Studies with a slow-release formulation of propranolol in angina.
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Biomedical subjects
Publications and source records attributed to R G Shanks.
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1. The effects of 160 mg of propranolol and 160 mg of a long-acting (LA) formulation of propranolol were studied in healthy subjects. 2. Both drugs reduced an exercise tachycardia but the peak was less and the 24 h effect greater after long-acting propranolol than after propranolol. 3. These differences were maintained on repeated dosing for 8 days. 4. In contrast to single doses of 400 mg of sotalol, 160 mg of oxprenolol and 160 mg of slow-release oxprenolol, the peak effect of long-acting propranolol was less and that at 24 h was greater.
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In vivo and in vitro techniques have been used to study the effect of catecholamines on gastrin release. The i.v. infusion of epinephrine in dogs produced a significant rise in plasma gastrin concentration. This response was prevented by the administration of propranolol to block beta-adrenergic receptors. The infusion of isoproterenol, a beta-adrenergic agonist, produced a significant rise in gastrin levels, while phenylephrine, an alpha-adrenergic agonist, had no effect. In in vitro studies using isolated pieces of rat antrum, isoproterenol stimulated acute phase release of gastrin, whereas phenylephrine was again without effect. The studies indicate that catecholamines directly influence G cell function.
1. Mexiletine was given to 156 patients by intravenous or oral routes of administration. 2. There was great interpatient variation in kinetics and plasma concentrations with both routes of administration. 3. The mean volume of distribution was 6.63 l/kg. The mean plasma elimination haf-life after chronic oral therapy was 11.31 h. 4. Plasma concentrations between 0.75 and 2.00 microgram/ml were usually effective. Within this therapeutic range severe side effects were uncommon. 5. Plasma concentrations within this range were achieved in 72% of patients when doses of 10--14 mg-1 kg-1 day were given orally.
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Dose-response curves for propranolol and oxprenolol were studied in healthy volunteers, with a standardized excercise test and percentage reduction in excercise heart rate (EHR) as the index of drug effect. The dose-response curves obtained were compared with similar curves previously reported for sotalol, practolol, and atenolol with identical experimental methods. Two distinct types of response were identified: in the first, shown by propranolol and sotalol, increasing doses of the beta adrenoceptor-blocking drug continued to produce increasing effects to the limits of the dose levels examined; with the second (oxprenolol and practolol), increasing the dose initially resulted in substantial increase in effect but subsequently larger doses produced almost no increase in effect. Consideration of the additional properties of these beta adrenoceptor-blocking drugs revealed that both practolol and oxprenolol have intrinsic sympathomimetric activity (ISA), whereas propranolol and sotalol do not. In addition, practolol is cardioselective. Further investigation of the possible influence of ISA or cardioselectivity on beta adrenoceptor-blocking activity was undertaken by studying the effects of combinations of drugs on EHR. Sotalol produced greater effect when given 2 hr after sotalol, oxprenolol, practolol, or atenolol. When oxprenolol was given after sotalol or oxprenolol, or practolol was given after sotalol or practolol, there was no further increase in percentage reduction in EHR. When atenolol was given, the combinations of sotalol and atenolol together with two doses either of sotalol or atenolol all induced increases and similar final percentage reductions in EHR. Thus atenolol induces effects like those of sotalol, which are quite different from those of oxprenolol or practolol. The presence or absence of ISA would appear to be the important difference between these two groups of drugs: ISA would, therefore, appear to be demonstrated in man by flattening of the dose-response curves with exercise.
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The minimum current required to cause ventricular fibrillation was determined by electrical stimulation of the normal or ischemic canine left ventricle. The threshold for ventricular fibrillation in the normal heart decreased when the heart rate was rapid. Strong vagal stimulation did not affect the ventricular fibrillation threshold when the heart rate was fixed. The fall in the ventricular fibrillation threshold in the presence of acute myocardial ischemia was greater and more prolonged when the heart rate was rapid. These findings indicate the importance of the immediate correction of tachycardia in patients suffering from acute myocardial infarction.
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