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One class of pharmaceutical compounds identified in U.S. and European waters are the B-adrenergic receptor blocking compounds (B-blockers). However, little information is available on the potential aquatic toxicity of these compounds. Therefore, Hyalella azteca, Daphnia magna, Ceriodaphnia dubia, and Oryias latipes (Japanese medaka) were exposed to metoprolol, nadolol, and propranolol to determine potential toxicity. Average 48-h LC(50) for propranolol to H. azteca was 29.8 mg/L. The no-observed-effects concentration (NOEC) and lowest-observed-effects concentration (LOEC) for propranolol affecting reproduction of H. azteca were 0.001 and 0.1 mg/L, respectively. The average propranolol and metoprolol 48-h LC(50)s for D. magna were 1.6 and 63.9 mg/L, respectively. C. dubia 48-h LC(50)s were 0.85 and 8.8 mg/L for propranolol and metoprolol, respectively. The NOEC and LOEC of propranolol affecting reproduction in C. dubia were 0.125 and 0.25 mg/L, respectively. In O. latipes, the propranolol 48-h LC(50) was 24.3 mg/L. Medaka growth was decreased at 0.5 mg/L propranolol. A 2-week medaka reproductive study indicated significant changes in plasma steroid levels; however, no changes in the average number of eggs produced or number of viable eggs which hatched was observed. In a 4-week follow-up propranolol exposure, the total number of eggs produced by medaka and the number of viable eggs that hatched were decreased at concentrations as low as 0.5 microg/L. Based on this study and the expected aqueous environmental exposure levels, adverse effects of propranolol to invertebrate populations is unlikely; however, further reproductive studies are need to elucidate the risk to teleosts.
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We studied 32 patients with idiopathic DCM who had been treated with digitalis, diuretics and angiotensin-converting enzyme inhibitors. In addition to this combination therapy, beta-blockers were started in all patients. Serum levels of interleukin (IL)-10, tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors (sTNF-R1 and R2) were measured at baseline and 12 weeks after the initiation of beta-blocker therapy. We also measured plasma levels of neurohumoral factors, as well as left ventricular (LV) size and function. Ten age-matched subjects with no cardiac disease served as the control group.
In the final section of this paper we provide our opinions regarding initiating and optimizing beta blocker therapy for patients with HFRef.
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Metoprolol was well tolerated in the majority of dogs with naturally occurring dilated cardiomyopathy or endocardiosis. Further studies are required to determine if the administration of metoprolol is beneficial for this patient population.
Fifty rabbits were randomly divided into a blank group, a model group, a metoprolol group, a irbesartan group and an acupuncture group, 10 rabbits in each group. The model was established by ear vein intravenous injection with C-BSA. The positive control groups were treated by intragastric administrated with metoprolol and irbesartan, respectively. The acupuncture group was treated by acupuncture at "Fengmen" (BL 12) and "Shenshu" (BL 23). No interventions were added on the blank group and the model group. The changes of blood pressure (BP), heart rate (HR), plasma norepinephrine (NE), serum creatinine (Scr), blood urea nitrogen (BUN) and 24 hours urine protein (24 h UP) in rabbits at the time points of 3rd, 6th and 8th week of treatment were observed.
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POTS is a global public-health disease, but predictor for therapeutic response to metoprolol in children with POTS is lacking. This study was designed to investigate predictive value of plasma C-type natriuretic peptide (CNP) in the therapeutic efficacy of metoprolol on postural tachycardia syndrome (POTS) in children. Totally 34 children with POTS and 27 healthy children were included in the study. The head-up test or head-up tilt test was used to check heart rate and blood pressure from supine to upright in subjects. A double antibody (competitive) sandwich immunoluminometric assay was used to detect plasma CNP. Metoprolol was used to treat children with POTS. The difference in plasma concentrations of CNP between responders and non-responders was compared. An ROC curve was used to analyze plasma CNP to predict efficacy of metoprolol on POTS in children. Plasma CNP in children with POTS was significantly higher than that of healthy children [(51.9 ± 31.4) vs. (25.1 ± 19.1) pg/ml, P <0.001]. Plasma CNP in responders to metoprolol was significantly higher than non-responders [(59.1 ± 33.5) vs. (34.8 ± 16.7) pg/ml, P = 0.037] before treatment. The ROC curve showed that area under the curve was 0.821 (95% CI 0.642-0.999). The cut-off value of plasma CNP > 32.55 pg/ml yielded a sensitivity of 95.8% and specificity of 70% in predicting therapeutic efficacy of metoprolol on POTS children. Plasma CNP might serve as a useful predictor for the therapeutic efficacy of metoprolol on POTS in children.
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General clinical research center.
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The purpose of this study was to compare the amount of bleeding using different doses of oral metoprolol during three common types of nasal operation; rhinoplasty, septoplasty and functional endoscopic sinus surgery, as this is one of the complications during head and neck surgery.
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.
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Carvedilol treatment caused a 20% reduction in myocardial free fatty acid extraction while metoprolol had a neutral effect. These differences are most probably related to the differential effects of these two agents on efferent cardiac sympathetic activity and may be relevant to the reported differential effects of these drugs on clinical outcomes.
Nebivolol is a β-blocker with distinctive characteristics. Initiated at 1.25 mg and titrated up to 10 mg/day, it has shown safety and efficacy in one large outcome trial, when added to standard medical therapy, in elderly patients (≥ 70 years) affected by HF.
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The main objective of this study was to develop an effective potentiometric saturation titration protocol for determining the aqueous intrinsic solubility and the solubility-pH profile of ionizable molecules, with the specific aim of overcoming incomplete dissolution conditions, while attempting to shorten the data collection time. A modern theory of dissolution kinetics (an extension of the Noyes-Whitney approach) was applied to acid-base titration experiments. A thermodynamic method was developed, based on a three-component model, to calculate interfacial, diffusion-layer, and bulk-water reactant concentrations in saturated solutions of ionizable compounds perturbed by additions of acid/base titrant, leading to partial dissolution of the solid material. Ten commercial drugs (cimetidine, diltiazem hydrochloride, enalapril maleate, metoprolol tartrate, nadolol, propoxyphene hydrochloride, quinine hydrochloride, terfenadine, trovafloxacin mesylate, and benzoic acid) were chosen to illustrate the new titration methodology. It was shown that the new method is about 10 times faster in determining equilibrium solubility constants, compared to the traditional saturation shake-flask methods.
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Based on our in vitro and in vivo findings and until further clinical drug interaction experiments are conducted, the co-administration of drugs, especially those primarily cleared via CYP2D catalyzed metabolism, with T. arjuna extracts should be done with caution.
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Porous microcrystalline pellets were manufactured and evaluated as drug delivery system. Pellets consisting of Avicel PH 101 and NaCl (70%, w/w) were prepared by extrusion/spheronization. The NaCl fraction was extracted with water and after drying porous pellets were obtained (33.2% porosity). Immersion of the porous pellets in a 15% and 30% (w/v) metoprolol tartrate solution, ibuprofen impregnation via supercritical fluids and paracetamol layering via fluidized bed coating were evaluated as drug loading techniques.
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We have previously found that oral or intravenous (i.v.) administration of the polysaccharide fraction PB-2, extracted from the lichen Flavoparmelia baltimorensis, facilitated the induction of long-term potentiation (LTP) in the dentate gyrus (DG) in vivo. In this study, the mechanism underlying the effect of PB-2 on the induction of LTP was investigated in the DG of anesthetized rat focusing on the contribution of the interleukin-1 (IL-1) receptor and the adrenaline beta-receptor. An i.v. injection of IL-1ra (10(-9) g/kg), an antagonist of the IL-1 receptor, had no effect on the basal response in the DG; however, this treatment augmented the enhancement of LTP induced by a single i.v. injection of PB-2 (10(-3) g/kg). This potentiating effect was also observed following intracerebroventricular (i.c.v.) injection of IL-1ra (10(-15)-10(-11) g). An i.v. injection of IL-1beta (3.5 x 10(-15)-3.5 x 10(-9) g/kg) inhibited the induction of LTP, which was diminished by the previous application of IL-1ra. These results suggest that the activation of the IL-1 receptor induces the suppression of LTP in PB-2-treated rats, and that endogenous IL-1beta contributes to the IL-1 receptor activation. An i.c.v. infusion of metoprolol (7.5 x 10(-6) g), an antagonist of the adrenaline beta(1)-receptor, attenuated the enhancement of LTP induced by an i.v. injection of PB-2. These results suggest that PB-2 has two different effects on the LTP, an enhancing effect and an inhibiting one, and that it exhibited the significant enhancing effect on the LTP as a total balance of these effects.
The effects of various beta-adrenoceptor agents on radioiodine release from the thyroid were studied in mice pretreated with 125I and thyroxine. The non-selective beta-adrenoceptor agonist isopropylnoradrenaline and the selective beta 2-adrenoceptor agonist terbutaline both, and with the same efficacy, enhanced radioiodine release, whereas the selective beta 1-adrenoceptor agonist prenalterol had no such effect. The non-selective beta-adrenoceptor antagonist L-propranolol and the selective beta 2-adrenoceptor antagonist ICI 118,551 both abolished the radioiodine release induced by isopropylnoradrenaline or by terbutaline. The selective beta 1-adrenoceptor antagonist metoprolol inhibited the radioiodine response to isopropylnoradrenaline, but not that to terbutaline. Neither of the beta-adrenoceptor antagonists influenced the radioiodine release induced by TSH. It is concluded that the beta-adrenoceptors involved in the regulation of thyroid hormone secretion are mainly of the beta 2-subtype, and, further, that beta-adrenoceptor agonists and TSH exert their thyroid hormone secretory effects through different mechanisms.
The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups.
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In modern drug discovery, 2-D similarity searching is widely employed as a cost-effective way to screen large compound collections and select subsets of molecules that may have interesting biological activity prior to experimental screening. Nowadays, there is a growing interest in applying the existing 2-D similarity searching methods to combinatorial chemistry libraries to search for novel hits or to evolve lead series. A dilemma thus arises when many identical substructures recur in library products and they have to be considered repeatedly in descriptor calculations. The dilemma is exacerbated by the astronomical number of combinatorial products. This problem imposes a major barrier to similarity searching of large combinatorial chemistry spaces. An efficient approach, termed Monomer-based Similarity Searching (MoBSS), is proposed to remedy the problem. MoBSS calculates atom pair (AP) descriptors based on interatomic topological distances, which lend themselves to pair additivity. A fast algorithm is employed in MoBSS to rapidly compute product atom pairs from those of the constituent fragments. The details of the algorithm are presented along with a series of proof-of-concept studies, which demonstrate the speed, accuracy, and utility of the MoBSS approach.
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Our results suggest that ER stress could be induced by abnormal Ca(2+) homeostasis in CHF. The restoration of calcium-handling protein function and resultant decrease in ER stress might, in part, explain the beneficial effects of β-blockade observed in CHF. Whether this mechanism occurs in other animal CHF models or human CHF warrants further study.
Autoantibodies specific for the beta(1)-adrenoceptor (beta(1)-AR) have been implicated in the pathology of congestive heart failure (CHF). We hypothesized that the presence of autoantibodies against beta(1)-AR (anti-beta(1)-AR) is associated with left ventricular (LV) remodelling in response to metoprolol. Synthetic beta(1)-AR peptides served as the target antigen in an ELISA (enzyme-linked immunosorbent assay) were used to screen the sera of 106 CHF patients. Patients were separated into positive (+) anti-beta(1)-AR or negative (-) anti-beta(1)-AR groups according to their anti-beta(1)-AR reactivity. Echocardiography (ECG) was performed at baseline and after one year of metoprolol therapy in combination with standard treatment regime for CHF, that is, digoxin, diuretics and an ACEI (angiotensin-converting enzyme inhibitor). The dose of metoprolol was doubled on a biweekly basis up to 50 mg x 2 daily (b.i.d./day) or attainment of maximum tolerated dose. Ninety-six patients completed final data analysis. Fifty-four patients with (+) anti-beta(1)-AR had greater improvements than 42 patients with (-) anti-beta(1)-AR in LVEDD (left ventricular end-diastolic dimension) (P < 0.01, from 69 +/- 0.8 to 58.0 +/- 0.5 mm vs. 69.0 +/- 0.8-63.6 +/- 0.9 mm) and LVESD (left ventricular end-systolic dimension) (P < 0.01, from 57.1 +/- 1.4 to 43.9 +/- 0.8 mm vs. 56.2 +/- 0.9-48.6 +/- 1.0 mm), and LVEF (left ventricular ejection fraction) (P < 0.01, from 35.4 +/- 1.3 to 49.8 +/- 0.6% vs. 34.4 +/- 1.0-44.3 +/- 1.1%) by metoprolol therapy in combination with standard treatment regime for one year. Of the CHF patients with (+) anti-beta(1)-AR, 65.4% responded to target metoprolol dose as compared to 21.4% of CHF patients without anti-beta(1)-AR (P < 0.01). Response to target metoprolol dose occurred more rapidly in (+) anti-beta(1)-AR than (-) anti-beta(1)-AR of CHF patients (67.5 +/- 2.4 vs. 100.8 +/- 3.0 days, P < 0.01). These results demonstrated that CHF patients with (+) anti-beta(1)-AR had greater improvements in LV remodelling and heart function by metoprolol as compared to (-) anti-beta(1)-AR patients. Moreover, patients with (+) anti-beta(1)-AR have better tolerance to metoprolol therapy than patients without anti-beta(1)-AR.
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A 38-year-old female had felt exertional dyspnea for six months. Physical examination and laboratory data including angiotensin-converting enzyme, failed to diagnose sarcoidosis. Her chest X-ray showed cardiomegaly but no hilar lymph node enlargement. Holter ECG showed nonsustained and sustained ventricular tachycardias, monomorphic or polymorphic tachycardia. Echocardiography and contrast left ventriculography showed left ventricular dilatation and generalized hypo- and akinesis. Endomyocardial biopsy revealed myocardial sarcoidosis. Administration of corticosteroids, metoprolol of 20 mg/day and cibenzoline of 300 mg/day was markedly effective for the treatment of ventricular tachycardia. This patient is alive for one year after treatment and the combination therapy seems to contribute to good prognosis.
The aim of the study is to develop modified, branched versions of the Noyes-Whitney and the Weibull equations, including explicitly the solubility/dose parameter, for the analysis of dissolution data, which reach the plateau either at infinite or finite time.
Consumption of functional foods based on extracts from selected herbs to alleviate hypertension is an increasingly common practice in China. Adulteration of these foods with pharmaceuticals can significantly impact a consumer's health. To control the quality of the functional foods effectively, a method for the simultaneous determination of 10 common adulterants including chlortalidone, hydrochlorothiazide, indapamide, metoprolol, nifedipine, nimodipine, nitrendipine, reserpine, triamterene and valsartan in antihypertensive functional foods was developed. The target chemicals in samples were ultrasonically extracted with acetonitrile, and then cleaned-up with multi-walled carbon natotubes-dispersive solid-phase extraction. Finally, the analytes were separated with a C18 column using binary mobile phases consisting of acetonitrile and 0.03 mol/L KH2PO4 solutions (pH 3.0). The flow rate of the mobile phase was 0.80 mL/min, and the column temperature was 35°C. The detection wavelength was set at 220 nm. The limits of detection and quantification of the method ranged from 0.014 to 0.053 and 0.047 to 0.178 μg/mL, respectively. The recoveries of the method were in the range of 80.1-98.1% with relative standard deviations <9.53%. The method was successfully applied to the determination of the target chemicals in real samples and simulated samples, and respirine was detected in one tonic wine sample with a concentration of 56.8 ± 1.2 mg/L.
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A shortage of ticlopidine prompted the use of prasugrel in a clopidogrel-allergic patient requiring dual antiplatelet therapy. Prasugrel therapy was well tolerated, with no evidence of allergic reaction.
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In the review the basic studies devoted to researching of effectiveness of metoprolol in treatment of essential hypertension and also influence of this drug in the prognosis in this group of patients, are summarized. The specification on pharmacokinetic properties of the drug is shown. Outcomes of two studies (BCAPS and ELVA) devoted to influence of metoprolol on progression of atherosclerosis in patients with the risk factors are explained. The outcomes of these trials have confirmed, that the long-term therapy with metoprolol is one of the factors retentive atherosclerosis progression and allow more precisely to judge about mechanisms of positive influence of metoprolol therapy on the prognosis of the patients with cardiovascular diseases.
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Mahaim fiber tachycardia is an uncommon cause of palpitations among the pediatric population. This case report describes an adolescent female who presented with recurrent episodes of tachycardia with chest pain and dizziness. Her ECG showed tachycardia with wide QRS complexes and left bundle branch block pattern. Repeat ECG after adenosine treatment revealed sinus rhythm with persistence of the left bundle branch block pattern. Metoprolol was started however she continued to have episodes of sustained tachycardia.Electrophysiologic study then confirmed the diagnosis of Mahaim fiber tachycardia. Treatment was successful with mapping of the accessory pathways followed by radiofrequency ablation.
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The effects on renal function and urinary albumin excretion of 7 years of antihypertensive treatment compared to the effects of normal aging were studied in a random sample of 40 men with newly diagnosed primary hypertension and in 17 normotensive men of the same age, respectively. The hypertensives were treated with metoprolol either as monotherapy (n = 21) or combined with hydrochlorothiazide or hydralazine. Glomerular filtration rate (GFR; inulin clearance), renal blood flow (RBF; para-aminohippurate clearance), renal vascular resistance (RVR), and the 24 h urinary albumin excretion were determined. GFR was significantly reduced from 104 +/- 15 mL/min (mean +/- SD) to 86 +/- 20 mL/min (P < .001) in the hypertensive group, but the reduction was not significantly greater than in the normotensive group. As judged from the study of a subgroup of the hypertensives, most of the decrease in GFR occurred early as an immediate drug-induced, functionally explained decrease. The changes in RBF and RVR after 7 years of treatment did not differ significantly from those due to normal aging. RVR remained higher and RBF remained lower in the hypertensives than in the normotensives. The urinary albumin excretion in the hypertensives was significantly reduced after 7 years but remained higher than in the normotensives. In conclusion, the changes in renal function and hemodynamics seen after long-term treatment with metoprolol in primary hypertension were not significantly different from the changes caused by normal aging in normotensives.