Large-scale in silico identification of drugs exerting sex-specific effects in the heart.

BACKGROUND: Major differences exist between men and women in both physiology and pathophysiology. Dissecting the underlying processes and contributing mechanisms of sex differences in health and disease represents a crucial step towards precision medicine. Considering the significant differences between men and women in the response to pharmacotherapies, our aim was to develop an in silico model able to predict sex-specific drug responses in a large-scale. METHODS: For this purpose, we focused on cardiovascular effects because of their high morbidity and mortality. Our model predicted several drugs (including acebutolol and tacrine) with significant differences in the heart between men and women. To validate the sex-specific drug responses identified by our model, acebutolol was selected to lower blood pressure in spontaneous hypertensive rats (SHR), tacrine was used to assess cardiac injury in mice and metformin as control for a non-sex-specific response. RESULTS: As our model predicted, acebutolol exhibited a stronger decrease in heart rate and blood pressure in female than male SHRs. Tacrine lowered heart rate in male but not in female mice, induced higher plasma cTNI level and increased cardiac superoxide (DHE staining) generation in female than male mice, indicating stronger cardiac toxicity in female than male mice. To validate our model in humans, we employed two Chinese cohorts, which showed that among patients taking a beta-receptor blocker (metoprolol), women reached significantly lower diastolic blood pressure than men. CONCLUSIONS: We conclude that our in silico model could be translated into clinical practice to predict sex-specific drug responses, thereby contributing towards a more appropriate medical care for both men and women.

Comparative efficacy and usefulness of acebutolol and diltiazem for the prevention of atrial fibrillation during perioperative time in patients undergoing pulmonary resection.

BACKGROUND: Postthoracic surgery atrial fibrillation (AF) is the most frequently occurring arrhythmia. Strategies for preventing AF have been amply evaluated, but currently there are no clearly defined guidelines for treatment of AF after thoracic surgery. METHODS: The study was prospective and randomized controlled trial. Acebutolol and diltiazem versus placebo were compared, among 117 patients postpneumonectomy or lobectomy at the Thoracosurgery Clinic, Poznan University of Medical Sciences in Poland. Patients who were enrolled in the study were randomly assigned to one of the three groups: those who received acebutolol (Group 1) or diltiazem (Group 2) and compared with patients without antiarrhythmic drugs (Group 0). Each group consisted of 39 patients. The patients were continuously monitored postoperatively with 24 ECG (Holter monitor) in the intensive care unit. RESULTS: In patients receiving acebutolol AF occurred in 5% compared with 23% of patients receiving diltiazem and 20% of patients receiving placebo (difference not statistically significant). CONCLUSIONS: Acebutolol and diltiazem appear to have been non-effective for the treatment or prevention of AF. Side effects were mild. In comparison to diltiazem, however, acebutolol had a beneficial effect on the circulatory system. Patients who had received acebutolol proved to have had fewer tachycardia episodes and supraventricular ectopy during the postoperative period. It seems that acebutolol can be useful, especially in patients with sympathetic activity dominance.

A proposed mechanism for the adverse effects of acebutolol: CES2 and CYP2C19-mediated metabolism and antinuclear antibody production.

Acebutolol, a ß-adrenergic receptor-blocker, occasionally causes drug-induced lupus erythematosus (DILE). Acebutolol is mainly metabolized to diacetolol. Because metabolic activation has been considered to be related to acebutolol-induced toxicity, we sought to identify the enzymes that are responsible for acebutolol metabolism and investigate their involvement in acebutolol-induced toxicity. By using human liver microsomes (HLM) or intestinal microsomes and recombinant enzymes, we found that diacetolol was produced via hydrolysis by carboxylesterase 2 (CES2) and subsequent acetylation by N-acetyltransferase 2 (NAT2). When acetolol, a hydrolytic metabolite of acebutolol, was incubated with HLM and an NADPH-generating system, a metabolite conjugated with N-acetylcystein was generated. This metabolite was found to be formed by CYP2C19 based on studies with a panel of recombinant cytochrome P450 enzymes and an inhibition study using HLM with tranylcypromine, a CYP2C19 inhibitor. Because antinuclear antibody (ANA) production is associated with DILE, we investigated whether ANA was detected in plasma from mice treated with acebutolol. Administration of acebutolol (100mg/kg, p.o.) to female C57BL/6 mice for 30 days resulted in ANA production in plasma in seven of thirteen mice. The number of mice that showed ANA production was larger in mice co-treated with pregnenolone 16α-carbonitrile, an inducer of P450s, whereas it was lower in mice co-treated with tri-o-tolylphosphate or 1-aminobenzotriazole, which are inhibitors of esterases or P450s, respectively. These results suggested that the hydrolysis and oxidation of acebutolol was associated with ANA production. In summary, this study demonstrated that metabolic activation may be a causal factor of adverse reactions of acebutolol.

Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS)

Problems with sexual function have been a long-standing concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. The Treatment of Mild Hypertension Study (TOMHS) provides an excellent opportunity for examination of sexual function and effects of treatment on sexual function in men and women with stage I diastolic hypertension because of the number of drug classes studied, the double-blind study design, and the long-term follow-up. TOMHS was a double-blind, randomized controlled trial of 902 hypertensive individuals (557 men, 345 women), aged 45 to 69 years, treated with placebo or one of five active drugs (acebutolol, amlodipine maleate, chlorthalidone, doxazosin maleate, or enalapril maleate). All participants received intensive lifestyle counseling regarding weight loss, dietary sodium reduction, alcohol reduction (for current drinkers), and increased physical activity. Sexual function was ascertained by physician interviews at baseline and annually during follow-up. At baseline, 14.4% of men and 4.9% of women reported a problems with sexual function. In men, 12.2% had problems obtaining and/or maintaining an erection; 2.0% of women reported a problem having an orgasm. Erection problems in men at baseline were positively related to age, systolic pressure, and previous antihypertensive drug use. The incidences of erection dysfunction during follow-up in men were 9.5% and 14.7% through 24 and 48 months, respectively, and were related to type of antihypertensive therapy. Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months than participants randomized to placebo (17.1% versus 8.1%, P = .025). Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between the chlorthalidone and placebo groups. Incidence was lowest in the doxazosin group but was not significantly different from the placebo group. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group. In many cases, erection dysfunction did not require withdrawal of medication. Disappearance of erection problems among men with problems at baseline was common in all groups but greatest in the doxazosin group. Incidence of reported sexual problems in women was low in all treatment groups. In conclusion, long-term incidence of erection problems in treated hypertensive men is relatively low but is higher with chlorthalidone treatment. Effects of erection dysfunction with chlorthalidone appear relatively early and are often tolerable, and new occurrences after 2 years are unlikely. The rate of reported sexual problems in hypertensive women is low and does not appear to differ by type of drug. Similar incidence rates of erection dysfunction in placebo and most active drug groups caution against routine attribution of erection problems to antihypertensive medication.

Development of antinuclear antibodies during acebutolol therapy.

Eleven patients were studied while taking the beta blocker acebutolol for a period ranging from 12 to more than 24 wk. Control titers for fluorescent antinuclear antibody (ANA) were obtained in all. Serial testing was performed over the duration of the therapy and following its discontinuation. Additional immunologic testing was performed in most patients. The patients were observed closely for the development of clinical autoimmune disease. Using a sensitive assay, fluorescent ANA developed in 8 of 9 patients with negative values in the control period. In no patient has evidence of clinical autoimmune disease developed. In general, the titers of ANA tended to rise with increasing duration of therapy and decline after its discontinuation. Positive lupus erythematosus cell preparations were also observed in several patients. These data suggest that autoantibodies are frequently induced by acebutolol and, although no evidence of clinical autoimmune disease has been reported, immunologic surveillance is warranted.

Effects of acebutolol on the serum lipid profile.

Epidemiological and recent interventional studies have emphasised the relationship between plasma lipid parameters and the incidence of coronary heart disease. beta-Blockers, particularly those without intrinsic sympathomimetic activity (ISA), are generally reported to increase triglyceride levels and decrease high density lipoprotein (HDL)-cholesterol levels, both changes theoretically increasing the risk of coronary heart disease. A review of all published trials concerning the effects of acebutolol (a cardioselective beta-blocker with mild ISA) on the plasma lipid profile was carried out, with a particular emphasis on studies reporting a comparison with other beta-blockers. The results indicate that, on average, acebutolol does not have any adverse effects on plasma lipids and may even reduce total and low density lipoprotein (LDL)-cholesterol by 7 and 5%, respectively. In contrast, the other beta-blockers compared under the same conditions (propranolol, pindolol and penbutolol) tended to increase triglyceride levels (+19% when compared with acebutolol) and decrease HDL-cholesterol (-7% when compared with acebutolol) to an extent that was consistent with previous reports in the literature. In interpreting these differences in lipid parameters in the light of epidemiological and interventional study data, the use of acebutolol as opposed to the other beta-blockers could theoretically lead to a relative reduction in coronary risk of 20% or more.

Multicentre study of the efficacy and tolerance of acebutolol versus atenolol in the long term treatment of mild arterial hypertension.

The efficacy, tolerance and effect on serum lipids of acebutolol were compared with those of atenolol over a 6-month period in a large group of patients with mild arterial hypertension. Both drugs were equally effective in reducing blood pressure, and tolerance was generally excellent. High density lipoprotein (HDL)-cholesterol concentrations were reduced to a similar extent by both treatments at 2 months and this change was reflected in measurements of the total cholesterol concentrations. However, no significant changes occurred in serum triglyceride levels and at 6 months all serum lipid parameters had returned to baseline values. These observations suggest that cardioselective beta-blockers have no adverse effects on serum lipids at 6 months, after a temporary reduction of HDL-cholesterol at 2 months.

Favorable effects of acebutolol on exercise performance and angina in men with coronary artery disease.

Acebutolol, a relatively cardioselective beta-adrenergic blocking drug, was administered to 20 men with coronary artery disease and angina. A three month double-blind cross-over (placebo and acebutolol) design was used following a 12-week placebo phase and a six-week dose-titration phase. During the cross-over phase, acebutolol (400 mg in 19 men and 300 mg in one, orally three times per day) increased the duration of treadmill exercise (placebo, 6.8 +/- 0.5) min [average +/- SEM]; acebutolol, 8.1 +/- 0.6 min; P less than 0.05) and decreased the frequency of ST segment depression during exercise (placebo, 12 or 20 men; acebutolol, 6 of 20 men). The heart rate x systolic blood pressure product (x 10(-2)) was decreased both at rest (placebo, 105.0 +/- 4.0; acebutolol, 84.0 +/- 3.0; P less than 0.01) and during exercise (placebo, 199.0 +/- 10.0; acebutolol, 144.0 +/- 8.0; P less than 0.01). Acebutolol treatment decreased the frequency of angina (diary cards) (placebo, 9.0 +/- 2.4 episodes per week; acebutolol, 6.4 +/- 2.2 episodes per week; P less than 0.05) and decreased the consumption of nitroglycerin (placebo, 9.0 +/- 4.4 tablets per week; acebutolol, 7.4 +/- 4.0 tablets per week; P less than 0.05). Results suggest that acebutolol increases exercise performance and decreases the occurrence of angina in men with coronary disease.

Effects of long-term antihypertensive therapy on physical fitness of men with mild hypertension.

This study was conducted to investigate the effects of long-term administration of a calcium-channel antagonist (nifedipine) and a beta-blocker (acebutolol) on physical fitness in men with mild hypertension. All subjects underwent symptom-limited treadmill stress testing and routine echocardiographic studies. Twenty-two subjects who had either a causal diastolic blood pressure of more than 105 mmHg or a left ventricular mass index (LVMI) of 125 g/m2 or more during follow-up were assigned to receive medical therapy. The other 31 men who did not meet either criterion were continuously followed-up without medication. Among the 22 treated men, the age-adjusted treadmill time (normalized treadmill time, TMTn) significantly decreased before the initiation of medication, while 31 untreated men showed no change in TMTn throughout the study. The 22 treated subjects were subsequently divided into two groups; 13 were given nifedipine and 9 were given acebutolol. All treated subjects were followed-up for more than 3 years. After treatment, the two groups showed similar reductions in blood pressure and LVMI, but a different outcome for TMTn: TMTn increased from 104 +/- 8% to 115 +/- 16% in subjects given nifedipine (p < 0.05) and decreased from 106 +/- 12% to 99 +/- 10% (p < 0.01) in those given acebutolol. Thus, the physical fitness of subjects who required medication significantly deteriorated without medication; their physical fitness improved after treatment with a calcium-channel antagonist and deteriorated after treatment with a beta-blocker.

Low-dose acebutolol given once daily in the treatment of chronic angina pectoris.

Acebutolol, a beta-1 selective beta blocker with intrinsic sympathomimetic activity has been shown to be an effective agent in chronic angina pectoris therapy, with twice or three times daily dosing. The long-term effects of 400 mg of acebutolol given only once a day versus placebo on exercise hemodynamics, ST segment depression, and rate pressure product were studied. Eleven patients (mean age, 60 +/- 12 years) with hypertension and chronic angina pectoris were enrolled. Resting heart rate was not significantly altered after therapy, (80 vs 72 bpm). Objective measurements from exercise treadmill tests showed significant reduction in peak heart rate from 130 to 103 bpm, systolic blood pressure from 197 to 167 mm Hg, rate pressure product (from 25 to 18 bpm-mm Hg X 1000), and ST depression in patients receiving acebutolol compared with those receiving placebo. No significant adverse effects were reported. These data indicate that acebutolol may be efficacious as once daily therapy for chronic stable angina pectoris.

Merits of adding a beta blocker (acebutolol) to a diuretic (hydrochlorothiazide) in the treatment of hypertension.

In a double-blind crossover study, the antihypertensive effect of hydrochlorothiazide alone and in combination with the beta blocker acebutolol was assessed in 18 patients suffering from mild to moderate hypertension. After a placebo period, the patients were placed on hydrochlorothiazide alone for four weeks at a dose of 50 mg daily. Acebutolol was than gradually titrated into the regimen until the optimum dose was established. The average dose was 555 mg per day, with the usual optimum dose 200 mg b.i.d. The patients then entered the crossover portion of the trial during which patients received either hydrocholorothiazide with acebutolol or hydrochlorothiazide with placebo. Each treatment period lasted six weeks. Blood pressure and heart rate were significantly lower with the combination treatment than with hydrochlorothiazide alone. At the end of each treatment period, the mean diastolic blood pressure (erect) was 90.5 mm Hg with hydrochlorothiazide-acebutolol but remained above 100 mm Hg with the diuretic alone. Neither hydrochlorothiazide nor acebutolol produced any significant changes in plasma renin activity or plasma aldosterone. There were very few side effects and no reports of bradycardia.

Efficacy of acebutolol in chronic stable angina using single-blind and randomized double-blind protocol.

The clinical effects of a cardioselective beta-adrenergic blocking drug, acebutolol, were studied in 25 patients with chronic stable angina, using a seven-week single-blind placebo leads to acebutolol (mean dose 913 mg/day) phase followed by 12-week randomized double-blind placebo leads to acebutolol (mean dose 968 mg/day) crossover protocol. Objective parameters from exercise treadmill tests showed consistent reduction in resting and maximal exercise heart rate and rate-pressure product during both single- and double-blind phases. Duration of exercise and maximal ST segment depression were not significantly altered. Subjective improvement following acebutolol was observed with reduced frequency of anginal attacks and nitroglycerin consumption during the single-blind phase. However, no differences were seen during the double-blind phase due to significant subjective improvement during the latter placebo period. Adverse effects observed were mild in nature and were similar to those seen with other beta blockers. These data establish acebutolol as a potent beta-blocking agent and emphasize the importance of utilizing objective parameters over subjective variables in demonstrating the clinical antianginal efficacy of a beta blocker.

Multi-centre study of acebutolol in hypertensive subjects: results for patients from the 50 to 64-years' old and over 65 years' old age groups.

The results of a multi-centre general practice study on acebutolol in the treatment of hypertension were examined for two age groups of patients, namely those aged from 50 to 64 years and those aged 65 years and over. A total of 1501 patients was studied and followed-up over a period of 3 months. There was a marked reduction in systolic and diastolic blood pressure with treatment and the results, in terms of efficacy and tolerance, were comparable in both age groups. These findings indicate that acebutolol is warranted in the treatment of elderly patients with hypertension.

An open, multicentre study of acebutolol in hypertension.

Four hundred and twenty-seven hypertensive patients in the United Kingdom have so far been admitted to two on-going open multicentre trials, and have been treated with acebutolol for periods ranging from 1 to 6 months. Oral dosages were within the range of 100 mg to 1200 mg/day in divided doses and were increased or decreased to suit individual requirements. The data on 366 patients completing more than 1 month's treatment were analysed. A high significant reduction in mean diastolic pressure was observed. This reduction was progressive up to 6-month's treatment and was the more marked as pre-treatment values were higher. There was a highly significant correlation between pre-treatment mean diastolic pressure and mean fall of diastolic pressure at 6-months' treatment. There was also a highly sigificant association between initial values and response, and between duration of treatment and response. The higher the pre-treatment value, the less likely was non-response. Response also increased as treatment duration increased. Although asthmatic patients were not excluded, only 2 of the 427 patients included in the present study had to discontinue treatment because of the occurrence of airways obstruction; only 1 of these patients had experienced asthma previously.

Comparison of effect on psychomotor performance of single doses of propranolol and acebutolol.

Propranolol has recently been shown to produce some impairment of psychomotor performance in human volunteers. This beta-blocking compound, however, is lipophilic and readily penetrates the blood-brain barrier to gain access to the central nervous system. Acebutolol has a lower lipid solubility. A study was carried out, therefore, to compare the psychomotor effect of the two beta-blocking drugs. Any subjectively experienced side-effects were also recorded. Ten healthy volunteers were given single doses of 40 mg propranolol, 100 mg acebutolol and placebo on a random double-blind basis and the effect, if any, on performance was measured using a particularly sensitive complex reaction time technique. Propranolol produced a significant prolongation of complex reaction time when compared with placebo or acebutolol. Acebutolol did not significantly increase complex reaction time over the placebo value. Two subjects reported mild feelings of 'muzziness' after taking propranolol. No side-effects were reported after acebutolol.

A randomized crossover comparison of acebutolol and methyldopa in the treatment of mild to moderate essential hypertension.

In a randomized crossover comparison between acebutolol and methyldopa for the treatment of mild to moderate essential hypertension in 30 patients, acebutolol, a cardioselective beta-one-adrenergic blocker, at 400 to 800 mg daily was found to be significantly better (p less than 0.002) than 500 to 1000 mg methyldopa daily in reducing both systolic and diastolic blood pressures and pulse rate. Patient compliance with therapy was excellent, and there were no side-effects on acebutolol, whereas patients on methyl-dopa reported a significant number of side-effects (p less than 0.002). The potassium-sparing effect due to acebutolol was significant (p less than 0.005) and this has not been reported before. This may be beneficial in diuretic-induced hypokalaemia in the hypertensive patient.

A multicentre study of twice daily acebutolol ('Sectral') in the treatment of hypertension in general practice.

An open multicentre study was carried out under uncontrolled conditions in general practice to investigate the efficacy and acceptability of twice daily acebutolol in patients with mild to severe hypertension. Data from 1007 patients were analyzed. Most (901) had been treated previously with other hypertensive agents before starting on acebutolol. Oral dosages of acebutolol ranged from 200 mg to 1200 mg/day, according to individual requirements, and 331 patients received concomitant therapy, usually with a diuretic, either from the start of therapy or after 4 to 8 weeks. A significant reduction (p less than 0.001) was observed in mean diastolic blood pressure over the 12-week assessment period, and response increased with treatment duration. There were 280 reports of side-effects and 63 patients were withdrawn from the study for this reason.

Acebutolol: a review of its pharmacology, pharmacokinetics, clinical uses, and adverse effects.

Acebutolol is a new hydrophilic, cardioselective beta-adrenergic-blocking agent that possesses partial agonist and membrane-stabilizing activities. In the treatment of mild to moderate essential hypertension, once-daily acebutolol as monotherapy provides effective control in a large majority of patients and produces a further reduction in blood pressure when used concomitantly with diuretics. Acebutolol is as effective as other beta-blocking agents, and in a large, double-blind, parallel study against propranolol was found to cause less reduction in heart rate, and fewer neurologic side effects and patient withdrawals due to adverse effects. Oral acebutolol is also effective in suppressing premature ventricular contractions, and in small numbers of patients generally beneficial results were obtained in supraventricular and ventricular arrhythmias with intravenous administration. These salutary effects are attributable to beta blockade. Controlled clinical trials documented the antianginal actions of oral acebutolol in chronic stable angina pectoris; its efficacy in this regard is comparable to that of other beta-blocking agents. The drug produces smaller decreases in heart rate and cardiac output and alterations in peripheral vascular hemodynamics than beta-blocking drugs without partial agonist activity, and because of its cardioselectivity, it may be used cautiously in patients with bronchospastic disease. Acebutolol has minimal metabolic effects and does not elevate levels of blood lipids during long-term therapy; high-density-lipoprotein cholesterol increased with acebutolol in a small number of patients.

Effect of intravenous and oral acebutolol in patients with bundle branch block.

We studied the effect of intravenous (1 mg/kg) and oral (400 mg) acebutolol on atrioventricular conduction in 22 patients with idiopathic bundle branch block and 1 to 1 atrioventricular conduction. Seven patients had previously symptomatic complete heart block (Group 1) and 15 were asymptomatic with bundle branch block only (Group 2). Following intravenous acebutolol heart rate decreased 82 +/- 16 to 63 +/- 16/min (P less than 0.01), A-H interval lengthened 98 +/- 22 to 121 +/- 30 msec (P less than 0.005) and H-V time was prolonged 60 +/- 13 to 70 +/- 17 msec (P less than 0.02) in those with previous heart block. The corresponding changes in the patients with no previous block were 74 +/- 14 to 61 +/- 8/min (P less than 0.01), 90 +/- 17 to 109 +/- 22 msec (P less than 0.05) and 48 +/- 15 to 56 +/- 14 msec (P less than 0.01). There was no difference between the basal or induced changes between these two groups. After intravenous acebutolol infusion 2 of 6 patients with previous spontaneous heart block and none of those without previous heart block developed atrioventricular block distal to His. The induced block was temporary (less than 10 min) and corresponded to the time of peak plasma acebutolol levels. Temporary atrioventricular block followed oral acebutolol administration in 4/7 patients with previous spontaneous heart block and 0/14 in those without block. In patients with bundle branch block intravenous acebutolol prolonged H-V conduction times in 19/20 patients and intravenous and oral acebutolol induced A-V block in 4/7 patients with previous spontaneous block.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of hypotension on cochlear blood flow in polycythemic condition.

We examined the influence of hypotension by infusion of acebutolol hydrochloride (AH), a cardioselective beta-receptor antagonist, on cochlear blood flow in guinea pigs with various hematocrit values. AH infusion lowered the mean blood pressure to almost the same degree in all animals, regardless of the hematocrit level. The degree of the concomitant decrease of CBF varied with the hematocrit, being greater in animals with a higher hematocrit. In those with the highest hematocrit CBF did not return to the initial level. From these values we calculated the O2 transport capacity after AH infusion and found it to be lower than in animals without AH infusion. The difference was greater at higher hematocrits. These findings suggest that the microcirculation of the inner ear is responsive to transient decreases of perfusion pressure at high hematocrits.