Epanolol (Visacor)

Epanolol. A new once-daily antianginal agent: dose finding and long term efficacy

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.

Effects of epanolol and metoprolol on the heart measured by 24-hour holter monitoring

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.

Efficacy of epanolol versus metoprolol in angina pectoris: report from a Swedish multicentre study of exercise tolerance

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.

Investigation of possible pharmacokinetic and pharmacodynamic interactions between epanolol and digoxin

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.

Effects on physical performance of intrinsic sympathomimetic activity (ISA) during selective beta 1-blockade

In 15 healthy, not specifically trained volunteers (age: 26.6 +/- 2.7 years) single equipotent doses of a selective beta 1-blocker with intrinsic sympathomimetic activity (ISA) (200 mg Epanolol-Visacor; V) and of a selective beta 1-blocker without ISA (100 mg Metoprolol; M) were compared with placebo (P) with respect to their influence upon physical performance capacity and metabolism in a random, double blind, cross-over experimental setting. The subjects underwent three step by step incremental treadmill tests and three treadmill endurance tests until volitional exhaustion. Maximum running speed and maximum oxygen uptake were used as measures of maximum performance capacity. Running speed and oxygen uptake related to individual anaerobic threshold, and running time and running distance in the endurance tests were used as measures of endurance capacity. Both maximum and endurance performances were reduced significantly by beta-blockade. No relevant differences were discerned between V and M. The uniform reduction in exercise heart rate with both beta-blockers demonstrated the application of equipotent doses. At rest, heart rate was significantly higher under V than under M. Carbohydrate metabolism was unaffected, both beta-blockers showing equal inhibition of lipolysis during exercise. We conclude that intrinsic sympathomimetic activity has no influence upon physical performance and metabolism during selective beta 1-blockade.