guar gum three-layer matrix tablets in comparison with the immediate release tablet dosage form. The results of the study indicated that guar gum three-layer matrix tablets were able to provide oral controlled delivery of highly water-soluble drug such as metoprolol tartrate in humans.

J Am Coll Cardiol. 2004 Oct 6;44(7):1459-66.
Tissue Doppler-derived myocardial acceleration for evaluation of left ventricular diastolic function.
Hashimoto I, Bhat AH, Li X, Jones M, Davies CH, Swanson JC, Schindera ST, Sahn DJ.
Clinical Care Center for Congenital Heart Disease, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
OBJECTIVES: Our purpose was to evaluate a tissue Doppler-based index-peak myocardial acceleration (pACC)-during isovolumic relaxation and in evaluating left ventricular (LV) diastolic function. BACKGROUND: Simple, practical indexes for diastolic function evaluation are lacking, but are much desired for clinical evaluation. METHODS: We examined eight sheep by using tissue Doppler ultrasound images obtained in the apical four-chamber views to evaluate mitral valve annular velocity at the septum and LV wall. The pACC thus derived was analyzed during isovolumic relaxation (IVRT) and during the LV filling period (LVFP). We then changed the hemodynamic status of each animal by blood administration, dobutamine, and metoprolol infusion. We compared the pACC values during IVRT and LVFP over the four different hemodynamic conditions with a peak rate of dropin LV pressure (-dP/dt(min)) and the time constant of LV isovolumic pressure decay (tau), as measured with a high-frequency manometer-tipped catheter. RESULTS: The pACC of the septal side of the mitral valve annulus during IVRT showed a good correlation with -dP/dt(min) (r = -0.80, p < 0.0001) and tau (r = -0.87, p < 0.0001). The mean left atrial pressure (LAP) correlated well with the septal side pACC during LVFP (r = 0.81, p < 0.0001). There was a weak correlation between the mitral valve annulus pACC at the LV lateral wall and mean LAP. CONCLUSIONS: The pACC during IVRT is a sensitive, preload-independent marker for evaluation of LV diastolic function. In addition, pACC during LVFP correlated well with mean LAP.

Am J Physiol Regul Integr Comp Physiol. 2004 Oct;287(4):R749-58. Epub 2004 May 06.
Mice lacking melanin-concentrating hormone receptor 1 demonstrate increased heart rate associated with altered autonomic activity.
Astrand A, Bohlooly-Y M, Larsdotter S, Mahlapuu M, Andersen H, Tornell J, Ohlsson C, Snaith M, Morgan DG.
Dept. of Integrative Pharmacology, AstraZeneca R&D Molndal, S-431 83 Molndal, Sweden.
Melanin-concentrating hormone (MCH) plays an important role in energy balance. The current studies were carried out on a new line of mice lacking the rodent MCH receptor (MCHR1(-/-) mice). These mice confirmed the previously reported lean phenotype characterized by increased energy expenditure and modestly increased caloric intake. Because MCH is expressed in the lateral hypothalamic area, which also has an important role in the regulation of the autonomic nervous system, heart rate and blood pressure were measured by a telemetric method to investigate whether the increased energy expenditure in these mice might be due to altered autonomic nervous system activity. Male MCHR1(-/-) mice demonstrated a significantly increased heart rate [24-h period: wild type 495 +/- 4 vs. MCHR1(-/-) 561 +/- 8 beats/min (P < 0.001); dark phase: wild type 506 +/- 8 vs. MCHR1(-/-) 582 +/- 9 beats/min (P < 0.001); light phase: wild type 484 +/- 13 vs. MCHR1(-/-) 539 +/- 9 beats/min (P < 0.005)] with no significant difference in mean arterial pressure [wild type 110 +/- 0.3 vs. MCHR1(-/-) 113 +/- 0.4 mmHg (P > 0.05)]. Locomotor activity and core body temperature were higher in the MCHR1(-/-) mice during the dark phase only and thus temporally dissociated from heart rate differences. On fasting, wild-type animals rapidly downregulated body temperature and heart rate. MCHR1(-/-) mice displayed a distinct delay in the onset of this downregulation. To investigate the mechanism underlying these differences, autonomic blockade experiments were carried out. Administration of the adrenergic antagonist metoprolol completely reversed the tachycardia seen in MCHR1(-/-) mice, suggesting an increased sympathetic tone.

Biol Pharm Bull. 2004 Oct;27(10):1642-8.
Nonlinear mixed effects model analysis of the pharmacokinetics of metoprolol in routinely treated Japanese patients.
Taguchi M, Nozawa T, Mizumaki K, Inoue H, Tahara K, Takesono C, Hashimoto Y.
Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University.
This study was performed to estimate the mean pharmacokinetic parameters of routinely administered metoprolol in middle-aged and elderly Japanese patients. Whole blood concentration data (65 samples) at steady-state following repetitive administration to 34 patients were analyzed using a nonlinear mixed effects model. A one-compartment model was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). We evaluated the effect of polymorphic alleles (CYP2D6*2, CYP2D6*10, CYP2C19*2 and CYP2C19*3), age, gender, and heart failure on the pharmacokinetic parameters of metoprolol. The CL/F value in patients homozygous for the CYP2D6*10 allele was 64% lower than that in patients with a CYP2D6*1/*1 or *1/*2 genotype. The CL/F value in older (>70 years old) patients was 26% lower than that in younger (

Chemosphere. 2004 Oct;57(2):107-26.
Pharmaceuticals in the river Elbe and its tributaries.
Wiegel S, Aulinger A, Brockmeyer R, Harms H, Loffler J, Reincke H, Schmidt R, Stachel B, von Tumpling W, Wanke A.
Bundesamt fur Verbraucherschutz und Lebensmittelsicherheit, Messeweg 11/12, 38104 Braunschweig, Germany. wiegel@bvl.bund.de
Medicinal drugs were found to be ubiquitous in the river Elbe, its tributary the river Saale and in other tributaries at their points of entry into the Elbe. The distribution of concentration peaks along the investigated river stretches provides an indication that they are mainly due to the emission of treated waste water from municipal sewage treatment works. This leads to the conclusion that medicinal substances can be regarded as faecal indicators for water pollution caused by human activity. The main substances found in the Elbe in 1998 were diclofenac, ibuprofen and carbamazepine as well as various antibiotics and lipid regulators in the concentration range of <20-140 ng/l. The more thorough investigations carried out in 1999 and 2000 show that in addition to the drugs (phenazone, isopropyl-phenazone and paracetamol) metabolite concentrations contributed significantly to the total concentration of pharmaceuticals in the Elbe. The metamizole metabolites N-acetyl-4-aminoantipyrine (AAA) and N-formyl-4-aminoantipyrine (FAA) were found in concentrations from <20 to 939 ng/l. A multivariate statistical analysis revealed a high correlation in respect of the distribution of persistent substances. The metoprolol distribution throughout the Saale demonstrated that the tributaries cause either an increase (Weisse Elster, Unstrut, Ilm) or a reduction (Wipper, Bode) in the concentration, depending on the respective load of waste water. Wide scale sampling in Saxony during 2002 showed the ubiquitous occurrence of carbamazepine in surface waters. The ecotoxicological effects of this contamination cannot be assessed at present. This is due to the fact that no legal framework in respect of these medicinal drugs for human consumption has been established and therefore little research and no risk assessment has been carried out. Therefore it is urgently necessary to include at least the quantitatively most significant substances in the new assessment concept of the EC White Paper.

Circ J. 2004 Oct;68(10):968-71.
Beneficial effect of cibenzoline on left ventricular pressure gradient with sigmoid septum.
Konishi C, Shiraishi J, Muraguchi N, Ohtsuki K, Inoue M, Tatsumi T, Azuma A, Matsubara H.
Department of Cardiology, Kyoto Prefectural Rakuto Hospital, Japan.
An 83-year-old woman with hypertension was admitted to hospital with episodes of dyspnea on effort after having breakfast. Physical examination revealed a systolic murmur at the left sternal border in the third to fourth intercostal space. Cross-sectional echocardiography showed a sigmoid-shaped interventricular septum markedly protruding into the left ventricle, concentric left ventricular hypertrophy, systolic anterior motion of the mitral valve, and a resultant left ventricular outflow tract obstruction with a pressure gradient of 121.8 mmHg. She began daily treatment with 60 mg metoprolol. However, the chest symptoms were not relieved and the left ventricular outflow tract obstruction was still visible on echocardiography. She was then given 200 mg daily of cibenzoline, in addition to 40 mg metoprolol, and the left ventricular pressure gradient significantly decreased and she was free of symptoms without any complications. This case shows that cibenzoline may be useful in the treatment of left ventricular outflow tract obstruction caused by sigmoid septum.

Clin Pharmacol Ther. 2004 Oct;76(4):302-12.
Impact of the ultrarapid metabolizer genotype of cytochrome P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics.
Kirchheiner J, Heesch C, Bauer S, Meisel C, Seringer A, Goldammer M, Tzvetkov M, Meineke I, Roots I, Brockmoller J.
Institute of Clinical Pharmacology, Humboldt University, Berlin, Germany. julia.kirchheiner@uk-koeln.de
INTRODUCTION: In the treatment of heart failure and hypertension with metoprolol, ultrarapid metabolizers (UMs) may not achieve optimal target concentrations with recommended doses. We compared metoprolol pharmacokinetics and effects in UMs with extensive metabolizers (EMs) and with poor metabolizers (PM) as an additional reference group. METHODS: After a single dose of 100 mg metoprolol, pharmacokinetics, resting and exercise heart rate, and blood pressure were analyzed in relation to the CYP2D6 genotypes. We included 12 UMs, 13 EMs, and 4 PMs (healthy volunteers). CYP2D6 genotyping covered alleles *1 to *6 , *9 , *10 , *35 , and *41 and the duplications. beta 1 -Adrenergic receptor polymorphisms Ser49Gly and Arg389Gly were included as factors possibly interfering with the pharmacokinetic-pharmacodynamic relationship of metoprolol. RESULTS: Median total metoprolol clearance values were 31, 168, and 367 L/h and median maximum plasma concentrations were 260, 118, and 67 microg/L in PMs, EMs, and UMs, respectively ( P < .0001). At 6 hours after administration, metoprolol reduced the exercise heart rate by median values of 31, 21, and 18 beats/min in PMs, EMs, and UMs, respectively ( P = .01). Blood pressure did not significantly differ according to CYP2D6 . CONCLUSIONS: A linear relationship between the number of active CYP2D6 genes and metabolic clearance of metoprolol was found and the the median clearances differed by more than 10-fold between the PM and the UM groups. Metoprolol pharmacodynamics, however, differed only by less than 2-fold, and there was only a marginal difference in metoprolol efficacy on heart rate between the EM and UM groups.

Hypertension. 2004 Oct;44(4):478-83. Epub 2004 Sep 07.
Inhibition of Rho-kinase in the brainstem augments baroreflex control of heart rate in rats.
Ito K, Hirooka Y, Sagara Y, Kimura Y, Kaibuchi K, Shimokawa H, Takeshita A, Sunagawa K.
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
The Rho/Rho-kinase pathway in the nucleus tractus solitarii (NTS) of the brain stem contributes to blood pressure regulation. Activation of this pathway might be involved in the central nervous system mechanisms of hypertension. The aim of the present study was to determine whether baroreflex control of heart rate is altered by inhibition of Rho-kinase in the NTS. Adenovirus vectors encoding dominant-negative Rho-kinase or beta-galactosidase were transfected into the nucleus tractus solitarii of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Baroreflex control of heart rate was examined by changing arterial pressure with an intravenous infusion of phenylephrine or sodium nitroprusside. The maximum gain of baroreflex control of heart rate was attenuated in SHR compared with WKY before the gene transfer. Transfection of adenovirus vectors encoding dominant-negative Rho-kinase significantly augmented the maximum gain in both WKY and SHR. The extent of this augmentation, however, was greater in SHR than in WKY. After treatment with metoprolol, the maximum gain was significantly decreased in rats transfected with adenovirus vectors encoding dominant-negative Rho-kinase, but not in nontransfected rats. In contrast, after treatment with atropine, the maximum gain was greater in rats transfected with adenovirus vectors encoding dominant-negative Rho-kinase compared with nontransfected rats, although it was decreased in both groups. These results suggest that inhibition of Rho-kinase in the NTS augments baroreflex control of heart rate, in both WKY and SHR, probably because of a cardiac sympathoinhibitory effect.

Hypertension. 2004 Oct;44(4):410-8. Epub 2004 Aug 23.
Norepinephrine-induced changes in cardiac transforming growth factor-beta isoform expression pattern of female and male rats.
Briest W, Homagk L, Rassler B, Ziegelhoffer-Mihalovicova B, Meier H, Tannapfel A, Leiblein S, Saalbach A, Deten A, Zimmer HG.
Carl-Ludwig-Institute of Physiology, University of Leipzig, Liebigstr. 27, D-04103 Leipzig, Germany. briestw@medizin.uni-leipzig.de
Transforming growth factor-beta (TGF-beta) is a ubiquitous growth-regulating protein with an essential role in tissue repair and formation of extracellular matrix (ECM). To better understand the role of different isoforms of TGF-beta in the cardiac remodeling process induced by norepinephrine (NE), the expression of TGF-beta1, TGF-beta2, and TGF-beta3 was studied and compared with the expression of collagen. NE (0.1 mg/kg. h) was intravenously infused in female and male Sprague-Dawley rats for several time periods, and freshly obtained ventricular myocardium after 1 day was dissociated into myocyte and nonmyocyte fractions. Prazosin (0.1 mg/kg x h) and metoprolol (1 mg/kg. h) were used to block alpha- and beta-adrenoceptors, respectively. After NE infusion, the three isoforms of TGF-beta were differentially induced as far as the magnitude and the time course is concerned. The increased expression of TGF-beta2 started earlier with a maximum after 12 hours and was more pronounced (10-fold elevation) than that of the other two isoforms, with a clear specificity for the left ventricle in female hearts. This specificity was also seen in male rats with 16-fold elevation of TGF-beta2 after 1 day of NE-stimulation. The increase of TGF-beta2 was significant only in the myocyte fraction obtained from female as well as from male hearts. The expression of the mRNA of all TGF-beta isoforms of collagen type I and type III, and of the matrix metalloproteinase (MMP)-2 and its inhibitor TIMP-2 was reduced predominantly by alpha-adrenoceptor blockade with prazosin. The increase in TGF-beta isoforms correlated with that of the mRNA expression of collagens, MMP-2 and TIMP-2.

J Nucl Med. 2004 Oct;45(10):1626-1631.
beta}-Adrenergic Blockade and Myocardial Perfusion in Coronary Artery Disease: Differential Effects in Stenotic Versus Remote Myocardial Segments.
Koepfli P, Wyss CA, Namdar M, Klainguti M, von Schulthess GK, Luscher TF, Kaufmann PA.
Nuclear Cardiology Section, University Hospital, Zurich, Switzerland.
beta-Adrenergic blocking agents are widely used in coronary artery disease (CAD), although their impact on myocardial blood flow (MBF) and coronary flow reserve (CFR) remains unclear. We studied the effect of long-term beta-blocker treatment (carvedilol or metoprolol) on coronary microcirculation in CAD patients using PET. METHODS: Regional and global resting and adenosine-induced hyperemic MBF and CFR were measured with (13)N-ammonia and PET in 36 CAD patients before and after 12 wk of oral therapy with either carvedilol, 50 mg/d, or metoprolol, 100 mg/d. RESULTS: beta-Blockade decreased global resting MBF in proportion to cardiac work (from 0.86 +/- 0.20 to 0.77 +/- 0.14 mL/min/g, P < 0.05) without affecting global hyperemic flow. Hyperemic MBF was significantly lower in stenosis-dependent segments than in remote segments (1.76 +/- 0.64 vs. 2.04 +/- 0.67 mL/min/g, P < 0.05) at baseline but was comparable in both after treatment (2.02 +/- 0.68 vs. 1.90 +/- 0.78 mL/min/g, P = not statistically significant [NS]), resulting in a significant CFR increase in stenotic segments (+15%, P < 0.05) but not in remote segments (+9%, P = NS). CONCLUSION: The beneficial effect of beta-adrenergic blockade can be explained by the reduction in oxygen consumption (= decreased demand) but also by a modest improvement in vasodilator capacity (= increased supply). The improvement in CFR is found predominantly in stenosis-dependent rather than remote segments.

J Chromatogr B Analyt Technol Biomed Life Sci. 2004 Sep 25;809(1):9-14.
Determination of metoprolol, and its four metabolites in dog plasma.
Fang J, Semple HA, Song J.
Metoprolol and its metabolites alpha-hydroxymetoprolol, O-desmethylmetoprolol, metoprolol acid and deaminated metoprolol were quantified in dog plasma using an isocratic high-performance liquid chromatographic method (with a BetaBasic Cyano column) with fluorescence detection. A solid phase extraction technique (Oasis HLB, Waters) was used to extract metoprolol and its four metabolites from dog plasma with high recovery rates. The method was shown to be sensitive and reproducible and was used to determine the pharmacokinetic profile of metoprolol in dog. To the best of our knowledge, this is the only method that can extract and analyze metoprolol and its four metabolites in a single assay.

Circulation. 2004 Sep 14;110(11):1477-83. Epub 2004 Sep 07.
Effectiveness of beta-blockade in experimental chronic aortic regurgitation.
Plante E, Lachance D, Gaudreau M, Drolet MC, Roussel E, Arsenault M, Couet J.
Groupe de Recherche sur les Valvulopathies, Centre de Recherche Hopital Laval, Institut de Cardiologie de Quebec, Universite Laval, Quebec, Canada.
BACKGROUND: Past studies have suggested that the adrenergic system becomes abnormally activated in chronic volume overload, such as in severe aortic valve regurgitation (AR). However, the effectiveness of agents directed against this adrenergic activation has never been adequately tested in chronic AR. We therefore tested the effects of metoprolol treatment on the left ventricular (LV) function and remodeling in severe chronic AR in rats. METHODS AND RESULTS: Severe AR was created in adult male Wistar rats by retrograde puncture of the aortic leaflets under echocardiographic guidance. Two weeks later, some animals received metoprolol treatment (25 mg/kg) orally for 24 weeks, and some were left untreated. LV dimensions, ejection fraction, and filling parameters were evaluated by echocardiography. Hearts were harvested at 1, 2, 14, and 180 days for the evaluation of hypertrophy, beta-adrenergic receptor status, and extracellular matrix remodeling. We found that metoprolol treatment prevented LV dilatation and preserved the ejection fraction and filling parameters compared with untreated animals. Metoprolol increased the expression of beta1-adrenoreceptor mRNA and reduced G protein receptor kinase 2 levels. Collagen I and III mRNA levels were reduced. Cardiac myocyte hypertrophy was also prevented. CONCLUSIONS: In our experimental model of severe AR, metoprolol treatment had a significant beneficial global effect on LV remodeling and function. These results suggest that the adrenergic system is important in the development of volume-overload cardiomyopathy in AR and that adrenergic-blocking agents may play a role in the treatment of this disease.

Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1003-12. Epub 2004 Apr 22.
Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy.
Kawai K, Qin F, Shite J, Mao W, Fukuoka S, Liang CS.
Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its beta-adrenergic blocking, antioxidant, and/or alpha-adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin, or placebo pellets for 8 wk and compared with sham-operated rabbits without pacing. We found rapid cardiac pacing produced clinical heart failure, left ventricular dilation, and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine, increase of Bax, decrease of Bcl-2, and increase of apoptotic myocytes as measured by anti-single-stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with changes of left ventricular end-diastolic dimension (r = -0.678, P < 0.0001), fractional shortening (r = 0.706, P < 0.0001), and apoptotic myocytes (r = -0.473, P = 0.0001). Thus our findings suggest antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of beta-receptors in the treatment of CHF.

Am J Physiol Regul Integr Comp Physiol. 2004 Sep;287(3):R534-40. Epub 2004 May 20.
Cerebral carbohydrate cost of physical exertion in humans.
Dalsgaard MK, Ogoh S, Dawson EA, Yoshiga CC, Quistorff B, Secher NH.
Department of Anesthesia, Rigshospitalet 2041, Blegdamsvej 9, DK-2100 Copenhagen O, Denmark. madskd@tiscali.dk
Above a certain level of cerebral activation the brain increases its uptake of glucose more than that of O(2), i.e., the cerebral metabolic ratio of O(2)/(glucose + 12 lactate) decreases. This study quantified such surplus brain uptake of carbohydrate relative to O(2) in eight healthy males who performed exhaustive exercise. The arterial-venous differences over the brain for O(2), glucose, and lactate were integrated to calculate the surplus cerebral uptake of glucose equivalents. To evaluate whether the amount of glucose equivalents depends on the time to exhaustion, exercise was also performed with beta(1)-adrenergic blockade by metoprolol. Exhaustive exercise (24.8 +/- 6.1 min; mean +/- SE) decreased the cerebral metabolic ratio from a resting value of 5.6 +/- 0.2 to 3.0 +/- 0.4 (P < 0.05) and led to a surplus uptake of glucose equivalents of 9 +/- 2 mmol. beta(1)-blockade reduced the time to exhaustion (15.8 +/- 1.7 min; P < 0.05), whereas the cerebral metabolic ratio decreased to an equally low level (3.2 +/- 0.3) and the surplus uptake of glucose equivalents was not significantly different (7 +/- 1 mmol; P = 0.08). A time-dependent cerebral surplus uptake of carbohydrate was not substantiated and, consequently, exhaustive exercise involves a brain surplus carbohydrate uptake of a magnitude comparable with its glycogen content.

Biol Pharm Bull. 2004 Sep;27(9):1422-7.
Intestinal absorption and hepatic extraction of propranolol and metoprolol in rats with bilateral ureteral ligation.
Okabe H, Higashi T, Ohta T, Hashimoto Y.
Graduate School of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University; 2630 Sugitani, Toyama 930-0194, Japan.
To investigate the mechanism responsible for the increased bioavailability of propranolol in bilateral ureter-ligated (BUL) rats, the intestinal absorption and hepatic extraction of propranolol and metoprolol were evaluated. The initial absorption rate of these drugs after intra-intestinal administration was only slightly increased in the BUL rats, whereas the blood drug concentration in these rats was higher than that in control rats. The blood propranolol and metoprolol concentrations during intra-portal infusion in the BUL rat were significantly higher than that in the control rat. In the presence of NADPH, the intrinsic metabolic activity of metoprolol in hepatic microsomes was not altered by BUL. On the other hand, the NADPH generation rate in the hepatic cytosol in the BUL group was lower than that in the control group. These results indicate that the absorption rate-dependent decrease in hepatic first-pass clearance of propranolol and metoprolol due to saturation kinetics is marginal, and that the hepatic metabolic activity and extraction of the drugs is significantly decreased in BUL rats probably due to the reduced NADPH generation rate in the liver.

Br J Clin Pharmacol. 2004 Sep;58(3):288-97.
A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study.
Sharma A, Pilote S, Belanger PM, Arsenault M, Hamelin BA.
The Quebec Heart and Lung Institute, Laval Hospital, Quebec, Canada. ashish.sharma@biovail.com
AIMS: To assess the feasibility of administering at the same time low doses of five probe drugs, metoprolol (25 mg), chlorzoxazone (250 mg), tolbutamide (250 mg), dapsone (100 mg) and caffeine (100 mg) to determine simultaneously the activities of CYP2D6, CYP2E1, CYP2C9, CYP3A4, CYP1A2, N-acetyltransferase-2 and xanthine oxidase. METHODS: Ten healthy young non-smoking males received the following drugs or combinations of drugs over a 5-week period: week 1) metoprolol; 2) tolbutamide; 3) caffeine, chlorzoxazone and dapsone; 4) caffeine, chlorzoxazone, dapsone and metoprolol; 5) caffeine, chlorzoxazone, dapsone, metoprolol and tolbutamide. The drugs were self-administered at bedtime and urine was collected for the following 8 h. RESULTS: Mean molar phenotypic ratios obtained after administering metoprolol (mean change of -11%) or tolbutamide (mean change of -0.3%) alone, were not significantly different from those obtained when other drugs were co-administered (P > 0.05). The mean within-subject coefficients of variation were 33%, 18%, 22%, 13%, 16%, 13% and 5% for CYP3A4, CYP2D6, CYP2C9, CYP2E1, CYP1A2, N-acetyltransferase 2 and xanthine oxidase metabolic ratios, respectively. No significant interactions (P > 0.5) were observed during the simultaneous administration of various combinations of the five probe drugs. CONCLUSIONS: We propose that this cocktail, composed of five widely available drugs, constitutes a promising means of simultaneously determining the activities of the major CYP enzymes in large populations.

Eye. 2004 Jan;18(1):41-3.
Metoprolol responding uveitis.
Kassif Y, Rehany U, Rumelt S.
1Department of Ophthalmology, Western Galilee, Nahariya Medical Center, Nahariya, Israel.
BACKGROUND: Noninfectious uveitis is usually managed by topical and systemic corticosteroids and in refractory cases by immunosuppressive drugs. OBJECTIVE: To describe a patient with noninfectious anterior and posterior uveitis, refractory to corticosteroids, and immunosuppressive therapy, which responded to systemic metoprolol. PATIENT AND METHODS: A 49-year-old patient was treated for 3 years with topical and systemic corticosteroids and systemic cyclosporin A for a bilateral anterior and posterior uveitis of unknown origin. The treatment did not result in resolution of the uveitis. A bilateral uveitic glaucoma developed and necessitated neodymium : YAG laser iridotomies and antiglaucoma medications. A systemic beta-blocker, metoprolol tartrate 50 mg b.i.d., was administered for palpitations because of idiopatic paroxysmal supraventricular tachycardia and short ventricular tachycardia. RESULTS: Following administration of metoprolol tartrate, the bilateral uveitis resolved. The corticosteroids and the cyclosporin A were withdrawn after 6 weeks without any recurrence. A trial to discontinue metoprolol after 6 months resulted in flare-up of the disease and only following its readministration the inflammation resolved. The patient is currently under metoprolol for a year without flare-ups. CONCLUSIONS: The use of metoprolol tartrate in this patient resulted in resolution of bilateral noninfectious uveitis. This is the first report of non-antiinfectious, antiinflammatory, or immunosuppressive drug effective for uveitis. It is possible that a subgroup of resistant uveitis may respond to drugs other than the traditional drugs, such as metoprolol, and that other forms of uveitis of unidentified origin exist.Eye (2004) 18, 41-43. doi:10.1038/sj.eye.6700507

Bioorg Med Chem Lett. 2004 Jan 5;14(1):191-4.
Synthesis and cardiovascular activity of metoprolol analogues.
Melgar-Fernandez R, Demare P, Hong E, Rosas MA, Escalante J, Munoz-Muniz O, Juaristi E, Regla I.
Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autonoma de Mexico, 09230, D.F., Mexico, Mexico
The synthesis of four novel analogues of metoprolol, a well-known beta(1)-blocker used to reduce arterial blood pressure, is described. The preparation of (2S,2'S)-7, (2R,2'S)-7, (2R,2'R)-8, and (2S,2'R)-8 was based on the reaction of racemic 2-[4-(2'-methoxyethyl)-phenoxymethyl]-oxirane (4) with (R)- or (S)-2-amino-1-butanol. Salient characteristics of analogues 7 and 8 relative to metoprolol are the incorporation of an additional stereogenic center, as well as a methyl group and a hydroxyl function on the nitrogen-containing chain. These novel derivatives present significant hypotensive and bradycardiac activity, although no blocking action toward beta(1) and beta(2) adrenergic receptor.

Jpn Heart J. 2003 Sep;44(5):681-92.
Akbulut M, Ozbay Y, Ilkay E, Karaca I, Arslan N.
Department of Cardiology, Medical Faculty, Firat University, Elazig, Turkey.
Effects of spironolactone and metoprolol on QT dispersion in heart failure.
The effects of spironolactone or metoprolol added to a conventional treatment protocol on QT dispersion, which is accepted as a sudden cardiac death predictor, were evaluated in heart failure patients.? A total of 105 New York Heart Association class III patients were included in this study. The conventional treatment protocol was standardized by giving ramipril, furosemide, and digoxin to all patients for 3 weeks at the same doses. At the end of this period, the patients were divided into three groups. Conventional treatment was continued in group 1, 25 mg spironolactone was added in group 2, and 12.5 mg metoprolol was added in group 3. Patients were followed for 12 weeks and clinical and laboratory tests were conducted at 3 week intervals. No significant change in corrected QT dispersion was observed in group 1 at the end of 12 weeks (corrected QT dispersion: 80 +/- 2 msc to 79 +/- 2 msc, P: 0.22). However, corrected QT dispersion in group 2 was reduced by 32.5% (83 +/- 2 msc to 56 +/- 1 msc; P: 0.01). A 32.9% reduction in corrected QT dispersion (79 +/- 2 msc to 53 +/- 2 msc; P: 0.01) was observed in group 3. In conclusion, the addition of spironolactone or metoprolol to a conventional treatment in heart failure patients resulted in improved clinical conditions and the significant decrease in sudden death predictors corrected QT dispersion. The effects of spironolactone and metoprolol on corrected QT dispersion were similar.

Int J Impot Res. 2003 Aug;15(4):287-9.
Piha J, Kaaja R.
Mehilainen Co, Erectile Dysfunction Clinic, Turku, Finland.
Effects of moxonidine and metoprolol in penile circulation in hypertensive men with erectile dysfunction: results of a pilot study.
Centrally acting (moxonidine) and peripherally acting (metoprolol) sympatholytic agents might have different actions upon penile circulation in hypertensive men with erectile dysfunction. A total of 11 nonsmoking, hypertensive but otherwise healthy men with erectile dysfunction were studied after 8 weeks on moxonidine monotherapy (0.4 mg per day, increased to 0.6 mg if needed) and then after 8 weeks of metoprolol monotherapy (100 mg per day, increased to 200 mg if needed) in a crossover design. At the end of each treatment phase, the subjects were asked about their subjective erectile capacity (nocturnal and coital erections), and resting and stimulated (after intracavernosal injection of a mixture of alprostadil and phentolamine) penile deep artery diameters and systolic peak velocities were measured by color Doppler ultrasonography. There were no significant differences in blood pressure after either therapy. The change from earlier antihypertensive therapy, moxonidine produced significant subjective amelioration of sexual dysfunction in 9/11 of the men (< or = 0.001), whereas 9/11 returned to impaired dysfunction after crossover to metoprolol treatment. Resting and stimulated deep penile diameters and peak systolic velocities were higher after moxonidine treatment compared with metoprolol (diameters: < or = 0.004, < or = 0.0001; velocities: < or = 0.008, < or = 0.038). The centrally acting sympatholytic agent moxonidine seems to improve erectile function both subjectively and objectively and has a better effect on penile circulation compared with the peripherally acting sympatholytic agent metoprolol.

Am J Cardiol. 2003 Sep 1;92(5):548-53.
Blanchet M, Ducharme A, Racine N, Rouleau JL, Tardif JC, Juneau M, Marquis J, Larivee L, Nigam A, Fortier A, White M.
Research Center, Montreal Heart Institute, Quebec, Canada.
Effects of cold exposure on submaximal exercise performance and adrenergic activation in patients with congestive heart failure and the effects of beta-adrenergic blockade (carvedilol or metoprolol).
Patients with congestive heart failure (CHF) exhibit a decrease in maximal exercise capacity in response to a cold environment. The aim of this study was to further investigate the impact of cold exposure on submaximal exercise capacity, systemic adrenergic drive, and the effects of long-term beta-adrenergic blockade on these parameters. Thirty-three patients with CHF, with exercise limited by dyspnea and left ventricular ejection fraction of 26 +/- 4%, were randomized to receive metoprolol or carvedilol for 6 months. The observations were compared with 12 age-matched healthy volunteers. Maximal exercise performance with gas exchange analyses were assessed using a ramp protocol, and endurance capacity was measured using 2 constant-load exercise tests performed randomly at 20 degrees C and -8 degrees C. Healthy volunteers increased their submaximal exercise time by 20% (1,353 +/- 455 [20 degrees C] vs 1,635 +/- 475 seconds [-8 degrees C]; p <0.05), whereas patients with CHF exhibited a 21% decrease in exercise time (1,182 +/- 549 [20 degrees C] vs 931 +/- 524 seconds [-8 degrees C]; p <0.05) at -8 degrees C. Beta blockers increased submaximal exercise duration at 20 degrees C (+261 +/- 617 seconds; p <0.05) and -8 degrees C (+374 +/- 729 seconds; p <0.05). Norepinephrine increased to a greater extent at 4 minutes and at the time of exhaustion (at -8 degrees C) only in patients with CHF. Beta-adrenergic blockade caused no significant decrease in plasma norepinephrine levels. Patients with symptomatic CHF exhibited a significant decrease in submaximal exercise time in response to moderate cold exposure. Beta-blocker therapy with either metoprolol or carvedilol significantly increases submaximal exercise time and attenuates the impact of cold exposure on functional capacity.