Highly exfoliated functionalized MoS2 with sodium alginate-polydopamine conjugates for electrochemical sensing of cardio-selective ß-blocker by voltammetric methods.

Molybdenum disulfide (MoS2) surface functionalization was performed with a catechol-containing polymer sodium alginate (SA) and dopamine (DA) through simultaneous MoS2 exfoliation and self-polymerization of DA. The MoS2/SA-PDA nanocomposite was characterized using spectroscopic, microscopic, and electroanalytical techniques to evaluate its electrocatalytic performance. The electrocatalytic behavior of the MoS2/SA-PDA nanocomposite modified electrode for the detection of acebutolol (ACE), a cardio-selective ß-blocker drug was explored  through cyclic voltammetric and differential pulse voltammetric techniques. The influence of scan rate, concentration, and pH value on the oxidation peak current of ACE was investigated  to optimize the deducting condition. The electrochemical activity of the MoS2/SA-PDA nanocomposite electrode was attributed to the existence of reactive functional groups being contributed from SA, PDA, and MoS2 exhibiting a synergic effect. The MoS2/SA-PDA nanocomposite modified electrode exhibits admirable electrocatalytic activity with a wide linear response range (0.009 to 520 µM), low detection limit (5 nM), and high sensitivity (0.354 µA µM-1 cm-2) also in the presence of similar (potentially interfering) compounds. The fabricated MoS2/SA-PDA nanocomposite modified electrode can be useful for the detection of ACE in pharmaceutical analysis.

A case of fatal acebutolol poisoning: an illustration of the potential of molecular networking.

Acebutolol is a ß1-selective adrenergic receptor antagonist with moderate membrane-stabilizing activity and intrinsic sympathomimetic activity; accordingly, the drug is indicated in hypertension, angina pectoris, and arrhythmia. However, acebutolol's beta-blocking properties also extend the QRS and QTc intervals, and may predispose the patient to ventricular tachydysrhythmia. Here, we report autopsy and toxicological findings on a fatal case of acebutolol self-poisoning in a 70-year-old woman. Toxicological analyses of post-mortem samples (using a liquid chromatography high-resolution mass spectrometry (LC-HR-MS) method) highlighted high concentrations of acebutolol and its metabolite diacetolol in femoral blood (92.8 mg/L and 21.2 mg/L, respectively) and other matrices (cardiac blood, urine, bile, and gastric contents). A molecular networking approach provided useful information on acebutolol's metabolism and revealed the existence of an unknown phase II metabolite of acebutolol. Molecular networking also facilitated visualization of the complex LC-HR-MS/MS datasets and the sample-to-sample comparisons that confirmed massive acebutolol intoxication by ingestion.

Using supported liquid extraction together with cellobiohydrolase chiral stationary phases-based liquid chromatography with tandem mass spectrometry for enantioselective determination of acebutolol and its active metabolite diacetolol in spiked human plasma.

A high through-put, sensitive, and enantioselective LC-MS/MS-based bioanalytical method was developed and validated for the simultaneous determination of individual acebutolol (AC) and its active metabolite-diacetolol (DC) enantiomers in human plasma using cellobiohydrolase (CBH) chiral stationary phases (CSP). Systematic optimization of chromatographic conditions including organic content, buffer concentration, and pH of mobile phases was conducted to improve the through-put for the direct separation of both AC and DC on CBH column during method development. Complete baseline separation of enantiomeric AC and DC was achieved within 1.5 min with a LC flow rate of 0.9 ml/min under method validation conditions. To further improve the assay through-put, supported liquid extraction (SLE) in a 96-well plate format was used for sample extraction. The method validation was conducted over the curve range of 0.0500-50.0 ng/ml for each AC and DC enantiomer using 0.100 ml of plasma sample. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels showed

Determination of selected beta-receptor antagonists in biological samples by solid-phase extraction with cholesterolic phase and LC/MS.

A new method is presented for the determination of five selected beta-receptor antagonists by HPLC, which emphasizes sample preparation via retention on a new type of silica gel sorbent used for solid-phase extraction (SPE). Sorbents of this type were obtained by the chemical modification of silica gels of various porosities by cholesterol ligands. The cholesterol-based packing material was investigated by spectroscopic methods and elemental analysis. The recoveries obtained with the extraction procedure were optimum over a relatively broad sample pH range (3.08-7.50). Analytical factors such as the sample loading, the washing step and elution conditions, the concentration of beta-receptor antagonists to be extracted, and the type of sorbent were found to play significant roles in the sample preparation procedure and would therefore need to be controlled to achieve optimum recoveries of the analytes. Under optimum conditions, the recoveries of nadolol, acebutolol, esmolol, oxprenolol and propranolol from spiked buffers, blood and urine were reproducible and dependent on the polarity or hydrophilicity of the compounds. The above analytes were determined by reverse-phase high-performance liquid chromatography (HPLC) with UV and ESI-ion trap mass spectrometry (MS) detection. The described method was found to be suitable for the routine measurement of compounds that are both polar and basic, and can be applied for the analysis of biological samples such as urine and blood in clinical, toxicological or forensic laboratories. The recovery measurements were performed on spiked human urine and serum, and on real samples of mouse blood serum.

Prevention of postischaemic ventricular fibrillation by long term beta adrenoceptor blockade with acebutolol in the anaesthetised dog.

Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment underwent the same procedure. Coronary ligations in the randomised study were performed during seven consecutive days, and four dogs were operated on each day. This schedule was chosen in order to measure acebutolol plasma concentrations just before ligation from 60 to 540 min after the last dose of the drug. Long term oral treatment with acebutolol protected against postischaemic ventricular fibrillation and significantly reduced the incidence of both early phase (0-10 min postocclusion) ventricular arrhythmias and ventricular fibrillation. As a result the outcome was significantly improved after 60 min of ischaemia in acebutolol compared with placebo treated animals. The results in the control animals were similar to those in the placebo treated dogs. The protective effect of long term oral treatment with acebutolol lasted for nine hours and was apparently independent of the plasma concentrations of the drug. These data show that improved outcome in this canine model is due to the prevention of ischaemia induced ventricular fibrillation by long term beta adrenoceptor blockade, which is able to overcome the effect, if any, of partial agonist activity of acebutolol. A direct myocardial anti-ischaemic effect might explain the effectiveness of long term oral treatment, which is independent of plasma concentrations of the drug.

Graphite-based microextraction by packed sorbent for online extraction of ß-blockers from human plasma samples.

In the present work a new graphitic material (Carbon-XCOS) was used as a sorbent for microextraction by packed sorbent (MEPS). The ß-blockers metoprolol and acebutolol in plasma samples were extracted and detected online using Carbon-MEPS syringe and liquid chromatography and tandem mass spectrometry (LC-MS/MS). Factors affecting the MEPS performance such as conditioning, washing and elution solutions were investigated. The validation of the bioanalytical method was performed using human plasma. The standard curve ranged from 10 to 2000nM and the lower limit of quantification (LLOQ) was set to 10nM. The method validation showed good accuracy and precision for the quality control (QC) samples at three concentration levels (30, 800 and 1600nM). The accuracy values of the QC samples were in the range of 86-108% (n=18). The precision values of intra- and inter-day for QC samples ranged from 4.4% to 14.4% (RSD) for the both studied analytes. The coefficient of determination (R(2)) values were ≥0.999 (n=3).

Dose-dependent acebutolol disposition after oral administration.

The relationship between dose and area under the blood concentration-time curve has been studied in 6 healthy subjects following both oral and intravenous doses of acebutolol. There is a more than proportional increase in area with increasing oral doses, and the area over a dosing interval following multiple oral doses is greater than the total area after a single dose of the same size. The role of an acetyl metabolite in producing these effects is discussed, as is the relevance of these observations to the clinical use of acebutolol.

Acebutolol disposition after intravenous administration.

The disposition of acebutolol has been studied following intravenous doses of 0.25 to 1.0 mg/kg in 9 healthy subjects using a specific chromatographic assay to determine concentrations of drug in blood. The mean blood clearance was 6.55 ml/min/kg and the mean renal clearance, 2.68 ml/min/kg. Blood clearance was found to have a coefficient of variation of 14% for the group, to be independent of dose, and to remain essentially constant over approximately 3 wk. The fraction of the dose excreted in the urine unchanged was 0.405. Data were fitted to an equation for a two-compartment model. The mean fast and slow half-lives were 6.08 and 156.8 min, respectively. The volume of the central compartment was 0.223 L/kg, and the volume of distribution at steady-state was 1.165 L/kg. The fraction of acebutolol unbound to plasma proteins was 0.743 and was independent of drug concentration in the range examined. Data obtained from 15-min infusions were used to predict plateau blood concentrations with good accuracy during an 8-hr dosage regimen.

Circulatory effects of intravenous and oral acebutolol in acute myocardial infarction.

The hemodynamic dose-response effects of intravenous (25 and 50 mg) and oral (200 and 400 mg) acebutolol were compared in a randomized between-group study in men within 17 hours of an acute uncomplicated myocardial infarction. Six subjects were evaluated in each of the four groups. After a 1-hour control period, hemodynamic variables and plasma drug concentrations were determined at 15 (intravenous therapy only), 30, 60, 90, 120, and 240 minutes after dosing. At the doses studied, hemodynamic dose-response effects were not evident after either intravenous or oral acebutolol. In all groups acebutolol reduced systolic and mean systemic arterial pressure, heart rate, cardiac output, and stroke volume. Pulmonary artery occluded pressure and systemic vascular resistance were transiently increased. Maximum changes developed between 15 and 30 minutes after intravenous dosing and between 1 and 2 hours after oral dosing. However, there were substantial reductions in cardiac output (-0.7 L/min/m2; P less than 0.05) by 30 minutes after oral dosing. Effects lasted for 2 hours after intravenous dosing and for 4 hours after oral dosing. Our data confirm the hemodynamic safety of acebutolol after acute myocardial infarction. The relevance of the time-dependent hemodynamic differences between intravenous and oral initiation of beta-blockade to the overall goal of reducing myocardial oxygen requirements after acute coronary artery occlusion merits closer examination.

Comparison of four beta-blockers as assessed by 24-hour ECG recording.

beta-Blockers are used as if they were equivalent. With ECG recordings in 42 patients we investigated the effect on sinus heart rate of four beta-blockers given at three successive daily doses. Heart rate was dose-dependently decreased by all drugs except acebutolol, the effect of which decreased at a higher dosage. The maximal effects of metoprolol, nadolol, and propranolol were similar but the drugs differed in potency (dosage producing 50% of maximal effect, calculated from the dose-effect relationships; nadolol, 0.3 mg/day; metoprolol, 120 mg/day; propranolol, 47 mg/day). Similar relationships were found with drug plasma concentrations (concentration producing 50% of maximal effect: nadolol, 3.5 ng/ml; metoprolol, 21 ng/ml; propranolol, 36 ng/ml) and with supine or upright heart rates and blood pressures. However, the drugs were not equivalent: In addition to its greater potency, nadolol differed from propranolol and metoprolol in the slope of its dose-response curve. We conclude that beta-blockers can be compared by ECG recordings and that nadolol is different from the other beta-blockers without intrinsic sympathomimetic activity.

Effective treatment of supraventricular arrhythmias with acebutolol.

To evaluate the antiarrhythmic efficacy of the new beta adrenergic blocking agent acebutolol, 15 monitored patients with supraventricular arrhythmias received, in double-blind fashion, an intravenous infusion of either acebutolol or saline solution after a control period. Patients treated with saline solution demonstrated no change (P greater than 0.05) in heart rate or arterial blood pressure or conversion to sinus rhythm. After administration of acebutolol, significant (P less than 0.05) reductions in heart rate were noted at 5 minutes. Peak reduction occurred at 10 to 30 minutes and correlated with maximal acebutolol plasma concentrations, antiarrhythmic activity persisted for 24 hours. Mild reductions in systolic blood pressure were observed in the majority of patients. Two patients with atrial fibrillation and one with multifocal atrial tachycardia had conversion to sinus rhythm. Frequent premature atrial complexes noted in one patient were greatly suppressed after administration of the drug. In the nine patients with clinical evidence of chronic obstructive lung disease acebutolol was well tolerated. Adverse reactions were limited to transient dyspnea in one patient with prior heart failure and a decrease in systolic blood pressure to less than 90 mm Hg in three patients who remained asymptomatic. In the patients studied, acebutolol was an effective agent for the treatment of supraventricular arrhythmias and appeared to be of special value in those with chronic obstructive lung disease.

Acebutolol effects on lipid profile.

The relation between lipid profile and the incidence of coronary artery disease has been confirmed by the results of epidemiologic and intervention studies. Among antihypertensive agents, beta blockers, particularly those without intrinsic sympathomimetic activity (ISA), are generally reported to have negative effects on lipids, which may increase the risk of coronary artery disease. The ongoing Treatment of Mild Hypertension Study, now in its third year, has evaluated 847 patients to date with regard to lipid profile. Additional end points measured in this multicenter, randomized, controlled, double-blind study include blood pressure reduction and target organ deterioration. During the trial, all patients received nutritional and behavioral counselling to modify their diet, exercise habits and alcohol and sodium consumption to control their hypertension by nonpharmacologic means. In addition, some patients were randomized to receive low doses of 1 of the 5 classes of antihypertensive medication: acebutolol, a beta blocker with ISA (n = 124); amlodipine, a calcium channel blocker (n = 122); chlorthalidone, a diuretic (n = 125); doxazosin, an alpha blocker (n = 128); enalapril, an angiotensin-converting enzyme inhibitor (n = 127) or placebo (n = 221). At 1 year, acebutolol showed a statistically significant (p less than 0.001) decrease in total cholesterol (-12.7 mg/dl) compared with placebo (-5.2 mg/dl) and with chlorthalidone (1.0 mg/dl); a significant (p less than 0.001) decrease in low-density lipoprotein cholesterol (-6.0 mg/dl) compared with placebo (+0.7 mg/dl) and with chlorthalidone (+8.0 mg/dl) and no change in high-density lipoprotein cholesterol (-0.4 mg/dl).

Antiarrhythmic significance of dosing intervals in beta receptor blocking therapy of hypertension with acebutolol.

Six hypertensive patients with daily ventricular arrhythmias underwent a double-blind crossover study to examine whether a once daily regimen of beta receptor blockade was equipotent in antihypertensive and antiarrhythmic activity to a twice daily regimen. Acebutolol, a relatively cardioselective beta blocking compound with intrinsic sympathomimetic properties, was given in two regimens: 200 mg twice daily or 400 mg once daily. Ventricular ectopic beats were analyzed both during physical exercise and with multiple 24 hour ambulatory electrocardiographic (Holter) recordings. Serum concentrations of acebutolol and its acetyl metabolite were determined using high pressure liquid chromatography. The two regimens of acebutolol were equally potent in reducing the blood pressure and heart rate at rest and during physical exertion. The hourly heart rates during 24 hours were reduced to the same extent by both regimens. The single daily 400 mg dose did not significantly reduce the incidence of arrhythmias, whereas 200 mg twice daily evoked a significant reduction during 24 hours. Serum concentrations of acebutolol were twice as great with the twice daily regimen as with the single dose. Both treatments significantly shortened the Q-Tc interval. The data suggest that, despite apparent beta receptor blockade and good blood pressure control, beta blocking agents with a relatively short plasma half-life lose their antiarrhythmic potency when administered on a once daily basis. This property seems to be more related to the plasma concentration of the compound than to the degree of clinically assessed beta receptor blockade.

Documentation of the effective length of action of antihypertensive treatment.

The technique of automated ambulatory blood pressure (BP) monitoring offers an innovative means for measuring BP throughout the 24-hour period. Recently available compact monitoring instruments have been shown to be accurate and to provide reproducible measurements of the circadian BP pattern. The monitoring procedure is advantageous in that it minimizes or avoids placebo effects during therapeutic trials. Moreover, its power makes it possible to draw statistically valid conclusions regarding efficacy in fewer patients than would be required if conventional methods were used. This procedure also enhances the diagnosis of hypertension by identifying patients with "office" or "white coat" hypertension, and thereby facilitates assessment of treatment effects in those patients who are truly hypertensive. Automated monitoring measures BP at critical times of the day, including the preawakening and early morning hours, and it enables peak and trough antihypertensive drug effects to be carefully quantified. Since patient compliance appears to be enhanced with once- or twice-daily dosing, antihypertensive agents with long durations of action (24 hours) are of considerable interest. This report reviews some recent studies in which the monitoring technique has been used to measure the efficacy and duration of action of differing antihypertensive drugs.

Comparison of the beta 1 and beta 2 adrenoceptor blocking properties of acebutolol and propranolol.

The purposes of this study were to evaluate the beta 1 and beta 2 adrenoceptor blocking properties of acebutolol and propranolol and measure the plasma levels of acebutolol, its acetylated metabolite and propranolol. Ten patients with reversible obstructive airways disease and hypertension received two separate dose levels of acebutolol and propranolol for five days each. Cardioselective properties were assessed by determining the beta 1 and beta 2 adrenergic-stimulating effects of terbutaline 5 mg before and at the end of each five-day treatment period. Both acebutolol and propranolol were clinically well tolerated. Following study drug there was a 100 percent inhibition of the beta 1 terbutaline effect, and an approximate 83 percent inhibition of the beta 2 terbutaline effect. There were no clinically significant differences between acebutolol and propranolol. The acetylated acebutolol metabolite accumulated levels two to three times higher than the parent compound, and its effects may have destroyed the cardioselectivity of acebutolol. Thus, acebutolol did not demonstrate clinically relevant cardioselectivity.

Acebutolol overdose treated with hemodialysis and extracorporeal membrane oxygenation.

A case involving a 27-year-old woman who ingested an overdose of acebutolol is presented. Extracorporeal membrane oxygenation was initiated to stabilize the patient's condition before commencing hemodialysis. S-diacetolol (the N-acetelation product of acebutolol) was cleared with hemodialysis. It is suggested that extracorporeal membrane oxygenation may be of short-term benefit in the treatment of overdoses with beta-adrenergic agents such as acebutolol when accelerated clearance with hemodialysis is anticipated.

Selectivity of acebutolol, atenolol, and metoprolol in healthy volunteers estimated by the extent the drugs occupy beta 2-receptors in the circulating plasma.

The selectivity of acebutolol, atenolol, and metoprolol in healthy volunteers was estimated by determining the extent to which the drugs occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in the circulating plasma after drug intake. This ex vivo method had the advantage of including all drug components contributing to the drug-receptor equilibrium in vivo and of excluding the factors regulating organ sensitivity to catecholamine stimulation. The oral doses of 400 mg acebutolol, 100 mg atenolol, and 100 mg metoprolol were administered to six healthy male volunteers using a double-blind, randomized, and cross-over study design. The three drugs occupied beta 1-receptors to a similar extent at 2 hours after drug intake. The receptor fraction occupied by metoprolol at 3 to 8 hours after drug intake was usually smaller, however (analysis of variance for repeated measures, P < .05) than that of the other drugs. Acebutolol occupied significantly larger fractions of beta 2-receptors (analysis of variance for repeated measures, P < .05) than did atenolol and metoprolol. Therefore, at an identical beta 1-receptor occupancy, the beta 2-receptor occupancy of acebutolol was larger than that of the other agents. Apparently, active metabolites decreased markedly the selectivity of acebutolol, but not that of metoprolol. The receptor occupancy of the agents was well in agreement with the literature concerning the selectivity, intensity, and time-course of drug actions after identical doses.(ABSTRACT TRUNCATED AT 250 WORDS)

A simple radioimmunoassay of acebutolol in plasma.

Antisera against acebutolol were produced in rabbits immunized by means of this drug conjugated with bovine serum albumin. These antisera were used to develop a method of radioimmunoassay for acebutolol. The plasma radioimmunoassay, described here, requires no extraction and is very easy to perform besides being quick, specific and sensitive. As little as 2.97 X 10(-9) mol/l of acebutolol can be detected. This radioimmunoassay is suitable for assaying the large number of samples usually measured in pharmacological studies.

The influence of renal function on plasma levels and urinary excretion of acebutolol and its main N-acetyl metabolite.

The pharmacokinetics of acebutolol and its major N-acetyl metabolite diacetolol were determined following acute intravenous and chronic oral administration to 22 subjects with glomerular filtration rate (GFR) between 3 and 127 ml/min. Following chronic oral administration the mean terminal elimination half-life of unchanged acebutolol was about 10 hours independent of renal function, whereas the hall-life of the N-acetyl metabolite increased from 12.8 hr in subjects with normal renal function (GFR greater than 90 ml/min) to 24.0 hr in preuremic patients (GFR less than 10 ml/min). The mean area of the plasma level-time curve (AUC) of the metabolite was 14.2 mg 1-1 hr in patients with normal renal function and rose to a value of 81.4 mg 1-1 hr in preuremic patients. The mean AUC of the parent drug was not influenced by changes in renal function. The considerable accumulation of the acetyl metabolite, which has about the same beta blocking activity as the unchanged drug, necessitates dose reduction of acebutolol in the presence of different degrees of renal impairment (reduction by half of the normal daily dose in patients with GFR between 30 and 10 ml/min and by three quarters when GFR less than 10 ml/min). In subjects with normal renal function, the ratio between the AUC of the parent drug and that of its major N-acetyl metabolite was 3:1 after intravenous injection of the drug, while it was 1:2.5 following chronic oral administration, indicating a marked first pass metabolism of acebutolol.

Influence of cimetidine co-administration on the pharmacokinetics of acebutolol enantiomers and its metabolite diacetolol in a rat model: the effect of gastric pH on double-peak phenomena.

Acebutolol (AC) is a chiral beta-adrenergic receptor-blocking agent, which has been shown to be clinically effective in hypertension. The plasma concentration-time profiles of AC exhibit two peaks following oral administration of racemate for both R- and S-enantiomers. In the present study, the absorption of AC after a single dose was studied as a function of gastric pH in male Sprague-Dawley rats. Furthermore, the effect of cimetidine (CIM) on pharmacokinetic parameters of AC and its metabolite diacetolol (DC) was evaluated. CIM (50 mg kg(-1)) was administered via jugular vein 30 min prior to AC administration to elevate the intragastric pH. AC (50 mg kg(-1)) was administered orally by gavage and serial blood samples were collected before and for 8h after AC administration. Plasma samples were assayed for AC and DC, pharmacokinetic parameters were estimated and compared with those of control. The concentration-time profiles and the pharmacokinetics of AC were unchanged after co-administration of CIM. The oral absorption of AC, as assessed by the area under the plasma concentration-time curve (AUC) and the amount of unchanged drug recovered in the urine were not affected by CIM. The amount of metabolite recovered in the urine and the rate of absorption, however, were significantly altered. These are unlikely to be of clinically importance as we have found that the extent of absorption was not changed. We, therefore, concluded that intragastric elevation of pH has no effect either on generation of multiple peaking or on pharmacokinetic parameters of AC.