Search

Recently, different beta-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective beta(1)-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 +/- 0.03). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p

Recently, different beta-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective beta1-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 +/- 0.04). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p < 0.05). A similar effect was observed for angiotensin II. Further, in the LV-dysfunction group, coronary sinus blood flow increased less, and coronary vascular resistance decreased less (both values, p < 0.05). Despite the fact that the increase in double product was decreased to a similar extent in both groups, ischemia was reduced only in normal LV function (p < 0.05). In ischemic LV dysfunction, neurohumoral activation after epanolol may impair adequate coronary flow response, and this may limit its antiischemic properties. Because of the small size of the study, no definitive inference on the clinical benefit of epanolol in patients with ischemic LV function can be made from this study.

Beta-blockers with less cardiodepressive effect than traditional nonselective beta(1+2)-blocking agents could be useful in the treatment of hypertension, provided the reduction in blood pressure was satisfactory. Epanolol, a selective beta 1-receptor blocker with intrinsic sympathomimetic activity, induced a fall in intraarterial pressure of 8% at rest sitting and 11% during 100 W bicycle exercise after the first dose of 200 mg in 12 patients with essential hypertension. Heart rate, stroke index, and cardiac index initially fell by 14%, 11%, and 23%, respectively. The total peripheral resistance index increased by 21% after 2 hours, and then reverted towards the pretreatment level. After 10 months of epanolol treatment (mean 300 mg/day), the reduction in arterial pressure was 5% at rest and 10% during exercise. Cardiac index and heart rate were still reduced 14-21%, while total peripheral resistance was unchanged or slightly increased (2-10%). Twenty-four hour ambulatory blood pressure was higher on epanolol (300 mg/day) than on atenolol (150 mg/day) treatment (137/97 vs. 128/91 mmHg). Thus, the achieved blood pressure reduction induced by epanolol was moderate, while other characteristics of beta-receptor blockade, in particular, the reduction of heart rate and cardiac output, were maintained. This suggests that the compound may be useful for other cardiovascular disorders, e.g., angina pectoris in patients without hypertension or cardiac arrhythmia.

The effects of epanolol (a new selective beta-adrenoceptor antagonist), diltiazem and placebo were compared in a group of 16 patients with chronic stable angina pectoris. Each patient received each treatment in random order. Diltiazem reduced weekly angina attack rate from 7.2 (95% CI 3.9-10.5) to 3.9 (1.9-5.9) (P less than 0.01), whereas a lesser reduction was observed after epanolol. Both drugs produced a small but significant (P less than 0.05) increase in treadmill exercise time (placebo 474 s (374-574), epanolol 527 s (431-623) and diltiazem 554 s (462-646). However, aerobic work capacity, assessed by peak achieved oxygen consumption, was not different from the placebo value of 21.2 (18.0-24.4) ml.min-1.kg-1, and clearly subnormal when compared to age- and sex-matched controls (33.0 (30.1-35.9) ml.min-1.kg-1). Ventilatory abnormalities and increased lactate levels on active treatment were observed at peak exercise only. We conclude that the cardiodepressant effects of both active drugs limit blood supply to working skeletal muscle, and that chest pain may be replaced by dyspnoea or fatigue as the limiting factors to exercise.

Beta blockade constitutes efficient therapy for stable angina pectoris. The effects of lowering blood pressure and heart rate with such treatment are not always desired. Epanolol is a beta 1-selective partial agonist with minor effects on blood pressure and heart rate at rest. Atenolol is a pure beta 1-selective antagonist with more pronounced effects on blood pressure and heart rate at rest. The effects of epanolol, 200 mg o.d., and atenolol, 100 mg o.d., were compared in 173 middle-aged patients with stable angina pectoris in a randomized, double-blind, parallel group-controlled study for one year. No significant differences were shown in angina attack rate, nitrate consumption, or exercise performance. Resting heart rate and blood pressure were significantly lower on atenolol. Epanolol tended to be better tolerated than atenolol, as shown by visual analogue scales of well-being, activity, energy, and warm extremities, further supported by fewer reports on possible adverse reactions. In conclusion, epanolol appears to be as effective as atenolol and better tolerated in patients with stable angina pectoris.

The efficacy of epanolol vs. metoprolol in stable angina pectoris was compared in 114 patients recruited to a randomized double-blind cross-over study, consisting of a 4-week period on each drug. Epanolol (200 mg) or metoprolol (200 mg) was administered daily. Bicycle ergometry was performed at the end of each treatment period. The maximum workload was 134 +/- 18 W on epanolol and 133 +/- 37 W on metoprolol (NS). Values for resting heart rate (epanolol, 72 +/- 11 beats min-1; metoprolol, 64 +/- 12 beats min-1; P less than 0.001), systolic blood pressure (epanolol, 143 +/- 21 mmHg; metoprolol, 137 +/- 21 mmHg; P less than 0.05) and diastolic blood pressure (epanolol, 88 +/- 10 mmHg; metoprolol, 84 +/- 11 mmHg; P less than 0.01) were all higher on epanolol treatment. During exercise, the increase in heart rate and blood pressure was of similar magnitude during the two treatment periods, and these parameters did not differ significantly at the last identical workload. The rating of chest pain, fatigue and dyspnoea did not differ between the two drugs during submaximal or maximal exercise. In conclusion, 200 mg of epanolol and metoprolol have similar efficacy with regard to exercise tolerance. As expected from the partial agonist activity present in epanolol but not in metoprolol, the former drug resulted in a higher heart rate and blood pressure at rest. The observed increase in these parameters during exercise was similar for both drugs.

The chronotropic effect of three beta-1-adrenoceptor partial agonists prenalterol, xamoterol and epanolol has been compared on the right atria of the rat in order to evaluate their intrinsic activity and to place them in rank order of effectiveness. The results show that prenalterol, xamoterol and epanolol are all partial agonists. The intrinsic activities relative to that of isoprenaline are 0.84 for prenalterol, 0.59 for xamoterol and 0.29 for epanolol. This rank order of intrinsic activities should remain the same in different species and in man. Both atenolol and propranolol reversed the chronotropic effects of the three agonists. The KB of the two blockers was similar against prenalterol and xamoterol, which indicates that the two partial agonists are probably competing for the same population of receptors. The EC50 is twice as large than KB for xamoterol, which is consistent with isoprenaline working through both beta-1- and beta-2- receptors and xamoterol finds it more difficult to block the beta-2-receptors.

Epanolol (200 mg once daily) was compared with nifedipine (20 mg twice daily) in a multicentre, double-blind, randomised, crossover study in which 571 patients with stable angina pectoris were entered. Efficacy was assessed by anginal attack rate and short-acting nitrate consumption. Symptoms and treatment preference of the patients were assessed by questionnaires. Assessments were made at baseline and after each 4-week treatment period. Both treatments were equally efficacious as demonstrated by weekly anginal attack rates and nitrate usage. Of those patients who expressed a preference for treatment, 61% expressed a preference for epanolol compared with 39% for nifedipine. Significantly fewer patients reported experiencing flushing, pedal oedema or feeling generally unwell (p less than 0.01) during the epanolol treatment period. Patients withdrew from nifedipine treatment more often than from epanolol because of adverse effects. Hence, epanolol was found to be as efficacious as nifedipine in patients with stable angina pectoris, but exhibited a superior tolerability profile and was preferred by more patients.

The pharmacokinetics of ICI 141,292 (epanolol) were studied over 3 days after a single oral 200 mg dose and then over 24 h after 12 consecutive daily oral 200 mg doses in 16 elderly subjects (aged 65 to 94 years) with moderate renal impairment (mean creatinine clearance 33.2 ml · min−1). There was wide inter-individual variability in peak plasma ICI 141,292 concentrations (Cmax) but no significant difference was found between mean Cmax after a single dose (44.3 ng. ml−1) and after 12 doses (37.4 ng. ml−1). The mean observed time to peak plasma ICI 141,292 concentration (tmax) after a single dose (1.61 h) did not differ significantly from that after 12 doses (1.75 h). On several occasions an analytically significant second peak in ICI 141,292 plasma concentration was observed. Following the peak(s), the plasma concentrations declined biphasically and a mean terminal phase plasma half-life (t11/2) of 28.3 (range 10.2–84.8) h was calculated after a single dose. The inter-individual variability in the area under the plasma concentration-time curve to 24 h AUC (0-24) was 54 fold but there was no significant difference between AUC (0-24) after a single dose (mean 226.0 rig·h·m1−1) and AUC (0-24) after 12 consecutive doses of ICI 141,292 (mean 232.4 ng·h·ml−1). The results show that consecutive daily administration of 12 oral doses of IC1 141,292 (200 mg) does not result in significant accumulation of drug in elderly subjects with moderate renal impairment.

1. Epanolol is a novel anti-anginal agent which is a beta 1-adrenoceptor partial agonist exhibiting selective beta 1-adrenoceptor antagonist and selective beta 1-adrenoceptor agonist activity. It is mainly metabolised to conjugates prior to excretion in urine and it was of interest to determine if any accumulation occurred in elderly patients. 2. The pharmacokinetics of epanolol have been studied over 72 h after a single oral dose of 200 mg and then over 24 h after 12 consecutive daily oral doses in 13 elderly patients with stable angina pectoris. 3. The peak plasma concentrations (mean +/- s.d.) after the single dose (25.7 +/- 17.0 ng ml-1) were not significantly different (P = 0.35) from those at steady state (32.4 +/- 20.9 ng ml-1). There was wide inter-individual variation on both occasions. The time to peak did not alter significantly during the study with mean values of 1.5 and 1.2 h on acute and chronic dosing respectively. 4. Plasma concentrations declined biphasically with a mean terminal phase half-life of 17 h and 5 fold inter-individual variation. 5. The mean area under the curve to 24 h was not significantly different (P = 0.26) after the single dose (59.0 +/- 29.8 ng ml-1 h) from that at steady state (78.4 +/- 55.0 ng ml-1 h). There was also wide inter-individual variation in these values. 6. In conclusion, the lack of significant accumulation of epanolol indicates that no alteration of dose is necessary when using epanolol in elderly patients with normal renal and hepatic function.

Recently, different beta-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective beta(1)-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 +/- 0.03). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p

Antiischemic effects of beta 1-blocking agents are based on intrinsic negative inotropic and chronotropic properties. Partial beta 1-agonistic activity, although useful in preserving cardiac function, may counteract such antiischemic properties by modulating the intrinsic negative cardiac effects of beta-blockade. To investigate the acute hemodynamic and antiischemic profile of epanolol, a cardioselective beta 1-antagonist and partial agonist, 20 patients with left coronary artery disease underwent two incremental atrial pacing tests, 45 minutes before (APST I) and 15 minutes after (APST II) 4 mg intravenous epanolol, administered over 5 minutes. Additional measurements were carried out at 1, 3, 5, 10, and 15 minutes after epanolol, at basal and fixed heart rates. Epanolol immediately reduced heart rate with a maximum of 10% at 15 minutes and decreased contractility (Vmax) by 7% (both p.05), whereas cardiac output fell temporarily by 9% (p.05). Other hemodynamic parameters did not change, except for a significant 11% reduction in myocardial oxygen demand. Despite comparable pacing conditions, both the double product and contractility decreased significantly less during APST II, resulting in a 17% lower myocardial oxygen consumption (p.05). Myocardial ischemia was markedly reduced, indicated by normalization of lactate metabolism [lactate extraction 16 +/- 7% vs. -7 +/- 8% (APST I)], less ST depression (21%), and modulation of LV end-diastolic pressure postpacing (all p.05 vs. APST I), whereas angina was absent or less in 14 patients. None of the patients reported an adverse effect. Thus, under resting conditions intravenous epanolol induces moderate, short-lasting negative chronotropic and inotropic effects, but does not alter cardiac pump function or vascular resistance, reflecting its additional beta 1-agonistic properties. Alternatively, during pacing it still reduces ischemia through negative inotropic effects and diminishes myocardial oxygen demand, reflecting its beta 1-antagonistic profile.

This double-blind, randomized parallel group study investigated the effect of 6 months beta-adrenoceptor antagonist therapy with either metoprolol (beta 1-selective without intrinsic sympathomimetic activity [ISA]) or epanolol (beta 1-selective with ISA) on markers of endogenous fibrinolysis in 20 patients with chronic stable angina receiving concurrent treatment with nifedipine. Neither drug had an effect on tissue-type plasminogen activator or plasminogen activator inhibitor type 1 (PAI-1). A significant correlation between fasting insulin and PAI-1 has previously been described and was confirmed in this study. The group treated with metoprolol showed a significant rise in fasting insulin after 6 months with no change in PAI-1. This suggests that the previously described link between these two may not be causal.

Hypertension is due to disturbance of the complex interplay between numerous known and unknown mechanisms that normally control blood pressure. Antihypertensive agents may, therefore, reduce blood pressure through widely different actions and, at the same time, elicit counterregulatory responses. This is a review of the long-term hemodynamic effects at rest as well as during exercise of nine relatively new antihypertensive compounds: a beta-blocker (epanolol), an alpha-receptor blocker (doxazosin), two double-acting compounds (dilevalol and carvedilol), three calcium antagonists (amlodipine, felodipine, and diltiazem), an angiotensin-converting enzyme inhibitor (lisinopril), a serotonin antagonist (ketanserin), and low-salt diet as a nonpharmacological treatment in 171 patients with mild to moderate essential hypertension. The results in the treatment groups are compared to the hemodynamic changes seen in 28 hypertensive patients left untreated for 10 years. The patient populations of the different groups were comparable. The invasive hemodynamic technique, including intraarterial blood pressure recording and measurements of cardiac output by Cardigreen, was the same in all studies. While blood pressure remained nearly unchanged in the untreated group, all antihypertensive compounds induced significant and sustained blood pressure reduction both at rest and during exercise. The modest reduction (3–5%) in blood pressure during a low-salt diet was also statistically significant. This review shows the multiplicity of the long-term hemodynamic changes, ranging from a reduction in cardiac output to peripheral vasodilatation, during chronic antihypertensive therapy. In untreated hypertensives, the cardiac output is reduced by 1–2% per year and total peripheral resistance is increased by 2–3% per year. The review also focuses on counterregulatory responses that modify the initial reduction in blood pressure after drug treatment for hypertension. It is concluded that proper understanding of the hemodynamic effects of antihypertensive agents is useful in the selection of the right treatment for specific groups of hypertensive patients.

Since drug therapy of angina is likely to produce a similar degree of efficacy for most drugs in common use, treatment choice should additionally focus on other factors, notably adverse events, quality of life, and convenience. Improvements in these factors can also lead to better compliance and can aid the doctor by cutting down the number of patient visits required to optimize therapy. The authors have evaluated the patient's overall assessment of symptomatic relief and adverse experiences in a comparative manner by means of the two-period crossover design using the patient's declared treatment preference as the primary measurement. This encapsulates several factors in a single assessment that can be understood by both physician and patient. The authors carried out two such studies of epanolol (Visacor), a novel anti-anginal agent with both beta-1 selective antagonist activity and also beta-1 selective partial agonist activity. In one study (n = 608) the comparator was metoprolol, and in the other (n = 571) it was nifedipine. This article describes and evaluates the methodology of these studies. To assess preference optimally, each patient had to receive both treatments in short but clinically relevant treatment periods, with no washout. Re-entry into the second period, after withdrawal from the first, was permitted. Both studies showed advantages for epanolol, more marked in the case of nifedipine, arising from equivalent efficacy but fewer adverse events.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of nifedipine (0.5, 1.0, and 2.0 micrograms/kg/min), metoprolol (0.1, 0.5, and 1.0 mg/kg), the beta 1-selective adrenoceptor partial agonist epanolol (10, 50, and 200 micrograms/kg), or equivalent volumes of isotonic saline (n = 6, in each group), on coronary blood flow capacity were studied in anesthetized swine. Intracoronary bolus injections of adenosine (20 micrograms/kg/0.2 ml) were administered without and during three levels of coronary stenosis, prior to and following each dose of drug, to obtain maximal coronary blood flows at different perfusion pressures in the autoregulatory range. Coronary perfusion pressures were varied by partial inflation of a balloon around the left anterior descending coronary artery. Special care was taken that the stenoses not lead to myocardial ischemia. Three indices of coronary blood flow capacity were used: absolute coronary flow reserve (ACFR, the ratio of maximal to resting coronary blood flow), the slope and the extrapolated pressure at zero flow (Pzf) of the pressure-maximal coronary flow (PMCF) relationship, and relative coronary flow reserve (RCFR, the ratio of maximal coronary blood flow with a stenosis to maximal coronary blood flow without a stenosis) at two of the three levels of stenosis. Nifedipine decreased ACFR from 4.5 +/- 1.9 to 1.9 +/- 0.3 (mean +/- SD; p less than 0.05), reflecting in part the increase in resting coronary blood flow. The nifedipine-induced changes in maximal coronary blood flow were not only due to a drop in perfusion pressure, as the slope of the PMCF relationship decreased from 2.27 +/- 0.49 ml/(min.mm Hg) to 1.54 +/- 0.51 ml/(min.mm Hg) (p less than 0.05), and Pzf decreased from 30 +/- 4 mm Hg to 20 +/- 7 mm Hg (p less than 0.05). Consequently, calculated maximal coronary blood flow was attenuated from 114 +/- 31 ml/min to 93 +/- 37 ml/min at 80 mm Hg, but was enhanced from 23 +/- 13 to 37 +/- 24 ml/min at 40 mm Hg coronary perfusion pressure. In concert with the change in the PMCF relationship, RCFR at equivalent severe stenosis increased from 0.33 +/- 0.06 to 0.47 +/- 0.10 (p less than 0.05). No changes were observed with metoprolol, epanolol, or saline. The effect of nifedipine on the PMCF relationship not only provides a mechanism for the drug's antiischemic action, but should also be considered in the interpretation of coronary flow reserve measurements in patients on nifedipine treatment.

1. The effects of sustained moderate exercise in the sitting position on renal haemodynamics and glomerular filtration were measured in six normotensive patients with moderately impaired renal function and seven age-matched normal volunteers. 2. The changes in the effects of exercise on renal function induced by chronic cardioselective beta-adrenoceptor blockade by drugs with (epanolol) and without intrinsic sympathomimetic activity (atenolol) were examined. 3. Both beta-adrenoceptor blockers attenuated the heart rate increase with exercise, but only atenolol lowered blood pressure significantly. In resting volunteers on atenolol, associated with the fall in blood pressure there was a significant reduction in glomerular filtration rate. 4. Glomerular filtration fell significantly in all groups with exercise, and renal blood flow also fell in parallel. These changes were not influenced by drug treatment. 5. The exercise-induced rise in PRA was suppressed by atenolol but not by epanolol. 6. The renal function and haemodynamic responses to moderate exercise does not appear to be mediated by the systemic renin-angiotensin system or by beta 1-adrenoceptors.

The possibility of a pharmacokinetic and/or pharmacodynamic interaction between epanolol and digoxin has been investigated in 10 healthy male subjects taking digoxin 0.375 mg daily for 14 days. During that period epanolol 200 mg daily or matching placebo was also given, each for 7 days, according to a double-blind, randomized cross-over plan. The plasma digoxin concentration-time profiles after 7 days of concomitant placebo or epanolol were comparable. Trough and peak plasma digoxin levels were similar (placebo: 0.84 and 2.62 ng.ml-1; epanolol: 0.87 and 2.46 ng.ml-1). The renal clearances of digoxin and creatinine were lower during treatment with epanolol, but the differences were not significant (placebo 142.0 and 126.5 ml.min-1; epanolol 105.7 and 109.3 ml.min-1). STI indexes were lower during treatment with digoxin plus epanolol, than after digoxin alone. The difference was significant for QS2I (513 versus 503 ms), PEPI (119 versus 112 ms) and PEP/LVET (0.286 versus 0.304). The observations suggest that in healthy volunteers there is no pharmacokinetic interaction between epanolol and digoxin, and that epanolol does not interfere with the positive inotropic action of digoxin.

After a 2-week placebo period, 30 men, aged 60 years (mean), with mild or moderate hypertension were randomly assigned to one of three treatment groups: pindolol, 10 mg b.i.d.; epanolol, 200 mg b.i.d.; and epanolol, 400 mg q.d. At the end of the placebo period and of 4 weeks of active treatment, heart rate, blood pressure, plasma renin activity (PRA), and nonepinephrine (NE) concentration of subgroups of subjects, were measured during isoproterenol infusion (30 ng/kg.min-1 for 15 min) and submaximal ergometric exercise (89 W, mean). Sitting heart rates were reduced with 200 mg b.i.d. epanolol (p less than 0.01) but unchanged with pindolol and 400 mg q.d. epanolol. Reductions of systolic and diastolic blood pressures occurred in all treatment groups but were most pronounced with pindolol. Isoproterenol-induced cardioacceleration and rise in PRA and plasma NE concentration were abolished by pindolol but only attenuated by epanolol. Pindolol also abolished the isoproterenol-induced reduction in diastolic blood pressure; epanolol had no effect on it. The hemodynamic and hormonal responses to exercise were attenuated by pindolol and epanolol in proportion to their beta-blocking activities. In the doses used, epanolol had moderate beta 1-selective blocking action. The intrinsic sympathomimetic activity of epanolol is dose dependent.

The effects of a 21 infusion of isotonic sodium chloride on renal haemodynamics and sodium excretion were measured in nine normotensive volunteers. Changes in these responses to volume expansion induced by cardioselective beta-adrenoceptor blockade by drugs with (epanolol) and without intrinsic sympathomimetic activity (atenolol) were examined. Renal plasma flow was significantly lower before, during and after sodium chloride infusion whilst on treatment with atenolol compared with epanolol. Urinary sodium excretion was lower on atenolol than epanolol. Glomerular filtration rate was unchanged by either drug. Basal urinary kallikrein excretion was diminished by atenolol and both epanolol and atenolol inhibited the rise in urinary kallikrein excretion after sodium chloride infusion. Although some of these findings may be due to a more potent hypotensive effect of atenolol, intrinsic sympathomimetic activity may contribute to the apparent protective effects of epanolol on renal function.

Single doses of epanolol (ICI 141,292) were administered to 12 healthy young male volunteers in a randomised crossover study. Each volunteer received a 200mg tablet, 200mg in solution or 5mg intravenously under fasting conditions, or a 200mg tablet with food. Venous blood samples were collected up to 72 hours after oral administration and 12 hours after intravenous administration. The concentrations of epanolol in plasma were determined by use of a radio-immunoassay technique, whereas those in urine samples were measured by a high pressure liquid chromatographic (HPLC) method. Analysis of variance was used to assess the significance of the differences between the groups. Epanolol plasma concentrations declined biexponentially with time after an intravenous dose, with a half-life of 7 minutes for the first phase and about 3 hours for the second. Plasma clearance was high (2.1 L/min). Peak plasma concentrations of about 30 to 40 ng/ml were observed at mean times of about 1 to 1.5 hours after oral administration. After the peak, plasma concentrations declined biexponentially, with a terminal phase half-life of about 20 hours. The bioavailability of epanolol for the tablet and solution administered to fasted volunteers was similar (7-8%), but it was about 25% lower when administered as a tablet with food. Urinary recovery of epanolol was about 25% of the administered intravenous dose, but recoveries were much lower (about 1%) following oral administration. These data have been compared with those obtained after single oral doses of epanolol 200mg to elderly patients with angina and subjects with renal or hepatic impairment.

The clinical benefit of beta-adrenoceptor partial agonists is still debated. To clarify the situation, epanolol, ICI 141,292 [N-[-2-(3-o-cyanophenoxy-2-hydroxypropylamino)ethyl]-4- hydroxyphenylactamide], has been developed to assess the role of modest beta-adrenoceptor partial agonist activity in humans. Animal studies have shown that epanolol is a potent beta-adrenoceptor partial agonist with a greater affinity for beta 1- than beta 2-adrenoceptors. In vitro, the PA2 values obtained for espanolol at atrial and tracheal beta-adrenoceptors were 8.42 and 6.33, respectively (isoproterenol as agonist), giving a selectivity ratio of 123. The potency was studied in vivo in the dog, where it was also shown that as an antagonist at the cardiac beta 1-adrenoceptor, it was 18 and 40 times more potent than atenolol and practolol, respectively. Espanolol has less partial agonist activity in the rat than pindolol, but more than practolol. In this species, it is also a classical partial agonist, exhibiting agonist activity at all beta-adrenoceptor blocking doses. This is in contrast to pindolol, which caused predominantly beta-adrenoceptor blockade at low doses and partial agonist activity at higher doses. These differences were confirmed in haemodynamic studies in the dog. In contrast to many other partial agonists, the partition coefficient, log P, of epanolol in octanol and water is low (0.92).

After examination of the epanolol (‘Visacor’1) clinical package it became clear that, although efficacy and safety of epanolol were equivalent to efficacy and safety with other antianginal therapies, tolerability was improved. It was decided to initiate 2 studies with 500 patients in each to quantify the improved tolerability and examine patient preference for antianginal treatments. One study was a comparison of epanolol 200mg daily with metoprolol 100mg twice a day and the other compared epanolol 200mg daily with nifedipine retard 20mg twice a day. The rationale, design and statistical methodology are presented, together with a summary of the geographical spread of the study.

1 Eight men with primary hypertension were treated for 3 weeks with placebo, epanolol (200 mg or 400 mg), or atenolol 100 mg in a randomised cross-over study. Each active treatment period was preceded by a 3 week placebo treatment period and both investigators and subjects were blind to the active drug sequence. 2 At the end of each period, measurements were made of resting cardiovascular (heart rate, blood pressure, forearm blood flow) and biochemical variables (plasma renin, angiotensin II, aldosterone, adrenaline, noradrenaline, vasopressin, sodium and potassium concentrations and osmolality). Responses to exercise (including gas exchange, sweat rate, and ratings of perceived exertion) and the reflex cardiovascular adjustments to distal body subatmospheric pressure were also assessed. 3 The reduction of exercise-induced tachycardia by epanolol 400 mg was comparable to that of atenolol. There was very little difference in the effects of atenolol or epanolol 400 mg on resting blood pressure, but in both cases blood pressures were usually significantly lower than with epanolol 200 mg. 4 Although each active treatment influenced the renin-angiotensin system and circulating levels of catecholamines, the exercise-induced reduction in blood pressure was unaffected. Thus, the hypotensive effects of pharmacological and non-pharmacological interventions were additive.

The beta-adrenoceptor blocking properties and cardioselectivity of ICI 141, 292 were investigated in healthy male subjects. Seven subjects received in random order oral doses of ICI 141,292 20, 50, 100, 200 and 400 mg, atenolol 50 and 100 mg and placebo. ICI 14 292 had no effect on supine heart rate which was reduced by atenolol 100 mg. ICI 141,292 50, 100 and 200 mg had no effect on standing heart rate which was reduced by 400 mg at 2 h. Both doses of atenolol caused greater reductions. The maximum percent reduction of an exercise tachycardia after ICI 141,292 200 mg (23.9 +/- 3.7%) and 400 mg (24.3 +/- 5.2%) were similar to atenolol 50 mg (27.3 +/- 4.7%) but less than atenolol 100 mg (30.8 +/- 2.9%) (P less than 0.02). Six subjects received in random order single oral doses of ICI 141,292 100, 200 and 400 mg, atenolol 50 mg, propranolol 40 mg and placebo. Following each dose each subject received graded infusions of isoprenaline sulphate until heart rate increased by 40 beats min-1. Dose-response curves were constructed for the changes in heart rate, finger tremor, blood pressure and forearm blood flow produced by each infusion. At the 4 micrograms min-1 dose of isoprenaline, ICI 141,292 200 mg caused more attenuation than atenolol 50 mg but less than propranolol 40 mg in the changes of heart rate, diastolic blood pressure and finger tremor (P less than 0.02). ICI 141,292 400 mg caused more attenuation of the changes of all parameters than atenolol 50 mg but less attenuation of the changes in diastolic blood pressure and finger tremor than propranolol 40 mg (P less than 0.02). These results indicate that ICI 141,292 is a cardioselective beta-adrenoceptor antagonist with partial agonist activity.

Some side effects of the beta 1-adrenoceptor blocker atenolol may result from depression of cardiac output at rest. They may, therefore, be reduced by the use of drugs with beta 1-partial agonist activity, such as epanolol. We compared once-daily atenolol 100mg and epanolol 200mg in 20 patients reporting side effects while taking atenolol for chronic stable angina. A double-dummy, double-blind, crossover design was used to assess side effects by use of visual analogue scales and interviews, and antianginal efficacy by treadmill exercise tests and diary cards. In a comparison with atenolol, no significant differences in exercise time (686 +/- 11 seconds vs 685 +/- 10 seconds, maximum ST depression (1.02 +/- 0.09mm vs 1.07 +/- 0.08mm), time to 1mm ST depression (8.4 +/- 1.9 minutes vs 9.0 +/- 2.0 minutes), or days without angina (median 100% in both) were shown. All visual analogue scores were higher with epanolol (subjective energy 58.3 +/- 1.7 vs 54.3 +/- 1.5, well-being 61.8 +/- 1.8 vs 58.6 +/- 1.5 and warmth of extremities 68.4 +/- 3.6 vs 62.0 +/- 3.1). Although these differences did not attain statistical significance, 11 patients expressed a preference for epanolol and only 6 for atenolol. We conclude that, in this study, epanolol is as effective as atenolol as an antianginal agent for chronic stable angina. It improved the side effect profile in some but not all patients.

The concept of quality of life is used to determine clinically relevant aspects of subjective symptoms and well-being, and refined psychometric instruments are now being developed to assess changes in well-being during pharmacological therapy. In order to evaluate general well-being, subjective symptoms and common side effects during cardiovascular therapy, workers at this hospital have designed a quality of life questionnaire. This consists of a generic section for the evaluation of 3 global aspects of well-being (hedonic tone, activity and relaxation) and a specific symptoms section for assessing 21 common side effects of cardiovascular drugs. The test is based on visual analogue scales. This questionnaire was used in a Swedish subsample (n = 211) of the epanolol versus metoprolol study in patients with stable angina pectoris (VISA 1). In this double-blind crossover study, there were no significant differences between epanolol and metoprolol as regards general well-being with this sample size. The frequency of some specific symptoms (fatigue, sleep disturbances, vivid dreams and cold digits) was somewhat lower during epanolol treatment, but the differences did not attain statistical significance.

Experiments were performed on canine and human isolated coronary arteries to characterise human coronary beta adrenoceptors and to determine whether or not beta blocking agents with different ancillary properties unmask the alpha adrenergic effect of noradrenaline in a similar way. The inhibitory effects of atenolol (a beta1 selective antagonist), epanolol (a beta1 selective antagonist with modest intrinsic sympathetic activity), and propranolol (a non-selective antagonist) were assessed on isoproterenol concentration-response curves. Regression analysis provided slopes not significantly different from unity and similar pA2 values for each agent in both preparations. In a second group of experiments, the effects of noradrenaline (10 mumol.litre-1) were assessed in the absence and presence of beta blockade. At equipotent doses (1 log or 2 log units from the pA2 values) each beta blocking agent unmasked the alpha effect of noradrenaline in the same way. This alpha effect of noradrenaline (10 mumol.litre-1) was completely abolished by prazosin 1 mumol.litre-1 in canine coronary arteries but only partially antagonised in human coronary arteries. Thus the property of a beta blocking agent to unmask the alpha adrenergic effect of adrenaline is mainly related to its affinity for the coronary smooth muscle beta adrenoceptors. These beta adrenoceptors were very similar in both preparations and appear to be mainly beta1. The alpha adrenoceptors seem, nevertheless, to be different and resistant to prazosin in human preparations.

Epanolol is a new once-daily agent for the treatment of angina pectoris. This study was conducted in 2 parts. Firstly, a dose-finding study was performed using placebo and epanolol 100, 200, 300 and 400mg to assess the efficacy and safety of the drug. Once-daily epanolol 200mg was an effective dose, significantly reducing angina attack rate and increasing exercise duration and work output. At the same time, an improvement was noted in the patients' well-being and their ability to undertake normal daily activities. The 200mg dose regimen was used in a long term (12 months) assessment of the efficacy and safety of epanolol in the second part of this study. The efficacy of epanolol was clearly maintained throughout the full treatment period without adverse events or withdrawals as a result of treatment. The effectiveness and safety of epanolol are attributed to its selective beta 1-partial agonist activity. At rest, the degree of agonist activity (about 20% of that of isoprenaline) may prevent some of the untoward effects occasionally seen with full beta-blockers. During exercise, the antagonist activity becomes apparent and cardiac ischaemia is reduced.

Epanolol is a cardioselective l1-adrenoceptor antagonist with modest partial agonist activity (PAA) [Eriksen et al. 1988]. The PAA is I1 t-selective, about 20% of that of isoprenaline (isoproterenol) [Smith et al. 1983], and it is suggested that this may offer certain advantages as regards side effects. Clinical studies in patients with angina pectoris have shown considerable antianginal effect with epanolol 100, 200, 300 and 400mg (Akhras et al. 1985; Eriksen et al. 1988). However, the effect of epanolol 300 and 400mg once dail y does not seem to be greater than the 200mg (dose) [Akhras et al. 1985]. It will be of interest to evaluate the low dose of epanolol 50mg. The purpose of this Norwegian study was to compare the efficacy and tolerability of 3 different doses of epanolol (50, 100 and 200mg) with placebo in patients with chronic stable angina pectoris. Epanolol was administered in tablet form, once daily.

This overview of the safety and efficacy of the antianginal agent epanolol presents key features of the data from an international trial programme involving 1274 subjects. Additional information on the most frequently occurring possible adverse reactions is drawn from 2506 patients, which includes those in ongoing studies. Pooled analyses show that epanolol is as effective as reference therapies (nifedipine and atenolol), as assessed by work output during exercise tests, and in studies of anginal attack rate or work output during 12 months of treatment there was no evidence of tachyphylaxis with epanolol. Epanolol has a favourable safety profile, which compares well with those for placebo and for active antianginal therapies.

Epanolol has been shown in animal models to be a selective beta-adrenoceptor partial agonist with agonist activity about 20 to 25% of that of the full agonist isoprenaline. Evidence is presented in this review supporting the conclusion that epanolol has the same pharmacological properties in man and that the agonist activity at the beta-adrenoceptor is less than the activity present in pindolol, but greater than that present in acebutolol. The pharmacodynamic consequences in man of the degree of agonist activity possessed by the beta 1-selective partial agonist epanolol include little reductions at rest in heart rate, blood pressure, various measures of cardiac haemodynamic parameters, peripheral blood flow and renal function. On exercise there is attenuation of the heart rate and systolic blood pressure responses, with less perceived exertion than with atenolol. Evidence is available which shows that attenuation of the tachycardia of exercise persists for 24 hours after a single dose of epanolol 200mg, a dose which retains selectivity for the beta 1-adrenoceptor. This pharmacological profile of epanolol in man suggests that it would be an effective antianginal agent when 200mg once daily is administered. Moreover, its unique profile (compared with other antianginal agents) may make it more tolerable to patients than existing antianginal therapy.

The tolerability of epanolol, a new antianginal agent given as a single daily oral dose of 200mg, has been compared with the oral formulation of metoprolol (100mg twice daily) in a multicentre, randomised, double-blind, crossover study in 573 patients with stable angina (VISA 1). Patient preference for treatment was determined and efficacy was also monitored. Four weeks' treatment with one agent was followed by 4 weeks' treatment with the alternative agent. At the end of the study, patients were asked to express a preference, where possible, for 1 of the 2 treatments. The preliminary results of the study show that the preference question was answered by 524 patients (91.9%), and although 30 more patients preferred epanolol (45% preferred metoprolol, 55% preferred epanolol), the trend did not reach statistical significance (p = 0.137). Reasons for preference for epanolol were largely based on patients having fewer adverse effects, with fewer angina attacks and a general improvement in well-being as secondary reasons. Reasons for preference for metoprolol, however, were evenly divided between fewer adverse effects and fewer angina attacks, with a general improvement in well-being of less importance. Responses to a tolerability questionnaire consisting of 43 questions on 7 different body systems showed that epanolol had a significantly better profile than metoprolol for 10 of the side effects, particularly those associated with beta-blocker treatment. Responses to only one question indicated that patients tolerated metoprolol better than epanolol. Two patients died during the study (one on metoprolol treatment and one on epanolol treatment). Neither death was attributed to the study treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous 24-hour ECG monitoring was performed as an additional objective in 87 patients from 5 centres in the VISA 1 study. The aim of the study was to compare the continuous 24-hour ECG recordings before the study and during treatment with epanolol ('Visacor') or metoprolol. Parameters of particular interest were heart rate and premature ventricular contractions (PVCs). Using the Oxford 4000 system with a 5-lead recorder, 24-hour monitoring was carried out on entry to the study (no antianginal therapy was allowed, with the exception of short acting nitrates), and at the end of both treatment periods. Measurements included the total number of heart beats and PVCs and the incidence of bradycardia. 87 patients, of mean age 59 (range 32 to 80) years, were included in the study. 62 patients had evaluable tapes available on both active treatment periods. The mean heart rate during 24 hours was significantly lower with metoprolol compared with epanolol treatment (64 vs 72 beats/min, respectively, p less than 0.001). The total number of PVCs in 24 hours was similar in both treatment groups and not significantly different from the value recorded at entry. The median total duration of bradycardia (heart rate less than 60 beats/min) in 24 hours was significantly (p less than 0.001) less for epanolol (60 minutes) than metoprolol (428 minutes). Plots of the mean hourly heart rates show that during daytime, epanolol was associated with a mean heart rate in between the rate observed without treatment and with metoprolol treatment. At night-time, almost identical values were found in the groups treated with epanolol compared with the non-treatment period, whereas the metoprolol treatment induced significant lower heart rate levels. Thus, it was shown that there was greater heart rate reduction with metoprolol than with epanolol (p less than 0.001), and that there was no heart rate reduction at night with epanolol. No arrhythmogenic effect was seen for either drug.

The primary aim of this multicentre, randomised, double-blind, crossover study in 529 patients with stable angina pectoris was to compare the tolerability of epanolol, a novel antianginal agent, administered as a single oral daily dose of 200mg, with an oral retard formulation of twice-daily nifedipine 20mg and to determine patient preference (VISA 2). Confirmation of equal efficacy and safety monitoring were secondary aims of the study. Treatment consisted of 4 weeks on each therapy, and at the end of the study each patient was asked to state their treatment preference. 448 patients (85%) answered the preference question. Preliminary analysis of the data showed that 61% of patients preferred epanolol vs 31% who preferred nifedipine (p< 0.001). Reasons for a preference for epanolol were mainly fewer adverse experiences (11% vs 23% with nifedipine), a general improvement in well-being (16% vs 10% with nifedipine) and a decrease in the number of angina attacks (11% vs 10% with nifedipine). A tolerability questionnaire comprising 43 questions and covering 7 different body systems showed that epanolol had a better profile than nifedipine for the following 7 side effects: poor sleep, abdominal pain, flushing, swollen ankles, palpitations, headache and a general feeling of being unwell. Four patients died during the study; none of the deaths were associated with the study treatment. Treatment with nifedipine resulted in 63 patient withdrawals compared with 31 patient withdrawals during epanolol treatment; here were 5 patient withdrawals from both treatments. The main reasons for withdrawal of patients from nifedipine treatment were adverse events (9% vs 4% with epanolol) and a lack of efficacy (3% vs 2% with epanolol). There was no difference in efficacy between treatments, as shown by the weekly angina attack rate and glyceryl trinitrate (nitroglycerin) consumption. Although resting heart rate was significantly higher during treatment with nifedipine, there was no discernible difference in blood pressure. There were no unexplained clinically significant haematological or biochemical measurements.

1. The effect of chronic treatment with epanolol, a new cardioselective beta-adrenoreceptor antagonist with moderate beta 1-selective intrinsic sympathomimetic activity (ISA), on 24 h ambulatory intra-arterial blood pressure (24 h IABP) and the sino-aortic baroreceptor heart rate (SAB/HR) reflex was investigated in six hypertensive subjects. 2. All subjects demonstrated a greater than 10% reduction in mean arterial pressure with atenolol therapy (100 mg once daily) before entering a randomized, double-blind, placebo-controlled, crossover protocol with epanolol (100 mg twice daily for 4 weeks). 3. Epanolol treatment at this dose was not associated with significant reduction in systolic or diastolic 24 h IABP or heart rate. There was no change in SAB/HR reflex set point, sensitivity or latency with epanolol. 4. beta 1-selective ISA may be undesirable in beta-adrenoceptor antagonists used to treat hypertension.