Pharmacokinetic variability of routinely administered bisoprolol in middle-aged and elderly Japanese patients.
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The nonlinear mixed effects model (NONMEM) was used to analyze the pharmacokinetics of routinely administered bisoprolol in middle-aged and elderly Japanese patients. The subjects consisted of 29 males and 11 females with a mean age of 63.5+/-10.1. Data on the plasma concentration of bisoprolol from 94 blood samples obtained at steady-state following repetitive oral administration were analyzed using the NONMEM program, where a one-compartment model with repetitive bolus dosing was parameterized in terms of oral clearance (CL/F) and apparent volume of distribution (V/F). Individual CL/F values were correlated with body weight (WT) and creatinine clearance (CLcr). The relation between CLcr and the CL/F of bisoprolol was not altered by the CYP2D6 and CYP2C19 genotypes, gender, or age. The mean CL/F value estimated with NONMEM was 0.0612.WT+1.15.CLcr (l/h), and the mean V/F value was 2.61.WT (l). The residual interindividual variability of CL/F and V/F were 22.0% and 12.6%, respectively. The pharmacokinetic variability of bisoprolol is small even in routinely treated Japanese patients, provided that both body weight and renal function are taken into account for the prediction of oral clearance of the drug. (+info)
Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III.
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BACKGROUND: In patients with chronic heart failure (CHF), a beta-blocker is generally added to a regimen containing an angiotensin-converting-enzyme (ACE) inhibitor. It is unknown whether beta-blockade as initial therapy may be as useful. METHODS AND RESULTS: We randomized 1010 patients with mild to moderate CHF and left ventricular ejection fraction < or =35%, who were not receiving ACE inhibitor, beta-blocker, or angiotensin receptor blocker therapy, to open-label monotherapy with either bisoprolol (target dose 10 mg QD; n=505) or enalapril (target dose 10 mg BID; n=505) for 6 months, followed by their combination for 6 to 24 months. The 2 strategies were blindly compared with regard to the combined primary end point of all-cause mortality or hospitalization and with regard to each of these end point components individually. Bisoprolol-first treatment was noninferior to enalapril-first treatment if the upper limit of the 95% confidence interval (CI) for the absolute between-group difference was <5%, corresponding to a hazard ratio (HR) of 1.17. In the intention-to-treat sample, the primary end point occurred in 178 patients allocated to bisoprolol-first treatment versus 186 allocated to enalapril-first treatment (absolute difference -1.6%, 95% CI -7.6 to 4.4%, HR 0.94; 95% CI 0.77 to 1.16). In the per-protocol sample, 163 patients allocated to bisoprolol-first treatment had a primary end point, versus 165 allocated to enalapril-first treatment (absolute difference -0.7%, 95% CI -6.6 to 5.1%, HR 0.97; 95% CI 0.78 to 1.21). With bisoprolol-first treatment, 65 patients died, versus 73 with enalapril-first treatment (HR 0.88; 95% CI 0.63 to 1.22), and 151 versus 157 patients were hospitalized (HR 0.95; 95% CI 0.76 to 1.19). CONCLUSIONS: Although noninferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, our results indicate that it may be as safe and efficacious to initiate treatment for CHF with bisoprolol as with enalapril. (+info)
The Arg389Gly beta1-adrenoceptor polymorphism and catecholamine effects on plasma-renin activity.
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OBJECTIVES: The purpose of this research was to find out whether, in humans, dobutamine-induced hemodynamic effects and increase in plasma-renin activity (PRA) might be beta1-adrenoceptor (beta1AR) genotype-dependent. BACKGROUND: In vitro Arg389Gly-beta1AR polymorphism exhibits decreased receptor signaling. METHODS: We studied 10 male homozygous Arg389-beta1AR subjects and 8 male homozygous Gly389beta1AR subjects; to avoid influences of codon 49 polymorphism, all were homozygous Ser49-beta1AR. Subjects were infused with dobutamine (1 to 6 microg/kg/min) with or without bisoprolol (10 mg orally) pretreatment, and PRA, heart rate, contractility, and blood pressure were assessed. RESULTS: With regard to PRA, dobutamine increased PRA more potently in Arg389-beta1AR versus Gly389-beta1AR subjects. Bisoprolol markedly suppressed the dobutamine-induced PRA increase in Arg389- but only marginally in Gly389-beta1AR subjects. With regard to hemodynamics, dobutamine caused larger heart rate and contractility increases and diastolic blood pressure decreases in Arg389- versus Gly389-beta1AR subjects. Bisoprolol reduced dobutamine-induced heart rate and contractility increases and diastolic blood pressure decreases more potently in Arg389- versus Gly389-beta1AR subjects. CONCLUSIONS: Codon 389 beta1AR polymorphism is a determinant not only of hemodynamic effects but also of PRA. Thus, beta1AR polymorphisms may be useful for predicting therapeutic responses to betaAR-blocker treatment. (+info)
Cardiovascular effect of low-dose epinephrine infusions in relation to the extent of preoperative beta-adrenoceptor blockade.
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The relationship between the extent of preoperative beta-adrenoceptor blockade and the hemodynamic properties of epinephrine was investigated in patients scheduled for elective myocardial revascularization during the immediate preoperative period under steady-state hemodynamic and anesthetic conditions. Twenty patients had been treated with beta-adrenoceptor blocking drugs for at least 3 weeks before the study; 11 unblocked patients served as control group. The extent of clinical beta-adrenoceptor blockade was quantified using the isoproterenol sensitivity test. The dose of isoproterenol required to increase heart rate by 25 beats per min was defined as the chronotropic dose 25 (CD25), representing the degree of beta-adrenoceptor blockade. Geometric mean CD25 per 70 kg was 3.0 micrograms in the control group and 21.8 micrograms in the patients receiving beta-adrenoceptor blocking drugs. The authors found a significant inverse relationship between CD25 values and changes in cardiac index in response to three epinephrine infusion rates (0.01, 0.02, and 0.04 micrograms.kg-1.min-1), the correlation coefficients being -0.71, -0.81, and -0.86, respectively. Compared to unblocked patients, almost no change, or even a decrease, of the cardiac index was observed at greater degrees of clinical beta-adrenoceptor blockade, particularly in patients receiving nonselective blockers. Moreover, there was a significant linear correlation (r = 0.76-0.86) between CD25 values and the effects of epinephrine on systemic vascular resistance index (SVRI); i.e., SVRI significantly decreased in control patients but markedly increased in patients with high degrees of preoperative beta-adrenoceptor blockade. This unmasked vasoconstrictive response to low doses of epinephrine was observed despite the fact that the majority of our patients had received cardioselective adrenergic blocking drugs.(ABSTRACT TRUNCATED AT 250 WORDS) (+info)
Effect of amiodarone and sotalol on ventricular defibrillation threshold: the optimal pharmacological therapy in cardioverter defibrillator patients (OPTIC) trial.
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BACKGROUND: Many patients with implanted cardioverter defibrillators (ICDs) receive adjunctive antiarrhythmic drug therapy, most commonly amiodarone or sotalol. The effects of these drugs on defibrillation energy requirements have not been previously assessed in a randomized controlled trial. METHODS AND RESULTS: The Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) trial was a randomized clinical trial evaluating the efficacy of amiodarone plus beta-blocker and sotalol versus beta-blocker alone for reduction of ICD shocks. Within OPTIC, a prospectively designed substudy evaluated the effects of the 3 treatment arms on defibrillation energy requirements. Defibrillation thresholds (DFTs) were measured (binary step-down protocol) at baseline and again after 8 to 12 weeks of therapy in 94 patients, of whom 29 were randomized to receive beta-blocker therapy (control group), 35 to amiodarone plus beta-blocker, and 30 to sotalol. In the control group, the mean DFT decreased from 8.77+/-5.15 J at baseline to 7.13+/-3.43 J (P=0.027); in the amiodarone group, DFT increased from 8.53+/-4.29 to 9.82+/-5.84 J (P=0.091). In the sotalol group, DFT decreased from 8.09+/-4.81 to 7.20+/-5.30 J (P=0.21). DFT changes in the beta-blocker and the amiodarone group were significantly different (P=0.006). In all patients, adequate safety margins for defibrillation were maintained. No clinical variable predicted baseline DFT or changes in DFT on therapy. CONCLUSIONS: Although amiodarone increased DFT, the effect size with modern ICD systems is very small. Therefore, DFT reassessment after the institution of antiarrhythmic drug therapy with amiodarone or sotalol is not routinely required. (+info)
Pharmacokinetics and pharmacodynamics of bisoprolol in rats with bilateral ureter ligation-induced renal failure.
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The effect of renal failure on the pharmacokinetics and pharmacodynamics of bisoprolol was investigated in bilateral ureter-ligated (BUL) rats. The blood bisoprolol concentrations following 30-min intravenous infusion at a rate of 60 microg/kg/min were higher in renal artery-occluded (RAO) rats than in control rats, and were higher in BUL rats than in RAO rats. Increased blood bisoprolol concentrations accompanied decreased mean systemic clearances: 50.7, 36.4, and 26.2 mL/min/kg in control, RAO, and BUL rats, respectively. The finding indicated that approximately 30% of administered bisoprolol was excreted via the kidney, and that not only the renal clearance but also non-renal clearance of bisoprolol was decreased in BUL rats. The beta-blocking action of bisoprolol was assessed by the reduction in isoproterenol-induced increases in the heart rate. The relationship between blood concentration and the beta-blocking action of bisoprolol in BUL rats was similar to that in control rats. These results suggested that renal excretion and hepatic metabolism of bisoprolol were significantly reduced in BUL rats, but that pharmacodynamics of bisoprolol was not altered by acute renal failure. (+info)
Enantioanalysis of bisoprolol in human plasma with a macrocyclic antibiotic HPLC chiral column using fluorescence detection and solid phase extraction.
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A sensitive, enantioselective, high-performance liquid chromatographic (HPLC) method was developed and validated to determine S-(-)- and R-(+)-bisoprolol in human plasma. Baseline resolution was achieved using the teicoplanin macrocyclic antibiotic chiral stationary phase (CSP) known as Chirobiotic T with a polar ionic mobile phase (PIM) consisting of methanol-glacial acetic acid-triethylamine (100 : 0.02 : 0.025, v/v/v) at a flow rate of 1.5 ml/min and fluorescence detection set at 275 nm for excitation and 305 nm for emission. All analyses with S-(-)-atenolol as the internal standard were conducted at ambient temperature. The assay involved the use of a solid-phase extraction procedure for human plasma samples prior to HPLC analysis. The C18 cartridge gave good recovery rates for both enantiomers without any interference. The method was validated over the range of 20-200 ng/ml for each enantiomer concentration. Recovery rates for S-(-)- and R-(+)-bisoprolol enantiomers were in the range of 95-102%. The method proved to be precise (within-run precision expressed as % RSD ranged from 1.0-6.2% and between-run precision ranged from 0.9-6.7%) and accurate (within-run accuracies expressed as percentage error ranged from 0.2-4.8% and between-run accuracies ranged from 0.3-1.7%). The limit of quantitation and limit of detection for each enantiomer in human plasma were 20 and 5 ng/ml, respectively. (+info)
Beta blockers for congestive heart failure.
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The prognosis remains poor for many patients with congestive heart failure, despite maximal medical treatment with ACE inhibitor, diuretics and digitalis. In heart failure, activation of sympathetic nervous system has been described as one of the most important pathophysiologic abnormalities in patients with congestive heart failure and as one of the most important mechanisms that may be responsible for progression of heart failure. The use of beta blockers which may inhibit sympathetic activity, might reduce the risk of disease progression in heart failure, improve symptoms and increase survival. Several large clinical trials with metoprolol, carvedilol and bisoprolol have shown that long term use of these agents can improve left ventricular function and symptoms of CHF, it may also reduce hospital readmission and decrease mortality. Current guidelines recommend the use of beta blocker in mild, moderate and severe CHF, in the absence of contraindications or tolerance in combination with ACE inhibitor and diuretics. Beta blocker should be initiated in patients after maximal medical therapy with diuretics, ACE inhibitor and digitalis and patients already stabilized and in compensated conditions. Beta blocker should be started in low doses and require slow titration over weeks or months before patients can attain maintenance doses. (+info)