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.

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.

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.

Acebutolol-induced subacute cutaneous lupus erythematosus.

Beta-blocking medications are rarely associated with drug-induced lupus erythematosus syndrome and have never been incriminated as a cause of subacute lupus erythematosus (SCLE). We present herein the first case of SCLE induced by acebutolol. A 57-year-old woman presented with a 1-month history of a cutaneous eruption of the photo-exposed areas. One month ago, the patient had started a treatment with oral acebutolol to cure a hypertension of 1-year evolution. Physical examination revealed erythematous scaly annular plaques, involving the face, arms and trunk. Immunologic serology findings revealed a positive titer of antinuclear antibodies up to 1/1,280 with positivity of antihistone and Ro/SSA antibodies. Acebutolol was stopped, and the lesions cleared completely 4 months later. Literature data, along with our case, suggest a link between acebutolol therapy and the onset of a lupus syndrome. Although this is the first report of acebutolol-induced SCLE, we should be aware of this occurrence, and avoidance of acebutolol is recommended in patients with stigmata of lupus erythematosus.

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.

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.

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.

Randomised controlled trial of enalapril and beta blockers in non-diabetic chronic renal failure.

OBJECTIVE: To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with chronic renal failure. DESIGN: Open randomised multicentre trial with three year follow up. SETTING: Outpatient departments of six French hospitals. PATIENTS: 100 hypertensive patients with chronic renal failure (initial serum creatinine 200-400 mumol/l. 52 randomised to enalapril and 48 to beta blockers (conventional treatment). INTERVENTIONS: Enalapril or beta blocker was combined with frusemide and, if necessary, a calcium blocker or centrally acting drug in patients whose diastolic pressure remained above 90 mm Hg. RESULTS: 17 patients receiving conventional treatment and 10 receiving enalapril developed end stage renal failure. The cumulative renal survival rate was significantly better in the enalapril group than in the conventional group (P < 0.05). The slope of the reciprocal serum creatinine concentration was steeper in the conventionally treated patients (-6.89 x 10(-5)l/mumol/month) than in the enalapril group (-4.17 x 10(-5)l/mumol/month; P < 0.05). No difference in blood pressure was found between groups. CONCLUSION: In hypertensive patients with chronic renal failure enalapril slows progression towards end stage renal failure compared with beta blockers. This effect was probably not mediated through controlling blood pressure.

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.

[Hemodynamic and renal adaptation of newborn infants of hypertensive mothers treated with acebutolol]. / Adaptation hémodynamique et rénale du nouveau-né de mère hypertendue traitée par acébutolol.

A prospective study of the hemodynamic and renal changes was undertaken in 11 neonates whose mothers were treated with acebutolol for hypertension during pregnancy, compared with a control group of 11 infants born to normotensive mothers. Monitoring of the cardio-respiratory system was performed for a period of 4 days. Renal function was studied during 2 periods (12-36, 60-84 hours of life). Hemodynamic failure was observed in 5 of 11 children from treated mothers. The data concerning the renal function of treated group showed: 1) a diuresis significantly lower during the first period (p less than 0.05); 2) the absence of significant rise in the glomerular filtration rates during the second period; 3) a lower sodium balance during the 1st and 2nd periods (p less than 0.02 and p less than 0.05), a lower calcium balance during the 1st period (p less than 0.01). No relationship was found between the renal changes and the hemodynamic disturbances. The direct effect of the drug on the glomerular and tubular functions and/or the renal arteriolar vasomotricity could explain these changes in the renal function in the newborns prenatally exposed to acebutolol.

[The treatment of severe arterial hypertension in patients with chronic kidney failure with captopril and beta-adrenoblockaders]. / Lechenie tiazheloi arterial'noi gipertenzii u bol'nykh s khronicheskoi pochechnoi nedostatochnost'iu kaptoprilom i beta-adrenoblokatorami.

Twenty nine patients with chronic renal failure associated with severe essential hypertension, 10 of whom being on programmed hemodialysis, were treated with captopril, a converting enzyme inhibitor (n = 21) and sectral-400, a cardioselective beta-blocker (n = 11). Blood pressure (BP) changes and renin-angiotensin-aldosterone system parameters were studied by radioimmunoassay. When given in a daily dose of 25 to 100 mg for a long time, captopril provided a good and satisfactory antihypertensive effect in 9 patients; a weak or no effect was achieved in 9 and 5 patients, respectively. BP lowered by an average of 14.7%. There were 72% and 17.9% increases in active and total renin levels, respectively, and a reduction in the proportion of inactive in total renin. With sectral-400, 400-1200 mg/day, good, weak or no effects were observed in 6, 3, and 2 patients, respectively. BP decreased by an average of 13%, there were 59% and 12% reductions in active and total renin levels, respectively, whereas the content of inactive renin showed a 21% increase, suggesting a diminution of renin synthesis and activation. The initially higher plasma aldosterone levels in most patients (by an average of 4.2 times) decreased significantly by 23% with the two drugs. Thus, in severe essential hypertension it is advisable to use blockers of the renin-angiotensin system in patients with chronic renal failure, captopril is particularly indicated in those who have a high renin activity, and the hyperkinetic syndrome is an additional indicator for sectral-400 use.

[Does chronic therapy of hypertension with acebutolol or hydrochlorothiazide effect coronary risk factors?]. / Czy leczenie nadcisnienia tetniczego acebutololem lub hydrochlorotiazydem nasila biochemiczne czynniki zagrozenia choroba wiencowa?

In 78 patients with mild or moderate hypertension, effect of acebutolol and hydrochlorothiazide on plasma lipids, lipoproteins, fibrinogen and plasma fibrinolysis time were investigated. 42 patients were treated with acebutolol for 18 months and 36 with hydrochlorothiazide for 24 months. It was shown that neither acebutolol nor hydrochlorothiazide induced significant alterations in investigated biochemical risk factors. The possible causes of controversy encountered in literature and analysis of factors which may influence the character and severity of metabolic disorders resulting from antihypertensive therapy were discussed.

[Effects of medium-term treatment of acebutolol on lipid profile]. / Effetto sul quadro lipidico di un trattamento a medio termine con acebutololo.

The effects of a 12-week treatment with acebutolol on serum lipids have been studied in 18 patients. Acebutolol was given as a 400-, 600-, or 800-mg single daily dose in the morning. Standing and supine blood pressure diminished significantly, whereas the major indexes of lipid metabolism such as total serum cholesterol, HDL-cholesterol, triglycerides, and plasma lipoproteins were not significantly affected. The treatment was well tolerated.

[Monotherapy with acebutolol in hypertensive diabetic patients]. / Monoterapia nadcisnienia tetniczego za pomoca acebutololu u chorych na cukrzyce.

Monotherapy of hypertension with acebutolol in diabetics in daily dose of 200-400 mg for 6 weeks induced only non-significant and practically not acceptable hypotensive effect in groups of patients with hypertension and diabetes type I or type II without nephropathy. No therapeutical effect was observed in hypertension in diabetics type I with nephropathy. Administration of acebutolol to hypertensive diabetic patients with nephropathy resulted in tendency to increase in albuminuria. Values of creatinine clearance did not change at the same time. Also no effect of acebutolol on glycemic or lipid indices was observed. The lack of clear hypotensive effect under studied conditions of acebutolol in diabetic patients contrasted with its significant action in comparative group of hypertensive non-diabetic subjects.

Fulminant myasthenia gravis soon after initiation of acebutolol therapy.

We report the case of myasthenia gravis in a 74-year-old woman, 2 weeks after acebutolol had been introduced as the sole treatment for systemic hypertension. The disease developed at a fulminant and fatal course despite drug withdrawal. The possibilities of coincidental association between the two events, triggering of a preexisting latent myasthenia gravis or full induction of the disease by acebutolol, are discussed.