Management of infantile subglottic hemangioma: acebutolol or propranolol?

The successful management of subglottic hemangioma with propranolol has been reported. We report three cases of subglottic hemangioma treated with the cardioselective beta-blocker acebutolol, 8 mg/kg/day. Treatment was efficient in two cases while an open procedure was necessary in the third child. In our experience, acebutolol could be easily administered in oral form twice-a-day only with a dose that was adaptable according to the growth of the child and showed no side effects. We also report a case of rebound growth after beta-mimetic drug use and the efficiency of propranolol treatment in such a recurrence. Considering the lack of side effects and the advantages in terms of administration, we suggest acebutolol as a first-line treatment of subglottic hemangiomas for which intervention is required.

[Interrelationship between changes of rate and variability of cardiac rhythm under influence of beta-adrenoblockers].

BACKGROUND: Beta-blocking agents (BB) decrease mortality particularly sudden in post-myocardial infarction patients and in patients with chronic heart failure that is closely related to heart rate (HR) lowering at rest. The hypothesis exists that BB decrease mortality due to increase of cardiac vagal activity. AIM: To evaluate the relation between HR changes on therapy with BB and changes in heart rate variability (HRV). MATERIAL AND METHODS: Sixty patients with arterial hypertension randomized in three groups were studied before and after treatment with atenolol (AT), acebutolol (AC) or talinolol (TL) until doses of 100, 600 and 300 mg/d correspondingly were reached or resting HR was decreased by 10 bpm. 24-hour Holter monitoring was used to measure HR and HRV indexes. RESULTS: Arterial blood pressure decreased significantly in every group. HR max, min and average decreased significantly on AT. AC and TL lowered HR max and AT average but did not change HR min. AT did not change SDNN, SDANN, TotP and ULFP, but AC and NL decreased them significantly (p < 0.001). AT increased SDNNind, VLFP (p < 0.002), rMSSD, pNNSO and HFP (p < 0.003), but did not change LFP. AC and TL did not change these indexes. Changes of HRV indexes were closely related to changes of HR particularly HR min (r=0.53 - 0.84). Linear regressions of these relations did not differ between three drugs except for low frequency indexes of HRV between AC and TL. According to the equations the differences in HRV indexes between the drugs were well explained by the differences in HR changes. When all patients were evaluated together statistical significance of increase in rMSSD, pNN50 and HFP was not reached until HR average decreased by 10 bpm or more. The effect of TL on HR and HRV is very similar to AC what suggests its intrinsic sympathomimetic activity or anticholinergic properties.

Smith-Magenis syndrome: a case report of improved sleep after treatment with beta1-adrenergic antagonists and melatonin.

This report describes the case of a 4-year-old boy diagnosed with Smith-Magenis syndrome in whom treatment with a beta(1)-adrenergic antagonist in the morning (to suppress the diurnal melatonin secretion) and melatonin in the evening (to generate a nocturnal peak of melatonin) improved his sleep quality, evaluated by polysomnographic studies.

Pharmacokinetic changes of acebutolol after oral administration in rabbits with diabetes mellitus induced by alloxan.

Because physiological changes that potentially alter pharmacokinetics occurs in diabetes mellitus patients, pharamacokinetics of drugs used in the treatment of hypertension was studied using acebutolol as a model anti-hypertensive drug. Thus, the pharmacokinetics of acebutolol was investigated after oral administration of acebutolol (15 mg/kg) to control rabbits and rabbits with acute or chronic diabetes mellitus induced by alloxan. Kidney and liver functions were documented for acute and chronic diabetes mellitus groups based on plasma chemistry data. After oral administration of acebutolol to acute and chronic groups, the plasma concentrations appeared higher; As a result, area under the plasma concentration-time curve from time zero to time infinity10575 and 8668 microg x h/mL for acute and chronic group, respectively. In comparison, the area was apparently smaller in the control group (i.e., 7132 microg x h/mL). The half-life in acute groups was significantly prolonged 8.45 h compared with the half-life in the control group (i.e., 6.30 h). Alteration in acebutolol pharmacokinetics was more pronounced in the acute group as evidenced by the significantly higher values the area under the plasma concentration time curve, absorption rate constant and maximum plasma concentration compared with chronic or control group. Therefore, these observations indicate that acebutolol pharmacokinetics may be affected in patients with diabetes mellitus, especially in the early stage of the disease.

[The comparison of clinical effectiveness of perindopril and acebutolol in the primary hypertension treatment]. / Porównanie skutecznosci klinicznej perindoprilu i acebutololu w leczeniu pierwotnego nadcisnienia tetniczego.

Hypertension is one of the most important risk factors for ischaemic heart disease and stroke. The aim of our study was to assess the antihypertensive effect of angiotensine converting enzyme inhibitor (perindopril) versus beta blocker (acebutolol) in hypertensive patients. It was a double blind, placebo controlled study performed in the group of 31 patients (16 males, 15 females; mean age 46.6 +/- 8.7 years) with newly diagnosed (previously not treated) mild to moderate hypertension. Each patient in the wash-out period (two weeks) was given placebo and then was randomized to active treatment: perindopril (4 mg/day) or acebutolol (400 mg/day) for 3 weeks, following these drugs were cross matched (after one week wash out period). Blood pressure (BP) with mercury sphygmomanometer was measured three times: after 2 weeks of placebo treatment, after 3 weeks of perindopril and 3 weeks of acebutolol treatment. Both perindopril and acebutolol proved to be effective in monotherapy of hypertension. After 3 weeks of the treatment we observed BP systolic and diastolic normalization, but more patients had systolic BP normalization after perindopril treatment.

Pharmacokinetics of single oral and multiple intravenous and oral administration of acebutolol enantiomers in a rat model.

Acebutolol (AC), is a chiral, beta-adrenergic blocking agent which possesses partial agonist activity and is metabolized to an equipotent chiral metabolite, diacetolol (DC). The enantiomeric disposition of AC is reported following racemic administration as a single oral (p.o., 50 mg kg(-1)) or as a multiple thrice daily intravenous (i.v.) or p.o. dosing for four days in male Sprague-Dawley rats (n = 6). Enantiomeric concentrations of AC and DC in plasma and urine were determined using a stereospecific HPLC assay. The bioavailabilities of R- and S-enantiomer were 0.40 and 0.39 after single dose administration of AC respectively. These values were increased to 0.51 and 0.53 after multiple dosing. Although no significant differences were found in AUC0-infinity after single i.v. as compared with AUC0-tau after multiple i.v. dosing of AC, the 39 and 45% increase in mean AUC0-tau were found after multiple p.o. dosing over the corresponding AUC0-infinity, for the single p.o. dose of AC for R- and S-enantiomer, respectively. The disposition of DC as well as the urinary excretion of metabolite was stereoselective in favor of R-enantiomer after oral administration of AC. These results indicate that AC enantiomers have low availability and moderate extraction through the first-pass metabolism in a rat model. The higher AUC values after p.o. multiple dosing may suggest a saturable first-pass metabolism of AC.

Hydrogels of poly(ethylene glycol): mechanical characterization and release of a model drug.

Thermosensitive polymer networks were synthesized from poly(ethylene glycol), hexamethylene diisocyanate and 1,2,6-hexanetriol in stoichiometric proportions. By varying the amount of 1,2,6-hexanetriol and the molar mass of the poly(ethylene glycol), a wide range of networks with different crosslinking densities was prepared. The networks obtained were characterized by the temperature dependence of their degree of equilibrium swelling in water and by their Young's moduli. For each network, the molecular weight between crosslinks was estimated. The structure of the hydrogels was analysed with respect to scaling laws, and it was found that the results obtained with PEG 1500 and PEG 6000 hydrogels are in agreement with theoretical predictions, whereas those obtained with PEG 400 hydrogels are in disagreement. The release properties of PEG hydrogels were studied by the determination of the diffusion coefficient for acebutolol chlorhydrate and by an analysis of the effect of temperature on these coefficients. Finally, these release properties were correlated with the swelling and structural properties of the hydrogels.

Effects of antihypertensive agents on circadian blood pressure in hypertensive patients with previous brain infarction.

To evaluate the effects of antihypertensive agents on the circadian blood pressure (BP) of patients with previous brain infarction, the ambulatory BP was measured non-invasively for 24 h before and after administration of antihypertensive agents. One hundred milligrams of acebutolol twice daily (n = 15) is effective in lowering the BP during the daytime, but has little effect during the night and the morning. Twenty milligrams of slow-release nifedipine twice daily (n = 14) produced a consistent reduction in the BP over the entire 24-h period and effectively blunted the rise in BP in the morning. Captopril (12.5 mg) twice daily (n = 15) produced a mild reduction in BP with little change in the circadian pattern. The slow-release nifedipine group had the greatest decrease in mean systolic and diastolic BP. The heart rate significantly increased after administration of slow-release nifedipine and decreased after administration of acebutolol. To reduce stroke recurrence, we should consider the effects of antihypertensive agents on circadian BP in hypertensive patients with previous brain infarction.

Pharmacokinetics and multiple peaking of acebutolol enantiomers in rats.

Acebutolol (AC) is a chiral beta-blocker which is extensively metabolized to an active, chiral metabolite, diacetolol (DC). Similar to some other beta-adrenoceptors, AC exhibits multiple peaks in plasma concentration-time curves after oral doses to humans. We examined the suitability of the rat as an animal model and studied the effect of various factors including the route of administration, food, and bile on the pharmacokinetics of AC enantiomers. Pharmacokinetics of AC were delineated after oral (fed and fasted), i.v., and i.p. doses, and after oral and i.v. doses, to intact and bile-duct-ligated female Sprague-Dawley rats, respectively. The possibility of intestinal metabolism or saturable absorption was studied in vitro using everted rat gut. Multiple peaks were present but only after oral doses independent of food intake, suggestive of gastrointestinal tract involvement. Oral absorption of AC enantiomers was incomplete as bioavailability was lower after oral (R, 0.59; S, 0.63) as compared to i.p. off(R, 0.86; S, 0.84) doses. Food reduced bioavailability by 60%. A 250-fold increase in the dose did not alter the absorption kinetics of AC through the everted gut, ruling out the possibility of saturable absorption. No intestinal metabolism was detected in vitro. Enterohepatic recirculation cannot be responsible as ligation of the bile duct did not alter the pattern or route dependence of the multiple peaking. The rat appears to be a suitable animal model; a bile- and food-independent erratic absorption is probably responsible for the observed multiple peaking of AC.

Pharmacokinetics of acebutolol enantiomers after intravenous administration of racemate in a rat model: a dosing range comparison.

Acebutolol (AC) is a chiral beta-adrenergic blocking drug, possessing intrinsic sympathomimetic activity (ISA), and is useful clinically as the racemate in treating hypertension. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of AC and its major metabolite diacetolol (DC) are reported after intravenous administration of single 5, 15, 30, and 50 mg kg-1 doses of racemate to male Sprague-Dawley rats. The mean area under the plasma concentration versus time curve (AUC) values display a linear relationship with respect to the administered dose. No statistical differences are observed in apparent volume of distribution (Vd), terminal elimination half-life (t1/2), total body clearance (Clt), or renal clearance (Clr) with respect to dose administered. Generally, R-S ratios for AUC following AC administration are statistically different from unity (p < 0.05). However, for the 50 mg kg-1 doses the R-S ratio for AUC is not statistically different from one. For DC, the plasma disposition is nonstereoselective in plasma. The amount of R-DC recovered in urine, however, was greater than that of the antipode (R:S = 1.92 +/- 0.29). This study suggests that the enantiomeric disposition of intravenous AC is linear within the investigated range of 5-50 mg kg-1 racemate in rats.

Relationship between amount of beta-blockers permeating through the stratum corneum and skin irritation after application of beta-blocker adhesive patches to guinea pig skin.

We evaluated the relationship between the cumulative amounts of 5 kinds of beta-blockers (alprenolol, oxprenolol, timolol, acebutolol and atenolol) permeating through the stratum corneum and a* values obtained by measuring the formation of erythema, a skin irritation reaction, with a chromameter after transdermal application of adhesive patches containing 2 beta-blocker to the skin of guinea pigs. The cumulative amount of beta-blocker released from each adhesive patch to the skin increased with the increase in application time. The contents of alprenolol, oxprenolol and timolol in the stratum corneum and in the stripped skin increased markedly up to 4 h after application and thereafter were maintained at high levels up to 24 h. The contents of acebutolol and atenolol, on the other hand, increased up to 24 h, but these values were low. a* values of all adhesive patches 24 h after application were higher than those before application. The correlation coefficients between the cumulative amounts of alprenolol, oxprenolol, timolol, acebutolol or atenolol permeating through the stratum corneum and (delta a* -delta a*Placebo) values were 0.739, 0.717, 0.722, 0.551 and 0.633, respectively. The correlation coefficient calculated by averaging the cumulative amounts of 6 kinds of beta-blockers permeating through the stratum corneum [including propranolol which was reported previously (Kobayashi I., et al., Biol. Pharm. Bull., 19, 839-844 (1996))] was 0.731, higher than the correlation coefficient between contents of these beta-blockers in the stripped skin and (delta a* -delta a*Placebo) values (r = 0.552). This suggests that there was a high correlation between the cumulative amounts of beta-blockers permeating through the stratum corneum and (delta a* -delta a*Placebo) values.

Prolonged treatment with beta-adrenoceptor antagonists counteracts the aggression deficit induced by chronic stress.

Chronic stress-induced behavioral disturbances have been used as experimental models of depression. One of them is the deficit of fighting behavior induced by 16-day application of various unpredictable stressors. In the present study we investigated the effect of beta-adrenoceptor antagonists (propranolol, pindolol, nadolol and acebutolol) on electric footshock-induced fighting behavior in chronically stressed (14 various stressors over 16 days) male Wistar rats. It was found that the number of fighting attacks was reduced by about 50-80% in the rats submitted to chronic stress. Prolonged, 14-day, but not acute, treatment with propranolol, pindolol or nadolol (but not acebutolol) counteracted the deficit of aggression induced by chronic stress. It is suggested that beta-adrenoceptor antagonists which penetrate the blood-brain barrier may prevent the behavioral changes induced by chronic stress.

Effects of the beta-adrenergic blockers propranolol and acebutolol on stress-induced learned helplessness behavior of rats.

The latency time and escape ability of rats with learned helplessness behavior were studied after 1, 6 and 14 days of oral treatment with beta-adrenergic blockers propranolol (1 and 3 mg/kg) and acebutolol (10 and 30 mg/kg). A dose-dependent significant decrease in latency time and increase in number of avoidances was established after single, 6 and 14 days propranolol treatment. The selective beta 1-blocker acebutolol did not change the escape characteristics. These results suggest a greater impact of beta 1- than beta 2-adrenergic receptors for escape performance after unescapable foot shock, i.e., learned helplessness behavior.

Beta adrenergic blockade does not improve effort tolerance in patients with mitral stenosis in sinus rhythm.

OBJECTIVES: This study was designed to assess the effects of beta-blockade on cardiopulmonary exercise performance in symptomatic patients with tight mitral stenosis in sinus rhythm. BACKGROUND: The role of beta-blockers in these patients has been controversial and assessment of effort tolerance using treadmill exercise time has produced conflicting results. METHODS: Nineteen patients with isolated symptomatic (New York Heart Association class II or III) mitral stenosis received a beta-blocker (acebutalol or atenolol) or matching placebo for one week each in a randomized double-blind crossover fashion. Exercise on a treadmill with real time gas exchange analysis was performed six times over 4 weeks in each patient. The test was further repeated once within a week of percutaneous mitral valvotomy. RESULTS: Heart rate at rest and during peak exercise was significantly lower with beta-blockade compared to control state or placebo treatment. Mean peak oxygen consumption did not differ significantly between treatment groups. When patients were arbitrarily classified into those with (group I, heart rate < or = 130.min-1) and those without (group II, heart rate > or = 131.min-1) adequate beta-blockade, there was a significant difference in peak VO2. The peak VO2 for group I: 14.0 +/- 3.2 vs 17.5 +/- 4.0 ml.min-1.kg-1; peak VO2 for group II: 17.2 +/- 2.4 vs 18.0 +/- 2.4 ml.min-1.kg-1 (beta-blockade vs control state respectively). Treadmill exercise time did not differ between treatment groups. The slope of minute ventilation (MV) and carbon dioxide (CO2) excretion, and instantaneous carbon dioxide ventilatory equivalent (MV/VCO2) was unchanged with beta-blocker therapy indicating no improvement in ventilatory performance. CONCLUSIONS: Beta-blocker therapy in tight mitral stenosis appears to have no beneficial effect on aerobic capacity, nor does it improve ventilatory performance. Adequate beta-blockade may adversely effect peak oxygen consumption.

[Chronology of regression of hypertensive ventricular hypertrophy during antihypertensive therapy with beta blockers]. / Cronologia della regressione dell'ipertrofia ventricolare ipertensiva durante terapia antipertensiva con betabloccanti.

To define the time course of regression of left ventricular hypertrophy (LVH) during antihypertensive therapy with beta-blocking agents, 73 hypertensive patients were serially studied by echocardiography during 12-months therapy with beta-blockers. Blood pressure decreased significantly after 1 month and further on after 12 months (from 164 +/- 18/110 +/- 9 to 139 +/- 14/94 +/- 7 mmHg, p < 0.001). Left ventricular (LV) end-diastolic dimension increased significantly after 1 month (from 51.2 +/- 3.9 to 52.2 +/- 4.7 mm, p < 0.01) and decreased after 12 months (50.4 +/- 4.0 mm, p < 0.05). Septal and posterior wall thickness decreased progressively after 1 month and 3 months, respectively. LV mass index decreased significantly after 3 months, and further on after 12 months (from 164 +/- 42 to 145 +/- 33 g/m2, p < 0.001). LV fractional shortening did not significantly change throughout the study. Thus, a reduction of hypertensive LVH occurred after 3 months of therapy with beta-blocking agents and went on during the subsequent months without impairment of LV systolic function.

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)

Beneficial effects of beta-adrenergic blockade in coronary artery surgery: clinical research.

In an attempt to resolve the controversy concerning use of beta-adrenoceptor blockade in patients undergoing coronary artery revascularization, 40 consecutive patients with ischaemic heart disease receiving chronic beta-adrenergic blocking therapy (study group) were entered into a randomized trial and were compared with 40 patients receiving no beta-blocking therapy (control group). The postoperative requirement for positive inotropic agents between the two groups was compared. The clinical and operative characteristics of the two groups were similar. After surgery, 2% of patients in the study group required positive inotropic agents compared with 18% of those in the control group (P < 0.05). It is concluded that this difference resulted from an increase in density of beta 1-adrenergic receptors induced by beta-adrenergic blockade, and an increase in the level of catecholamines in the early postoperative period.

Therapeutic controversies with use of beta-adrenoceptor blockade in heart failure.

In response to early reports indicating a beneficial adrenoceptor effect of beta blockade, 2 small trials were conducted to investigate the hemodynamic effects of acute and chronic beta-adrenoceptor blockade in patients with congestive cardiomyopathy. Acute beta-blocker therapy with intravenous acebutolol, 25 mg, resulted in a significant decline in cardiac performance, whereas chronic therapy with acebutolol, 200 mg twice daily, resulted in no beneficial effects on exercise tolerance, as reported by the original Swedish investigators. Further, beta-adrenoceptor blockade has been associated with a number of clinical problems: beta blockers tend to interfere with the compensatory mechanisms that support circulation during early or mild heart failure and therefore have little value as routine therapy at that stage of the disorder. Although excessive beta-adrenoceptor blockade may worsen ventricular function by decreasing myocardial contractility, beta blockers appear to have a useful role in patients with moderate heart failure accompanied by tachycardia. Carefully titrated doses of beta blockers in conjunction with afterload-reducing agents may also provide a benefit in patients with rapid heart rates and grossly elevated levels of circulating catecholamines.