Usefulness of penbutolol for systemic hypertension. Penbutolol Research Group.

Dose-response relations with penbutolol--a beta-adrenergic blocking agent--were evaluated in a double-blind multiclinic study conducted in 302 outpatients with mild to moderate hypertension (untreated supine diastolic blood pressure [BP] greater than or equal to 95 and less than or equal to 115 mm Hg). Penbutolol was administered once daily in 10, 20 or 40 mg doses for 6 weeks and compared with placebo. Mean declines from baseline in supine diastolic BP were comparable in the 3 penbutolol treatment groups and significantly superior to placebo (p less than 0.05). A significant difference between penbutolol dosage groups was observed only for supine systolic BP; the mean decline at 20 mg/day was significantly larger than that at 10 mg/day (p less than 0.05). Maximum BP response developed in approximately 4 weeks at 10 mg/day and in 2 weeks at the higher dosages. Decline in mean heart rate after 6 weeks of penbutolol therapy significantly exceeded placebo only at 40 mg/day (7.2 vs 2.5 beats/min, p less than 0.05). Treatment was well-tolerated and discontinued because of adverse effects in only 7 patients receiving penbutolol and 3 receiving placebo. The lack of significant bradycardia and the low incidence of other troublesome adverse effects are potential advantages during antihypertensive therapy with penbutolol. With rapid onset of effect and good efficacy and tolerability, the 20 mg once-daily dose appears to be optimum for therapy with this new agent.

Penbutolol: a preliminary review of its pharmacological properties and therapeutic efficacy in hypertension and angina pectoris.

Penbutolol is a non-selective beta-blocking drug with 'moderate' intrinsic sympathomimetic (partial agonist) properties, and a relatively narrow dose-response range. In many other aspects its pharmacological profile resembles that of propranolol. Significant beta-blockade, as demonstrated by reduction in heart rate during exercise in healthy subjects, persists for at least 24 hours after penbutolol administration, and thus the recommended dosage schedule in both hypertension and angina involves single daily doses (20 or 40mg daily) in most patients, with a divided dose (40mg twice daily) if a higher dose is needed. However, most angina prophylaxis studies to date have not been designed to clearly demonstrate that the beneficial effects of beta-blockade with a single dose of penbutolol extend throughout a 24-hour dosing interval. Further studies are needed to provide such evidence. As might be expected, penbutolol appears to be about as effective as usual doses of propranolol in both mild to moderate hypertension and in angina, but much of the clinical experience with the drug is in unpublished form and is thus somewhat difficult to evaluate in detail. The choice of a beta-blocking drug should be based on a knowledge of the characteristic pharmacodynamic and pharmacokinetic properties of the individual drugs within this group, and on careful consideration of how these properties might be used to benefit the individual patient. As is the case with most other beta-blocking drugs, penbutolol has some specific properties (e.g. relatively narrow dose-response range minimising the difficulty of dose titration, moderate intrinsic sympathomimetic activity) which may be used to advantage in certain patients.

Penbutolol in the treatment of mild to moderate essential hypertension in black South Africans.

The antihypertensive effects of penbutolol, a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity, was assessed in nonobese black South Africans aged 25 to 65 years with uncomplicated mild to moderate essential hypertension. After a 4-week placebo run-in period 50 patients entered a randomized placebo-controlled study with a crossover design. For 8 weeks they received a once daily dose of 40 mg penbutolol (or placebo) which was increased to 80 mg per day for the next 4 weeks in poor responders. This was followed by a 4-week placebo washout period after which a crossover of treatment was achieved and a second 12-week period of treatment initiated. Thirty-five patients completed the whole study and in 15 patients diastolic blood pressure was reduced below 95 mm Hg. The mean systolic pressures of these patients decreased by 21 mm Hg and their mean diastolic pressure decreased by 11 mm Hg during treatment with penbutolol. These results suggest that penbutolol monotherapy is an alternative therapeutic approach to hypertension in black South Africans.

Penbutolol and carteolol: two new beta-adrenergic blockers with partial agonism.

Penbutolol and carteolol are two new long acting, nonselective beta-adrenergic blockers which have been approved for the treatment of systemic hypertension. Both drugs have intrinsic sympathomimetic activity (partial agonist activity), however, less than that seen with pindolol. They appear to cause less resting bradycardia than propranolol, have no effect on lipids and lipoproteins, and have favorable side effect profiles.

Antihypertensive efficacy and tolerance of penbutolol: results of a co-operative study in 227 patients.

An open, co-operative study was carried out in 227 patients with mild to severe essential hypertension to assess the efficacy and tolerance of penbutolol, given as monotherapy, in controlling blood pressure. Patients received a single daily dose (40 mg in the majority) for 8 weeks and were assessed every 2 weeks. The results showed that there was a significant reduction (p less than 0.01) in systolic, diastolic and mean arterial blood pressure and in pulse rate after 2 weeks compared with pre-treatment values, and there was a further significant reduction (p less than 0.01) comparing 8-week values with those measured after 2 weeks. Response to treatment did not differ significantly between those patients who were newly diagnosed and those who had received previous antihypertensive medication. The largest percentage reduction in blood pressure from initial values was recorded in those patients with the more severe hypertension (diastolic 116 to 130 mmHg) and a considerable number of all the patients became normotensive during the trial period. Records of side-effects indicated a global incidence of 17.6%, the most frequently reported being dizziness and mild gastro-intestinal disorders; only 1 patient complained of bradycardia and another of cold extremities. Eighteen (7.9%) patients dropped out of the study due to side-effects.

Efficacy of once daily penbutolol in chronic stable angina. An objective comparison with long-acting propranolol.

The effects of penbutolol (40 mg daily) and long-acting propranolol (160 mg daily) were assessed in 26 patients with chronic stable angina in a placebo-controlled randomised double-blind crossover study with 2-weekly treatment periods. In addition to conventional subjective assessment, serial multistage treadmill exercise was used to obtain objective data on drug efficacy and 24-hr ambulatory electrocardiography performed for diurnal heart rate analysis. The mean exercise time of 6.3 +/- 0.5 (SEM) min on placebo increased to 7.3 +/- 0.6 min on penbutolol (P less than 0.01) and to 7.9 +/- 0.5 min on propranolol (P less than 0.001). The pre-exercise resting heart rate was 73 +/- 2 beats/min on placebo and decreased to 63 +/- 2 beats/min on penbutolol (P less than 0.001) and 58 +/- 2 beats/min on propranolol (P less than 0.001). The maximum exercise heart rate was similarly reduced by both drugs and there was a corresponding reduction in peak exercise double product. The time-corrected maximum ST segment depression was reduced by both drugs and neither produced a delay in ST segment recovery. Both drugs effected significant reductions in ambulatory maximum hourly heart rates throughout 24 hr. The lowest observed heart rate on penbutolol was 40 beats/min and 34 beats/min on propranolol. Penbutolol is an effective antianginal agent with a profile of action similar to that of propranolol.

Angioscintigraphic assessment of hemodynamic effects of penbutolol in cirrhotics with portal hypertension. A double-blind, randomized, controlled study.

This randomized double-blind controlled study analyzed the hemodynamic effects of penbutolol, a new levorotatory beta-blocker, using radionuclide angiography. Twenty cirrhotics with esophageal varices were randomized to two groups: 10 received 40 mg/day of penbutolol orally and the others placebo. Angioscintigraphy was performed before and after an 8-day treatment period. Three cases in the penbutolol group were lost due to software damage, hence the data of 17 patients were analyzed. The two groups were matched for age, sex, etiology of cirrhosis and hepatic function. The index of portal perfusion decreased significantly (-29%; p = 0.018) and the hepatic artery index increased significantly (+23%; p = 0.018), while no changes were observed after placebo. The heart rate decreased significantly after penbutolol (-9%; p = 0.028), while neither penbutolol nor placebo modified the ejection fraction. In conclusion, penbutolol decreased portal perfusion index (the compensatory increase in the hepatic artery index confirmed this change) without major modification of total hepatic blood flow or systemic hemodynamics. Angioscintigraphy is reasonably accurate, reproducible, safe and can be considered suitable for routine use in the assessment of liver hemodynamics.

Efficacy of penbutolol + piretanide combinations in the treatment of arterial hypertension.

The efficacy and tolerability of penbutolol alone and in combination with piretanide at two dose levels were investigated in a double-blind parallel group study in patients with mild to moderate essential hypertension. All three treatments were given as a single daily dose. One hundred and eight patients entered the study; 82 completed a 7-day placebo run-in period followed by 3 weeks of active therapy. Penbutolol 20 mg plus piretanide 3 mg and penbutolol 40 mg plus piretanide 6 mg both produced a significantly greater reduction in supine diastolic blood pressure (16% and 19% respectively) than penbutolol 20 mg (9%). The reduction in supine diastolic blood pressure was significant for all three treatments with respects to the baseline reading. Side-effects were generally mild and transient and were similar in type and incidence in the three groups. Six patients did not complete the trial period because of an excessive response to the hypotensive medication: five in the high dose combination group, and one in the low dose combination group. Low doses of penbutolol (20 mg) and piretanide (3 mg) used in combination and in a once-daily administration provide a simple, effective and well tolerated regimen for patients with mild to moderate hypertension.

Effect of penbutolol on circadian blood pressure, and renin, aldosterone and cortisol levels in patients with essential hypertension.

We investigated the effect of an orally administered, long-acting, beta-adrenergic blocking agent, penbutolol, on the circadian rhythm of blood pressure (BP) and heart rate (HR), and plasma renin activity (PRA), aldosterone (PA) and cortisol (PC) levels in hospital patients with essential hypertension validated by a chronobiological inferential statistic method. After a wash-out period of three weeks, a group of 8 hypertensive patients (5 women and 3 men, 27 to 41 years old) underwent automatic BP and HR monitoring, and blood sampling for 24 hours in a hospital room before and after 4 weeks of treatment with penbutolol (40-mg tablet once a day at 9 a.m.). In basal conditions, a statistically significant mean circadian rhythm was demonstrated for HR, diastolic BP, PRA, PA, and PC. Systolic and diastolic BP were lowered by penbutolol, with only a minor decrease of HR. The treatment eliminated also the mean circadian rhythm of BP and HR. Penbutolol induced both a remarkable reduction of PRA with disappearance of the related circadian rhythm and a significant decrease in PA levels with maintenance of their circadian rhythmicity. The circadian secretory patterns of PC were similar before and after therapy. In conclusion, long-term treatment with penbutolol appears not only to set BP, PRA and PA values to lower levels, but also to decrease the within-day variation of BP, HR, and PRA. In addition, penbutolol does not influence the 24 h-secretion of PC.

Double-blind comparison of prenylamine and penbutolol in patients with angina pectoris.

This study was performed to re-evaluate the clinical position of prenylamine in the management of angina pectoris. After 1 week withdrawal of all anti-anginal agents, followed by another week of placebo administration, seventeen patients were allocated at random to 6 weeks treatment with either penbutolol 40 mg once a day or prenylamine 60 mg t.i.d. Clinical examination, exercise test and anginal attack rate were recorded every 2 weeks. Both drugs reduced the anginal attack rate. None of the drugs caused a significant increase in maximal workload or a significant change in ST-segment depression. Beside a substantially lower rate-pressure product at maximal comparable workload in the penbutolol group (p less than 0.001), no significant differences were observed between the two drugs. No adverse reactions were reported. From these results one can conclude that prenylamine and penbutolol do not differ in their anti-anginal effect. Therefore we are of the opinion that prenylamine has a place in the therapeutic armamentarium for the management of angina pectoris, particularly in patients where beta-blocking agents are contraindicated or in patients who have experienced side-effects of beta-blocking or calcium-entry blocking agents.

Once-daily penbutolol or atenolol can replace combination therapy in essential hypertension.

Antihypertensive therapy was stopped in twenty-one patients with moderate hypertension. Almost all of them had been on combination therapy, usually propranolol or metoprolol with chlorthalidone, for more than a year. After a placebo 'wash-out' period of 4 weeks patients were randomly allocated in a controlled trial to a fixed daily dose of either 100 mg atenolol or 40 mg penbutolol for 6 weeks. Single-agent therapy at these doses successfully controlled the blood pressure in nineteen of the twenty-one patients, including six previously inadequately controlled on a combination. Although no conclusions can be drawn about the long-term benefits, in the patient population under study either penbutolol or atenolol given at a standard dose should provide good initial blood pressure control in most patients with mild to moderate hypertension.

[Validity of the use of penbutolol in essential arterial hypertension]. / Validità dell'uso del penbutololo nell'ipertensione arteriosa essenziale.

Thirty patients suffering from WHO I-II class slight-moderate essential arterial hypertension were treated with a beta-blocker (Penbutolol) alone and once a day to assess its antihypertensive effectiveness and its affect on heart frequency, lipid metabolism and kidney function. The drug proved highly effective in reducing P.A.S. and P.A.D. values and no negative influence was documented on lipid metabolism, kidney function or heart frequency.

[The effect of beta blockers on the QT interval: the possible role of mechanisms other than beta block]. / Effetto dei beta-bloccanti sull'intervallo QT: possibile ruolo di meccanismi diversi dal beta-blocco.

The authors evaluated QT interval changes after 7 and 14 days of treatment with 3 different betablockers--acebutolol, atenolol and penbutolol--in 3 groups of hypertensive patients. Acebutolol (400 mg u.i.d.) prolonged QTc interval in a statistically significant fashion, atenolol (100 mg u.i.d.) induced a significant and constant reduction, whereas QTc interval was shortened by penbutolol only after the first week, shifting toward pretreatment values during the second week. The physiological correlation between QT and RR was slightly modified by acebutolol and penbutolol, but markedly reduced after atenolol. Such differences might be of importance in clinical practice because are likely to be linked to different mechanisms intrinsic to each agent.

[Penbutolol and arterial hypertension]. / Penbutololo e ipertensione arteriosa.

Penbutolol has proved particularly effective and suitable for the treatment, even on a long-term basis, of recently developed hypertension, especially in its hyperkinetic forms. The drug produces minimal side effects, is well tolerated and gives an early therapeutic response. In addition penbutolol does not cause any significant alterations in the biohumoral parameters of the patients treated and is ideal for combination with dihydralazine, reserpine and dihydrochlorotiazide in the treatment of more stubborn cases, making it possible to reduce the doses of the other drugs without causing bradycardia.

Effect of oral penbutolol on renal haemodynamics of hypertensive patients with renal insufficiency.

Acute or chronic administration of most beta-adrenoreceptor blocking drugs is associated with a fall in renal blood flow and glomerular filtration rate. In patients with renal insufficiency this effect on renal function may be clinically important. Penbutolol is a non-cardioselective, pure laevo, beta-blocker with intrinsic sympathomimetic activity. Previous studies have suggested that penbutolol may increase the glomerular filtration rate. In this study eight hypertensive patients with renal insufficiency were studied during a three-week placebo period and then for four weeks while taking penbutolol in a dose of 40 or 80 mg daily. Penbutolol produced a fall in the pulse rate in all eight patients. Five of the eight patients had a fall in their supine and standing blood pressure. Effective renal plasma flow and glomerular filtration rate did not change significantly. In seven of the eight patients there was a fall in the calculated renal vascular resistance but the mean fall did not reach statistical significance. Penbutolol appears to be an effective beta-blocker and one that could be used appropriately in patients with renal insufficiency.

[The noninvasive assessment of the effects of penbutolol on liver hemodynamics in cirrhotic patients using angioscintigraphy. A randomized controlled double-blind study]. / Valutazione non-invasiva delgi effetti del penbutololo sull'emodinamica epatica nei cirrotici mediante angioscintigrafia. Studio randomizzato, controllato, in doppio cieco.

This randomized double-blind controlled study analyzed the hemodynamic effects of penbutolol, a new levo-rotatory betablocker, using radionuclide angiography. Twenty cirrhotics with esophageal varices were randomized: 10 received 40 mg/day of penbutolol orally and the others a placebo. Angioscintigraphy was performed before and after an 8-day treatment period. Three cases in the penbutolol group were lost due to software damage, hence the data of 17 patients were analyzed. The two groups were similar for age, sex, etiology of cirrhosis and hepatic function. The index of portal perfusion decreased significantly (-29%; p = 0.018), and the hepatic artery index increased significantly (+23%; p = 0.018), whereas no changes were observed after placebo. The heart rate decreased significantly after penbutolol (-9%; p = 0.021); while neither penbutolol nor placebo modified the ejection fraction. In conclusion, penbutolol decreased portal perfusion index (the compensatory increase of hepatic artery index confirmed this change) without significant modification of total hepatic blood flow and systemic hemodynamics. Angioscintigraphy is reasonably accurate, reproducible, safe and can be considered suitable for routine use in the assessment of liver hemodynamics.

Ventricular arrhythmias during exercise testing and daily activities in patients with stable angina pectoris before and during Aldisem and penbutolol treatment.

The authors investigated the prevalence of ventricular ectopic activity (VEA) during exercise testing and 24-hour ambulatory Holter monitoring and its relation with ischemic episodes during daily activities before and during therapy with diltiazem and penbutolol in 41 patients with stable and typical angina pectoris. Seven (17%) of the 41 patients had exercise-induced ventricular ectopic activity (EIVA). Premature ventricular complexes (PVC) Lown grade I disappeared in 6 patients on therapy and appeared in another 6 new patients. PVC Lown grade IV A in one patient before therapy changed to Lown grade IV B upon therapy. There was no difference between patients with and without EIVA in the ages, average number of angina onset per day, percentage patients with exercise angina, average functional class, percentage of patients with exercise ST depression, average maximal ST depression, heart rate and systolic blood pressure at peak exercise and duration of exercise. The workload before therapy was similar in the 2 groups, but was significantly greater during therapy in patients without EIVA. During 984 hours of recording, 185 ischemic episodes were detected in 25 patients before therapy, and 111 ischemic episodes in 20 patients during therapy. PVC was observed in 12 (48%) of the 25 patients and in 81 (27%) of the 295 ischemic episodes. VEA during ischemic episodes was observed in patients with and without baseline PVC. The ventricular arrhythmias found were more complex types during ischemic episodes than baseline. Thus, the incidence of VEA in patients with stable and typical angina pectoris was 17% during exercise and 52% during daily activities.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmaco -- genetic approach to the improvement of beta-adrenoblocker therapy in the treatment of hypertension]. / Farmakogeneticheskii podkhod k optimizatsii terapii gipertonicheskoi bolezni beta-adrenoblokatorami.

A relationship between individual variations of the oxidative and acetylating metabolism rates of penbutolol, propranolol, acebutolol which produce a hypotensive effect was studied in patients with arterial hypertension. A study was performed in groups of patients, which comprised 22, 22, and 20 males, respectively. They all suffered from Stage II hypertensive disease. There was a predominant number of patients with partial and complete antihypertensive benefits in those with low oxidation rates than in those with high oxidative metabolism rates when penbutolol (89 and 54%, respectively; p < 0.05) and propranolol (78 and 31%, respectively; p < 0.01) were given. A graphic analysis of changes in blood pressure, which had been observed during a course monotherapy with penbutolol and propranolol identified two groups of patients differing in having benefits. Within each group, the relationship between the decrease in diastolic blood pressure to the elimination half-life of parmidine is described by a linear regression equation and it has a high positive correlation coefficient.

[Beta-adrenergic blockers and calcium antagonists in hypertrophic cardiomyopathy]. / Beta-adrenoblokatory i antagonisti kal'tsiia pri gipertroficheskoi kardiomiopatii.

Effects of beta-blockers (propranolol, penbutolol) and calcium antagonists (nifedipine, verapamil, diltiazem) were studied in 73 patients with hypertrophic cardiomyopathy (HC). Clinical data, ECG and echo-CG findings were assessed. It was found that beta-adrenoblockers and calcium antagonists improve quality of life in one-third of the patients. Penbutolol and nifedipine did so in half of the patients. Neither beta-adrenoblockers nor calcium antagonists decrease myocardial hypertrophy. Calcium antagonists may result in lowering of myocardial contractility while beta-adrenoblockers may increase the ejection fraction. Diltiazem produced a positive effect on diastolic function but had many side effects. Nifedipine increased lethality compared with verapamil and propranolol.