ß-Blocker Use and Risk of Mortality in Heart Failure Patients Initiating Maintenance Dialysis.

RATIONAL & OBJECTIVE: Beta-blockers are recommended for patients with heart failure (HF) but their benefit in the dialysis population is uncertain. Beta-blockers are heterogeneous, including with respect to their removal by hemodialysis. We sought to evaluate whether ß-blocker use and their dialyzability characteristics were associated with early mortality among patients with chronic kidney disease with HF who transitioned to dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adults patients with chronic kidney disease (aged≥18 years) and HF who initiated either hemodialysis or peritoneal dialysis during January 1, 2007, to June 30, 2016, within an integrated health system were included. EXPOSURES: Patients were considered treated with ß-blockers if they had a quantity of drug dispensed covering the dialysis transition date. OUTCOMES: All-cause mortality within 6 months and 1 year or hospitalization within 6 months after transition to maintenance dialysis. ANALYTICAL APPROACH: Inverse probability of treatment weights using propensity scores was used to balance covariates between treatment groups. Cox proportional hazard analysis and logistic regression were used to investigate the association between ß-blocker use and study outcomes. RESULTS: 3,503 patients were included in the study. There were 2,115 (60.4%) patients using ß-blockers at transition. Compared with nonusers, the HR for all-cause mortality within 6 months was 0.79 (95% CI, 0.65-0.94) among users of any ß-blocker and 0.68 (95% CI, 0.53-0.88) among users of metoprolol at transition. There were no observed differences in all-cause or cardiovascular-related hospitalization. LIMITATIONS: The observational nature of our study could not fully account for residual confounding. CONCLUSIONS: Beta-blockers were associated with a lower rate of mortality among incident hemodialysis patients with HF. Similar associations were not observed for hospitalizations within the first 6 months following transition to dialysis.

The development of the LC-MS/MS method based on S-9 biotransformation for detection of metabolites of selected ß-adrenolytics in surface water.

Pharmaceuticals consumption in Poland is high. One of the most frequently prescribed is cardiovascular drugs. Due to their relatively high hydrophilic properties, they are not completely eliminated during wastewater treatment processes. In contrast to parent compounds, the presence of cardiovascular metabolites is rarely investigated in surface waters. The goal of this paper was to develop the methodology for detection of metabolites of selected beta-blockers: metoprolol, bisoprolol and propranolol. These metabolites were obtained by the incubation of parent compounds with S9 rat's liver fraction and used for the development and optimization of the low resolution LC-MS/MS method. Accurate mass spectrometry measurements were applied for validation of this method. The incubation of the parent compound with S9 fraction resulted only in propranolol's metabolites generation. However, on the basis of hydroxypropranolol, theoretically transitions for mono- and dihydroxy-metoprolol and bisoprolol derivatives were generated for MRM mode and applied for surface water analysis. The analysis revealed the presence of some of the target metabolites in the Vistula river. This work is the first one proposing the application of biotrasformation in the methodology of low resolution LC-MS-MS analysis of metabolites of cardiovascular drugs in surface water.

Breast milk concentrations of amiodarone, desethylamiodarone, and bisoprolol following short-term drug exposure: two case reports.

Two cases of mothers given postpartum short-term administration of amiodarone, with and without bisoprolol, are described along with determinations of amiodarone and (±)-bisoprolol in the breast milk. In one mother given a cumulative total of amiodarone of 8 g over 1 week, concentrations 11 days after the drug had been stopped were initially deemed sufficient to pose a risk to an infant. Over the next 5 days the concentrations steadily dropped with amiodarone and desethylamiodarone concentrations being found to be at a level comprising minimal risk to the infant. Bisoprolol was not found in the expressed breast milk. In the second case the mother was given a single 150 mg dose of amiodarone and breast milk concentrations were measured on postpartum days 4 and 5. Breast milk amiodarone concentrations were very low and of little concern clinically had the mother breast fed her baby. The risk to the baby of ingesting breast milk after amiodarone administration postpartum depends on the duration of amiodarone exposure, with a single dose posing minimal risk. Bisoprolol does not appear to accumulate to any great extent in breast milk.

The control of skin-permeating rate of bisoprolol by ion-pair strategy for long-acting transdermal patches.

A moderate drug permeating rate (flux) is desirable for long-acting transdermal patches. In this work, a novel simple method of controlling bisoprolol (BSP) flux by ion-pair strategy was initiated. Different ion-pair complexes including bisoprolol maleate (BSP-M), bisoprolol tartarate, bisoprolol besilate, and bisoprolol fumarate were prepared and their fluxes through rabbit abdominal skin were determined separately in vitro. Furthermore, permeation behavior from isopropyl myristate, solubility index in pressure-sensitive adhesives, determined by DSC, and n-octanol/water partition coefficient (log P) were investigated to illustrate the mechanism of drug permeation rate controlling. The results showed that compared to free BSP (J = 25.98 ± 2.34 µg/cm(2)/h), all BSP ion-pair complexes displayed lower and controllable flux in the range of 0.11 to 4.19 µg/cm(2)/h. After forming ion-pair complexes, the capability of BSP to penetrate through skin was weakened due to the lowered log P and increased molecule weight. Accordingly, this study has demonstrated that the flux of BSP could be controlled by ion-pair strategy, and among all complexes investigated, BSP-M was the most promising candidate for long-acting transdermal patches.

Uptake from water, biotransformation, and biliary excretion of pharmaceuticals by rainbow trout.

An urgent need exists to assess the exposure of fish to pharmaceuticals. The aim of the present study was to assess the uptake and metabolism of waterborne pharmaceuticals in rainbow trout (Oncorhynchus mykiss). A further objective was to determine the possibility of monitoring exposure to low levels of pharmaceuticals by bile assays. Rainbow trout were exposed for 10 d under flow-through conditions to mixtures of five pharmaceuticals (diclofenac, naproxen, ibuprofen, bisoprolol, and carbamazepine) at high and low concentrations. The low concentration was used to mimic the conditions prevailing in the vicinity of the discharge points of wastewater treatment plants. The uptake and the bioconcentration were determined by blood plasma and bile analyses. The average bioconcentration factor in plasma ranged from below 0.1 for bisoprolol to 4.9 for diclofenac, the values being approximately similar at low and high ambient concentrations. The biotransformation of diclofenac, naproxen, and ibuprofen was considered efficient, because several metabolites could be detected in concentrations clearly exceeding those of the unmetabolized compounds. The glucuronides were the dominant metabolites for all three pharmaceuticals. The total bioconcentration in the bile was two to four orders of magnitude higher than in the plasma. The results of this work show that the exposure of fish to pharmaceuticals in environmentally relevant concentrations may be monitored by blood plasma and bile analyses, the latter allowing detection at markedly lower ambient concentration.

Bisoprolol for congestive heart failure.

BACKGROUND: beta-Blockers are a cornerstone in the treatment of systolic heart failure treatment, but not all beta-blockers are effective or in this setting. OBJECTIVE: To define the role of bisoprolol, a highly selective beta(1)-antagonist in congestive heart failure due to systolic dysfunction. METHODS: Using the keywords 'bisoprolol' and 'heart failure' PubMed and BIOSIS databases were searched for information regarding pharmacology and relevant randomised clinical trials. Supplementary publications were acquired by scrutinising reference lists of relevant papers. Additional information was obtained from the FDA website. CONCLUSION: Bisoprolol is an effective and well-tolerated first-line beta-blocker for patients with systolic heart failure. The knowledge is primarily based on study patients with moderate-to-severe heart failure from the three CIBIS trials.

Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein.

Transporter proteins such as P-glycoprotein are major determinants of intracellular drug concentrations. Moreover, inhibition or induction of transporters is an important mechanism underlying drug interactions in humans. However, very little is known whether beta-adrenoceptor antagonists are substrates and/or inhibitors of P-glycoprotein. Therefore, we investigated the P-glycoprotein-mediated transport of propranolol, metoprolol, bisoprolol, carvedilol and sotalol in P-glycoprotein-expressing Caco-2 monolayers and inhibition of P-glycoprotein-mediated digoxin transport by the beta-adrenoceptor antagonists. A significant inhibition of polarized, basal to apical drug transport by the P-glycoprotein inhibitor PSC-833 was observed for bisoprolol (0.5 and 5 microm) and carvedilol (0.5 microm). Moreover, propranolol and carvedilol inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 24.8 and 0.16 microm, respectively, whereas metoprolol and sotalol had no effect. Bisoprolol significantly inhibited directional digoxin transport at 50 and 250 microm by 31% and 44%, respectively. Taken together, P-glycoprotein is likely to be one determinant of bisoprolol and carvedilol disposition in humans. In addition, the beta-adrenoceptor antagonists propranolol and carvedilol significantly inhibit P-glycoprotein function thereby possibly contributing to drug interactions in humans (e.g. digoxin-carvedilol and cyclosporine-carvedilol).

Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies.

There is an ongoing discussion on whether or not high beta(1)-adrenoceptor selectivity of beta-adrenoceptor antagonists may be favorable in the treatment of patients with heart failure. The present study compared the beta(1)-adrenoceptor selectivity of nebivolol and bisoprolol with that of carvedilol in the human myocardium, using a binding assay in conjunction with either the hydrophilic ligand (+/-)-[3H]4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on HCl ([3H]CGP 12.177) or the lipophilic ligand [125I]iodocyanopindolol as radiolabeled compound. Measurements were made using membrane preparations obtained from identical nonfailing donor hearts. beta-adrenoceptor density was found to be slightly higher when [125I]iodocyanopindolol was used compared to [3H]CGP 12.177 (256+/-15 and 213+/-18 fmol/mg protein, respectively). When the highly beta(1)-adrenoceptor-selective compound 2-hydroxy-5-(2-(hydroxy-3-(4((1-methyl-4-trifluoromethyl)-1-H-imidazol-2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide (CGP 20.712A) and the highly beta(2)-adrenoceptor-selective compound erythro-(+/-)-1-(7-methylindan-4-yloyl)-3-isopropylaminobutan-2-ol HCl (ICI 118.551) were used in competition experiments, a similar proportion of beta(1)-adrenoceptors was seen for [3H]CGP 12.177 (69.3+/-1.6%) and for [125I]iodocyanopindolol (67.0+/-2.1%). K(i)(beta(1)) and K(i)(beta(2)) were obtained in the presence of 50 nM ICI 118.551 and 300 nM CGP 20.712A. The rank order of beta(1)-adrenoceptor selectivity (K(i)(beta(2))/K(i)(beta(1)) ratio) was nebivolol (for [3H]CGP 12.177 46.1 and for [125I]iodocyanopindolol 22.5)>bisoprolol (13.1 and 6.4)>carvedilol (0.65 and 0.41). To investigate whether in vivo metabolized nebivolol retains high beta(1)-adrenoceptor selectivity, serum specimens were collected before and 2 h after oral administration of 5 mg nebivolol. The samples were used for [125I]iodocyanopindolol binding studies with the myocardial membrane preparations. In these samples, the binding of [125I]iodocyanopindolol to beta(1)-adrenoceptors was inhibited by 46.4+/-5.3%, whereas the binding to beta(2)-adrenoceptors was inhibited by 20.5+/-1.1% compared to that of control samples. It is concluded that nebivolol is approximately 3.5 times more beta(1)-adrenoceptor-selective than bisoprolol in the human myocardium. Furthermore, in vivo metabolized nebivolol retains beta(1)-adrenoceptor selectivity.

Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium.

1. The present study investigated whether or not there may be differences in the direct cardiac actions of the novel, highly beta(1)-selective adrenoceptor antagonist nebivolol (NEB) in comparison to metoprolol (MET), bisoprolol (BIS), carvedilol (CAR) and bucindolol (BUC) in human myocardium (n=9). 2. The rank order of beta(1)-selectivity as judged by competition experiments to (3)H-CGP 12.1777 in the presence of CGP 207.12 A (300 nmol l(-1), K(i)beta(2)) or ICI 118.551 (50 nmol l(-1), K(i)beta(1)) were NEB(K(i)beta(2)/K(i)beta(1): 40.7) > BIS(15.6) > MET(4.23) > CAR(0.73) > BUC(0.49). 3. The rank order of the negative inotropic potency of the beta-adrenoceptor antagonists measured in left ventricular trabeculae (dilated cardiomyopathy, DCM) as judged by the concentration needed to induce a 50% decrease in isoprenaline (1 micromol l(-1))-stimulated force (IC(50)) was: MET (0.6 micromol l(-1)) > CAR (4.1 micromol l(-1)) > NEB (7.0 micromol l(-1)). 4. NEB, BUC, MET and CAR did not not exert an intrinsic sympathomimetic activity (ISA) as determined by measurements of force development in forskolin (0.3 micromol l(-1)) pre-treated left ventricular trabeculae, nor by measuring adenylate cyclase activity in forskolin (0.3 micromol l(-1))-stimulated assays (crude membranes). This also holds true for radioligand binding assays with or without guanine nucleotide guanyl-5'-yl imidodiphosphate (Gpp(NH)p). 5. Although all studied beta-adrenoceptor antagonists lack intrinsic sympathomimetic activity (ISA), they differ in the beta(1)-selectivity as well as in their direct negative inotropic action. These differences as well as the mode of extracardiac action may have an impact on outcome of patients treated with beta-adrenoceptor antagonists.

Asymmetric synthesis and preliminary evaluation of (R)- and (S)-[11C]bisoprolol, a putative beta1-selective adrenoceptor radioligand.

(+/-)-1-[4-(2-Isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2-propanol (bisoprolol) is a potent, clinically used beta(1)-adrenergic agent. (R)-(+) and (S)-(-) enantiomers of bisoprolol were labelled with carbon-11 (t(1/2)=20.4 min) as putative tracers for the non-invasive assessment of the beta(1)-adrenoceptor subtype in the human heart and brain with positron emission tomography (PET). The radiosynthesis consisted of reductive alkylation of des-iso-propyl precursor with [2-11C]acetone in the presence of sodium cyanoborohydride and acetic acid. The stereo-conservative synthesis of (R)-(+) and (S)-(-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-amino-2-propanol to be used as the precursors for the radiosynthesis of [11C]bisoprolol enantiomers was readily accomplished by the use of the corresponding chiral epoxide in three steps starting from the commercially available hydroxybenzyl alcohol. The final labelled product (either (+) or (-)-1-[4-(-isopropoxyethoxymethyl)-phenoxy]-3- [11C]isopropylamino-2-propanol) was obtained in 99% radiochemical purity in 30 min with 15+/-5% (EOS, non-decay corrected) radiochemical yield and 3.5+/-1 Ci/micromol specific radioactivity. Preliminary biological evaluation of the tracer in rats showed that about 30% of heart uptake of [11C](S)-bisoprolol is due to specific binding. The high non-specific uptake in lung might mask the heart uptake, thus precluding the use of [11C](S)-bisoprolol for heart and lung studies by PET. The remarkably high uptake of the tracer in rat brain areas rich of beta-adrenergic receptors such as pituitary (1.8+/-0.3% I.D. at 30 min) was blocked by pre-treatment with the beta-adrenergic antagonists propranolol (45%) and bisoprolol (51%, p<0.05). [11C](S)-bisoprolol deserves further evaluation in other animal models as a putative beta(1) selective radioligand for in vivo investigation of central adrenoceptors.

Stereoselective metabolism of bisoprolol enantiomers in dogs and humans.

To clarify the mechanism of the species difference in the metabolism of bisoprolol enantiomers, in vitro metabolic studies were performed using dog liver microsomes and human cytochrome P450 (CYP) isoforms. The O-deisopropylation of bisoprolol enantiomers showed biphasic kinetics in dog liver microsomes. The intrinsic clearance (Vmax/Km) for O-deisopropylation of R(+)-bisoprolol was higher than S(-)-isomer in both high-affinity and low-affinity components. The R/S ratio of the intrinsic clearance in high- and low-affinity components was 1.34 and 1.65, respectively. The inhibition studies in dog liver microsomes using CYP isoform-selective inhibitors indicated that the O-deisopropylation of both bisoprolol enantiomers was mediated via the CYP2D and CYP3A subfamily, and suggested that high-affinity oxidation was dependent on CYP2D. The kinds of CYP subfamilies in dogs, which contribute to the metabolism of bisoprolol enantiomers, were the same as those in humans. The intrinsic clearance for O-deisopropylation of R(+)bisoprolol by human recombinant CYP2D6 was also different from that of S(-)-enantiomers (R/S:1.50). However, unlike the dog microsomes, the intrinsic clearance by the human recombinant CYP3A4 did not show a stereoselective difference. Therefore, the species difference in the R/S ratio of metabolic clearance for the oxidation of bisoprolol enantiomers (dog > human) is mainly due to the species difference in the stereoselectivity of one of the cytochrome P450 subfamilies (CYP3A).

Microbial metabolism of the beta-adrenoreceptor antagonist bisoprolol.

Eighteen filamentous fungi and six actinomycetes species were screened for their ability to metabolize bisoprolol, a beta-blocking drug. All strains of Cunninghamella tested accumulated metabolite M4 = EMD 46193 ([4-(2-hydroxy-3-isopropylaminopropoxy)benzyloxy]ethanol). Among the strains investigated only Gliocladium deliquescens excreted the corresponding carbonic acid M1 = EMD 44025 into the culture medium. Biotransformation of bisoprolol by fungi occurred only during growth in complex medium or with resting cells after cultivation in complex medium. The screened Actinomycetes showed no biotransformation of the drug.

A metabolic assessment of the beta 1 selectivity of bisoprolol.

Twelve healthy volunteers were given single oral doses of bisoprolol 5 mg, 10 mg and 20 mg and atenolol 50 mg and 100 mg in a randomised, placebo-controlled study. The effects of these drugs on beta 2-stimulated hypokalaemia and hyperglycaemia (produced by intravenous terbutaline infusion) were studied. Comparable beta-blockade was achieved with bisoprolol 20 mg, and atenolol 50 mg and 100 mg as measured by attenuation of exercise heart rate. Measurements of areas under or over the curve (AUC and AOC) of hypokalaemic or hyperglycaemic response to terbutaline infusion showed that bisoprolol (10 mg and 20 mg) and atenolol (50 mg and 100 mg) were significantly less beta 1 selective than 5 mg bisoprolol. Furthermore, there was a trend towards decreasing beta 1 selectivity with increasing doses of bisoprolol. Bisoprolol, an effective once daily antihypertensive and antianginal treatment, has comparable beta 1 selectivity to atenolol as measured by metabolic response. At a dose of 5 mg, bisoprolol has a measurable impact on beta 1 receptors but minimal effect on beta 2 receptors.