[Production of anti-practolol antibodies in the rabbit after immunization with synthetic antigens combined with practolol].
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Comparative effects of acebutolol and practolol on the lipolytic response to isoprenaline.
1 The effects of beta-adrenoceptor blockade on the metabolic responses to isoprenaline have been studied in an in vitro system of isolated fat cells and in six normal subjects. 2 The inhibitory effects of varying concentrations of acebutolol, practolol and propranolol on free fatty acid (FFA) release produced by isoprenaline (10(-7) M) were compared in isolated fat cells prepared from rat epididymal adipose tissue. Acebutolol and practolol, at equimolar concentrations, showed a similar inhibitory effect whilst propranolol was approximately 100 times more potent then either drug. At 10(-5)M concentration of propranolol, lipolysis was virtually abolished whilst at the same molar concentration, acebutolol and practolol halved the response. 3 Six healthy volunteers received three successive 15 min intravenous isoprenaline challenges (0.03 mug kg-1 min-1) per individual experiment. The first acted as a control whilst the following two were given either after single oral doses of placebo, acebutolol or practolol. The mean (+/- s.e. mean) basal FFA level was 0.77 +/- 0.06 mE1/1 and subsequent resting values after the administration of placebo or beta-adrenoceptor blocker were not significantly different. 4 Acebutolol inhibited the respective mean rises in FFA, produced by both post-control isoprenaline challenges, by (mean +/- s.e. mean) 70 +/- 4% and 84% +/- 5%. The comparable figures for practolol were 33 +/- 15% and 24 +/- 20%. The higher serum concentration of acebutolol produced greater inhibition but correlation of log serum concentration of the drug with percentage inhibition of FFA rise did not achieve significance. 5 Administration of isoprenaline, acebutolol or practolol did not significantly alter serum glucose, triglyceride or cholesterol levels. 6 Acebutolol and practolol effectively blocked the isoprenaline-induced tachycardia. The degree of blockade produced by practolol was greater than its inhibitory effect on FFA release. The diatolic fall in blood pressure in response to isoprenaline was abolished by acebutolol suggesting that its beta-adrenoceptor blocking action encompasses peripheral vascular sites. The comparable effect with practolol was a partial inhibition of the diastolic fall.
Acebutolol↗
Practolol metabolism in various small animal species.
1. The metabolism of the beta-adrenergic blocking agent practolol has been studied in a variety of small animal species, using both ring- and acetyl-14C-labelled material. After oral dosing at 100 mg/kg, elimination of 14C in urine and expired air was monitored, and urinary metabolite patterns were examined by t.l.c. 2. Marmoset was unusual in extensively deacetylating practolol (c. 57% dose). Urinary elimination was low, with only 25% being recovered in 4 days; over 30% of urinary 14C was present as desacetyl practolol, whereas less than 50% was unchanged practolol. 3. Hamster was also atypical, in its extensive hydroxylation of practolol. Urine contained 60% dose; 11% of urinary radioactivity was present as 3-hydroxypractolol, much of the polar material present (48%) appeared to be a conjugate of this, and only 35% was present as practolol. 4. For the other species studied (rat, mouse, guinea-pig and rabbit, metabolism was more limited. Deacetylation was typically about 5%, but was somewhat higher in the mouse (8--14%). Urine was the major route of elimination and practolol represented 50--90% of urinary radioactivity. 5. Despite extensive toxicity studies, both in species which metabolize practolol similarly to man and in species such as the hamster and marmoset which metabolize practolol extensively, no animal model has been found for the human adverse reactions.
Animals↗
Relationship between bronchial effects and plasma practolol concentration in man.
A double-blind, balanced and randomised study in 8 healthy volunteers examined the effects of relatively high versus low single doses of practolol on heart rate and ventilation at rest and during standardised exercise. Practolol 1 and 4 mg/kg, a typically non-selective drug propranolol 0.2 mg/kg, and placebo were given intravenously at weekly intervals. Cardiac beta-adrenoceptor blockade was measured by the reduction in exercise heart rate greater than 160 beats/min, and bronchial beta-adrenoceptor blockade by the reduction in exercise peak expiratory flow rate (PEFR) up to 4 h after each treatment. Results were assessed by analysis of co-variance. All three active treatments reduced exercise heart rate markedly, practolol 4 mg/kg causing most reduction. Exercise PEFR was significantly reduced by propranolol 0.2 mg/kg compared with both practolol 1 mg/kg and placebo at all times of measurement, and by practolol 4 mg/kg compared with practolol 1 mg/kg and placebo at most times. Mean plasma concentrations after practolol 4 mg/kg were 3.5 to 4.5 times higher than after 1 mg/kg. Practolol may lose its 'cardioselectivity' and cause airflow obstruction at relatively high plasma concentrations above about 2 microgram/ml.
Adult↗
Practolol-induced autoantibodies and their relation to oculo-cutaneous complications.
Tissue auto-antibodies were investigated in fifty-one patients (twenty-five female, twenty-six male) receiving practolol for ischaemic heart disease or dysrhythmias and compared with those found in 204 patients (fifty-eight female, 146 male) with ischaemic heart disease who did not receive practolol. Antinuclear factor (ANF) was found in 24% female and 16% male patients receiving practolol, but only in 5% of female and 4% of male patients who were not taking practolol. Thyroid cytoplasmic antibody (TCA) was detected in 16% female and 20% of male patients receiving practolol, compared to 10% of females and 6% of males in the control group. The incidence of ANF and TCA was significantly higher (P less than 0-05) in patients receiving practolol compared to the control group. The occurrence of gastric parietal cell antibody (PCA) and smooth muscle antibody (SMA) was not associated with practolol therapy (odds ratio of 2-4 and 1-9 respectively). The incidence of skin and eye complications was found to be 10% and the female to male ratio of this complication was 4 : 1. The correlation between autoantibody production and oculo-cutaneous complications could not be established in such a small group but three of the patients with the complications were found to have PCA, although PCA was found not to be associated with practolol therapy. Four of the five patients with the complications did not have circulating ANF.
Adult↗
A study of practolol elimination in all grades of chronic renal failure.
Plasma and renal elimination of practolol have been studied in 12 patients with varying degrees of stable chronic renal failure and 14 normal volunteers. Each individual received 200 mg of oral practolol. The mean time to peak plasma level in the group of patients with renal failure was later than in the normal group, the difference between the two being significant. There were significant correlations between plasma practolol clearance and creatinine clearance, and also between renal practolol clearance and creatinine clearance. Total clearance of practolol from plasma was slightly higher than its renal clearance, the difference being significant, which suggested a small non-renal component to elimination. Renal practolol clearances tended to exceed creatinine clearances, the difference being significant, suggesting some renal tubular secretion of the drug. It is suggested that--in patients with chronic renal failure--the maintenance dose of practolol be reduced roughly in proportion to the reduction in creatinine clearance from normal. If effective plasma practolol concentrations are required quickly, the need for giving a loading dose becomes important under such circumstances.
Adult↗
The use of clonidine and practolol in the treatment of hypertension.
The antihypertensive effects of clonidine hydrochloride and practolol were compared in 42 men, aged 45 years, who had not received any antihypertensive therapy before, except one patient. The diastolic blood pressures were at least 110 mmHg on two successive visits to the health centre before their selection to the trial. One half of them were classified into the WHO group 1 and the other half into group 2. There was no statistical difference in the systolic and diastolic blood pressures between clonidine and practolol group at the end of placebo period. The study started with a three-week placebo period. Thereafter, 20 patients were given clonidine 0.225 mg and twenty-two practolol 200 mg daily. The next control was carried out after three weeks. The dosage was kept unchanged or increased according to the antihypertensive response. After three weeks, clonidine and practolol dosages were checked again, and 25 mg of chlorothiazide were added to the treatment in 15 clonidine cases and in 18 practolol cases. After the next three-week period, the same regimen was continued on most patients for 6-9 weeks. The daily dosage of clonidine varied from 0.225 to 0.900 (mean 0.394) mg and that of practolol from 200 to 600 (mean 382) mg. Both regimens resulted, when individually adjusted, in a mean systolic blood pressure level of less than 150 mmHg and diastolic pressures less than or equal to 100 mmHg. Hydrochlorothiazide potentiated the blood pressure effect almost equally in both regimens. The blood pressure reduction was statistically significant (p less than 0.05) both in the clonidine and practolol group. There was no significant difference of the mean blood pressures after the active drug therapy between these two groups. A moderate reduction of pulse rate was observed in both main groups, but it was not related to the antihypertensive efficacy. Side-effects were mild. Dryness of the mouth and sedation were more common in patients receiving clonidine. No oculocutaneous or other "immunological" manifestation were seen during the 15-18 weeks' practolol therapy.
Clinical Trials as Topic↗
Effects of practolol on exercise tolerance and cardiac haemodynamics and metabolism in patients with coronary artery disease.
Sixteen male patients with typical angina pectoris secondary to coronary atherosclerosis performed two daily standardized exercise tests during two consecutive days. Three hours before each exercise they received placebo or 400 mg practolol administered orally in double-blind fashion in order to complete a cross-over design. Practolol significantly prolonged the exercise duration by 30.6% and delayed the appearance time of ischaemic electrocardiographic changes by 67.7%. Maximal heart rate, systolic pressure, and pressure-rate product were also reduced after medication. In order to investigate further the effects of this beta blocking agent, myocardial function and metabolism at rest and during supine exercise were assessed in 12 male patients with coronary artery disease before and after practolol 30 mg, iv. At rest, practolol produced a decrease in tension-time index (18%), cardiac index (17%), heart rate (10%), and stroke index (7%). A significant reduction was also observed in resting stroke work index (14%) and systolic and mean aortic pressure (6%). Left ventricular end-diastolic pressure remained unchanged. During supine exercise, only time-tension index (12%), heart rate (12%), and cardiac index (10%) were significantly reduced after the beta blocking agent. Practolol did not significantly change the arterial glucose, lactate, inorganic phosphate, potassium, calcium, magnesium, pH, PCO2, or PO2. The beta blocking agent did not modify the myocardial extraction of any of these substrates at rest or during exercise. In the dosage used in both studies, practolol significantly improved the exercise tolerance and reduced the ischaemic manifestations. The efficacy of practolol in angina pectoris may result mostly from its ability to decrease heart rate and systolic pressure during exercise.
Adult↗
Comparative effects of propranolol and practolol in the early stages of experimental canine myocardial infarction.
1 The effects of propranolol and practolol, at equivalent myocardial beta-adrenoceptor blocking doses, (as assessed by the degree of shift of isoprenaline dose-response curves) were investigated in anaesthetized greyhounds before and after acute coronary artery ligation. 2 When administered intravenously to the intact close-chest dog, propranolol (0.1 mg/kg) and practolol (0.5 mg/kg) caused similar decreases in heart rate, left ventricular dP/dt max, myocardial blood flow and cardiac output. Only propranolol increased peripheral vascular resistance. 3 When administered 2-3h after acute coronary artery ligation, propranolol (0.1 mg/kg) significantly decreased blood flow in both normally perfused and ischaemic regions of the heart. There was also electrocardiographic evidence of further deterioration after propranolol; two out of seven animals died following this treatment. 4 Practolol (0.5 mg/kg) when administered after coronary artery ligation also decreased normal myocardial blood flow but flow in the ischaemic area remained unchanged. Evidence was obtained from electrocardiographic, myocardial temperature, myocardial O2 consumption and lactate measurements that the administration of practolol, in contrast to propranolol, benefited the ischaemic myocardium. 5 Analysis of the results suggests that this beneficial action of practolol may be related to at least two mechanisms. Firstly the ability of practolol to increase the period during diastole when perfusion of the subendocardium is possible, without decreasing the transventricular pressure during this period. Secondly that practolol does not unmask alpha-adrenoceptor vasoconstriction in the ischaemic region.
Animals↗
Selective beta-1 receptor blockade with oral practolol in man. A dose-related phenomenon.
The purpose of this study was to test the hypothesis that oral administration of a low dose of practolol in man produces selective beta-1 receptor blockade, whereas oral administration of a high dose blocks both beta-1 and beta-2 receptors. Normal men were studied 2-4 h after a single oral dose of practolol (1.5 or 12 mg/kg) and after placebo. Effects on beta-1 receptors were studied by measuring heart rate responses to exercise. Effects on beta-2 receptors were tested by measuring forearm vascular responses to brachial arterial infusions of isoproterenol. Neither dose of practolol altered base-line heart rate, forearm vascular resistance, and arterial pressure, Both low and high doses significantly attenuated heart rate responses to exercise. Forearm vasodilator responses to isoproterenol were attenuated by the high dose, but not the low dose, of practolol. Serum concentrations of practolol 2 h after administration of the drug and at the time of the studies of forearm vascular responses averaged 0.5+/-0.1 (SE) and 5.9+/-1.0 mug/ml for low and high doses of practolol, respectively. The results indicate that the phenomenon of selective beta-1 receptor blockade in man is related to the dose and serum concentration of practolol selectively block beta-1 receptors; a high dose and serum concentrations block both beta-1 and beta-2 receptors.
Administration, Oral↗
Differences between the effects of practolol and propranolol on the diastolic properties of the left ventricle.
To elucidate the mechanism by which left ventricular and diastolic pressure (LVEDP) is reduced by practolol, ventricular volumes, hemodynamics, and diastolic elastic stiffness were determined before and 10 min after intravenous practolol (400 mug/kg) in 12 patients. Heart rate decreased in all patients after practolol (avg., --9/min, p less than 0.02). There was an insignificant increase in stroke work index and decrease in cardiac index attributable to the fall in rate. Practolol did not change and diastolic volume or ejection fraction, but the average LVEDP fell from 21 to 15 mm Hg (p less than 0.01) which was sustained even with atrial pacing to prepractolol heart rates. Diastolic elastic stiffness was also reduced after practolol (0.665 to 0.593, p less than 0.0025). The data indicate that practolol exerts a negative chronotropic effect on the intact heart and, in contrast to other beta blockers such as propranolol, appears to decrease diastolic stiffness in the left ventricle.
Adult↗
Adverse reactions to practolol in hospitalized patients: a report from the Boston Collaborative Drug Surveillance Program.
Adverse reactions to practolol were studied in 198 prospectively monitored hospitalized medical patients. The mean age of the practolol recipients was 57 years; angina and cardiac arrhythmias were the most common indications for therapy. Adverse reactions were attributed to practolol in 20 patients (10%). Fifteen of these twenty reactions involved impairment of cardiac function (bradyarrhythmias, heart block, congestive heart failure, hypotension), and in three instances the reaction was considered life-threatening. Three additional patients had cutaneous reactions attributed to the drug. Adverse reactions to practolol were not dose-related, but toxicity appeared to be more frequent among patients concurrently receiving quinidine. The frequency of cardiovascular complications of propranolol in a similar series of patients was nearly identical. However, no skin reactions were attributed to propranolol. The findings suggest that practolol and propranolol produce unwanted cardiovascular effects with nearly equal frequency among hospitalized patients. Cutaneous reactions to practolol are evident even during short-term use.
Aged↗
The effects of practolol on the dysrhythmias complicating acute ischemic heart disease.
The cardioselective beta-adrenoceptor blocking agent practolol was used in the management of ventricular and supraventricular dysrhythmias associated with acute myocardial infarction in 134 patients, and in the management of these dysrhythmias in 19 atients with acute myocardial ischemia. Practolol was frequently effective in controlling ventricular dysrhythmias which occurred within the first 24 hours after the onset of symptoms of acute myocardial infarction. It was also effective in controlling the ventricular dysrhythmias which occurred after resuscitation from ventricular fibrillation. It was of particular value when therapeutic doses of lidocaine had been ineffective. Practolol was much less effective in controlling ventricular dysrhythmias which occurred more than 24 hours after acute infarction. Atrial fibrillation and atrial flutter were infrequently abolished by practolol in undigitalized patients after acute myocardial infarction. There was no correlation between the effectiveness of practolol and the blood concentration of the drug. One adverse effect of practolol was the occurence of sinus bradycardia with or without an increase in the frequency of ventricular ectopic beats. Bradycardia was sometimes accompanied by hypotension. Severe hypotension occasionally occurred in the absence of bradycardia.
Aged↗
Renal effects of propranolol, practolol and butoxamine in pentobarbital-anesthetized rats.
The renal effects of the beta-adrenergic blockers, propranolol, practolol and butoxamine, were examined in pentobarbital-anesthetized rats. All the beta-blockers, infused i.v., increased urine volume (V), urinary sodium excretion (UNaV) and p-aminohippuric acid clearance without change in inulin clearance. Indomethacin, an inhibitor of prostaglandin biosynthesis, did not affect the renal effects of these beta-blockers. Phentolamine abolished the renal effects of practolol, but not those of propranolol and butoxamine. Haloperidol abolished the renal effects of propranolol and butoxamine, but not those of practolol. A high correlation was found between the increased UNaV and the increased urinary phosphate excretion by butoxamine but not by propranolol and practolol. Therefore, it is suggested that alpha-adrenergic stimulation is involved in the mechanism of diuresis by practolol, a beta1-blocker, and that dopaminergic stimulation is involved in the diuresis caused by butoxamine, a beta2-blocker. Propranolol is similar to butoxamine, and partially similar to practolol.
Animals↗
A comparison of the beta-blocking activities of practolol, sotalol, and propranolol in human and guinea pig tracheal smooth muscle.
Beta adrenergic blockade was studied in vitro with human tracheal muscle strips and guinea pig tracheal chains. It was shown in isolated smooth muscle from both man and guinea pig that the order of potency for the three beta-blocking agents studied was: propranolol greater than sotalol greater than practolol. Under the conditions of this study, propranolol was about 30,000 times and sotalol about 30 times as potent as practolol. The order of potency suggests that the nature of adrenergic blockade induced by practolol on tracheal smooth muscle is only weakly beta2-relative to the blocking effects of propranolol and sotalol. Beta adrenergic blockade by propranolol, sotalol, and practolol produced different degrees of increased histamine lethality in mice. Whereas both propranolol at 0.01 mg/kg and sotalol at 1.0 mg/kg resulted in 100% histamine-induced lethality, practolol at 50 mg/kg resulted in only 50% histamine-induced lethality. These data, when added to those from our previous studies, suggest that the mechanisms responsible for resistance to the effects of histamine in untreated mice are at least partially mediated by the beta2-adrenergic system. Thus, in three different tissues, the blocking activity of practolol was shown to be less than that of sotalol or propranolol.
Animals↗
Plasma levels and beta-adrenoceptor blockade with acebutolol, practolol and propranolol in man.
1 The degree of beta-adrenoceptor blockade of isoprenaline-induced tachycardia has been determined in three healthy volunteers after the administration of single oral doses of acebutolol, practolol or propranolol. 2 Plasma levels of these drugs were determined either colorimetrically (acebutolol and practolol) or fluorimetrically (propranolol). The colorimetric assay of acebutolol in plasma is fully described but the other drugs were assayed by published methods. 3 The degree of beta-adrenoceptor blockade and the plasma level for acebutolol and practolol were well correlated, whereas in the case of propranolol correlation was poor, due in part to the presence in plasma of active metabolites not detected by the fluorimetric assay. The plasma levels of practolol and propranolol are in agreement with those previously reported. 4 The maximum cardiac beta-adrenoceptor blockade achieved in this study with the respective single oral doses of acebutolol (300 mg), practolol (400 mg) or propranolol (40 mg) were similar in each of the three subjects. Therefore the beta-adrenoceptor blocking potencies of these drugs against isoprenaline-induced tachycardia are inversely related to these doses; indicating that propranolol is 7-8 times more potent than acebutolol and the latter slightly more potent than practolol.
Acebutolol↗
Comparative trial of propranolol and practolol in hyperthyroidism.
The possible role of practolol in the management of hyperthyroidism has been studied by comparing it with propranolol. 2. In a double-blind cross-over trial, propranolol (40 mg), practolol (120 mg) and a placebo four times daily for one week were compared in twenty-one hyperthyroid patients by sequential analysis. 3. Judged by their effect on the symptoms and signs of thyrotoxicosis, both propranolol and practolol were significantly better than the placebo but no clear distinction could be made between the two active compounds. 4. Propranolol and practolol reduced heart rate by 24 and 17% respectively compared with placebo. 5. Patients generally preferred propranolol or practolol to placebo but this preference did not achieve significance with either drug. 6. Only in its effect on heart rate was practolol significantly inferior to propranolol, and it would appear to be a useful alternative to propranolol in the management of the peripheral manifestations of hyperthyroidism.
Clinical Trials as Topic↗
Comparison of the actions of acebutolol, practolol and propranolol on calcium transport by heart microsomes and mitochondria.
1 The effects of acebutolol, practolol and propranolol (0,5-3 mM) on calcium uptake, calcium binding and ATPase activities of the rabbit and rat heart microsomal and mitochondrial fractions were investigated. 2 Dose-response and time course experiments revealed that propranolol greatly inhibited microsomal and mitochondrial calcium uptake whereas both acebutolol and practolol showed slight depressant effects. 3 The ATPase activities of microsomal and mitochondrial fractions were decreased by acebutolol, practolol and propranolol; however, the latter agent was more effective than the other two. 4 The inhibitory effects of acebutolol, practolol and propranolol on mitochondria and microsomes were not antagonized by adrenaline. 5 Propranolol decreased calcium binding by the microsomal fraction only, whereas acebutolol and practolol had no effect on microsomal or mitochondrial calcium binding. 6 The sensitivity of the rabbit heart subcellular fractions to the beta-adrenoceptor blocking drugs was similar to that of the rat heart; however, the calcium uptake and ATPase activities of microsomes were more sensitive to propranolol than mitochondria in both species. 7 Perfusion of rat hearts with 0.2-1 mM propranolol decreased contractile force, and microsomal and mitochondrial fractions obtained from these hearts accummulated less calcium in comparison to the control. On the other hand, acebutolol and practolol (0.2-1nM) had no appreciable effects on contractile force or subcellular fractions under similar conditions. 8 The negative inotropic effect of propranolol may partly be due to its inhibitory actions on calcium transport by subcellular organelles of the myocardium; the depressant action of propranolol on calcium transport is unlikely to be due to its beta-adrenoceptor blocking property.
Acebutolol↗