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doi: 10.1111/j.1365-2125.1981.tb01119.xpmid: 7213519
1 The influence of spironolactone 25, 50, 100 and 200 mg daily, and placebo, on plasma potassium and other variables was examined in a random crossover study of 15 hypertensive patients taking bendrofluazide 10 mg daily. 2 Spironolactone produced significant dose‐ related increases in plasma potassium and aldosterone, and reductions in plasma sodium and bicarbonate. 3 In 14 compliant patients plasma concentrations of the major metabolite canrenone were related linearly to the dose of spironolactone, and there was less than twofold variation between patients. The plasma canrenone concentration correlated negatively with body weight (r = −0.77, P less than 0.001). 4 The plasma potassium response to spironolactone varied sevenfold between compliant patients. The response correlated negatively with placebo plasma potassium (r = −0.62, P less than 0.02), positively with plasma canrenone (r = +0.55, P less than 0.05), but was unrelated to plasma aldosterone (r = −0.22). In one patient relative resistance to spironolactone was attributed to exaggerated secondary hyperaldosteronism induced by the drug. 5 The variability in response to spironolactone between patients is such that fixed dose thiazide‐ spironolactone combination tablets are unlikely to prevent hypokalaemia reliably.
Kay, DC; Pickworth, WB; Neider, GL
doi: 10.1111/j.1365-2125.1981.tb01120.xpmid: 7213520
1 This study was performed because dose‐related effects of heroin on human sleep had not been described previously, and to discover if heroin produces a morphine‐like insomnia. 2 After three adaptation nights, the sleep of seven male nondependent opiate addicts was studied following i.m. doses of heroin (3, 6, 12 mg/70 kg), morphine (10, 20 mg/70 kg) or placebo at weekly intervals in a randomized double‐blind crossover design. 3 Heroin produces a dose‐related increase in wakefulness, drowsiness episodes, muscle tension, and shifts in sleep‐ waking states. 4 Heroin produces a dose‐related decrease in total sleep, sleep efficiency, delta sleep and REM sleep (REMS). 5 Heroin is about twice as potent as morphine in producing this type of insomnia. 6 'Morphine insomnia' appears to be a characteristic initial effect of several opioids, at least in nondependent opiate addicts, and might serve as a model insomnia for evaluation of hypnotics.
Balnave, K; Neill, JD; Russell, CJ; Harron, DW; Leahey, WJ; Wilson, R; Shanks, RG
doi: 10.1111/j.1365-2125.1981.tb01121.xpmid: 6111331
1 Observations were made in five subjects who exercised before and at 2, 3, 6, 8, 24, 33 and 48 h after the oral administration of placebo and 5, 10, 20 and 40 mg betaxolol. 2 The exercise heart rate remained constant at all times after the placebo. All doses of betaxolol significantly reduced the exercise tachycardia at all times. The maximum effect (34.4 +/− 2.2%) occurred after 40 mg. 3 There was a small decline in effect from the peak to 24 h when 40 mg produced a 23.3 +/− 2.7% reduction and a further decline to 48 h when there was a 14.6 +/− 1.8% reduction. 4 Plasma levels of betaxolol were measured in these studies. The peak plasma concentration occurred between 3 and 8 h with different doses. The plasma elimination half‐lives after 10, 20 and 40 mg were 11.4 +/− 2.5, 15.9 +/− 4.9 and 15.1 +/− 3.1 h. 5 The effects of 40 mg betaxolol, 200 mg atenolol, 160 mg propranolol, 160 mg oxprenolol, 400 mg sotalol and placebo on an exercise tachycardia were compared in five subjects who received all treatments in random order. 6 There was no significant difference in the maximum reduction produced in an exercise tachycardia by the different drugs. 7 The effect of all drugs decreased with time. The effect of oxprenolol had worn off at 24 h but at 48 h only atenolol and betaxolol produced significant reductions in the exercise tachycardia. 8 Plasma concentrations of the different drugs were measured and plasma elimination half‐lives determined. The half‐life for betaxolol was 24.5 h which was longer than that for any of the other drugs. 9 These observations show that betaxolol is a potent beta‐adrenoceptor antagonist with a long duration of effect on an exercise tachycardia and a long plasma elimination half‐ life.
Schenck‐Gustafsson, K; Dahlqvist, R
doi: 10.1111/j.1365-2125.1981.tb01122.xpmid: 7213521
1 This study was designed to evaluate pharmacokinetically the digoxin‐ quinidine interaction in patients with atrial fibrillation. 2 Five patients on maintenance digoxin therapy were given [3H]‐digoxin as a single i.v. dose before and during quinidine therapy and the elimination of [3H]‐digoxin from plasma and excretion in urine were determined. 3 The mean steady state plasma concentration of digoxin increased from 0.7 to 1.3 nmol/l after quinidine administration. 4 The apparent volume of distribution of digoxin decreased on the average 38%. Renal clearance and the total body clearance of digoxin decreased 51 and 56% respectively (mean values). Also non renal clearance was reduced. The fraction of digoxin excreted unmetabolised in urine did not change during quinidine treatment. The mean elimination half life of digoxin increased from 49 to 72 h during quinidine. 5 In two patients the DC‐shock did not cause a conversion to sinus rhythm. However, the quinidine induced changes in the pharmacokinetics of digoxin in these patients did not differ from the others. 6 Quinidine appears to decrease the amount of digoxin distributed to body tissue(s). In addition, the reduction of renal clearance of digoxin and the observed unchanged clearance of creatinine suggests an inhibition of the renal secretion of digoxin.
Holford, NH; Coates, PE; Guentert, TW; Riegelman, S; Sheiner, LB
doi: 10.1111/j.1365-2125.1981.tb01123.xpmid: 7213522
1 A combined pharmacokinetic and pharmacodynamic model has been used to analyze the relationship between electrocardiographic (ECG) and systolic time intervals (STI) and changes in plasma concentration of quinidine after oral and i.v. doses in ten normal subjects. 2 The major effects of quinidine were on cardiac repolarization. Contrary to previous descriptions, we found no important change in the U wave, but the T wave was split into two peaks. The amplitude of these two peaks (T and T') was reduced, and the QT' peak and QT intervals were prolonged. The QT peak interval and systolic intervals did not change appreciably. There were small increases in the PQ and QRS intervals. 3 The effect of quinidine on the QT interval could be explained by a linear pharmacodynamic model. The equilibration between plasma and effect site had a half‐time of 8 min. The slope of the pharmacodynamic model was 20.3 ms . mg 1(‐1) after i.v. dosing and 33.5 ms . mg 1(‐1) after oral dosing. 4 The difference in effect model slopes suggests pharmacologically active metabolites of quinidine are formed during absorption from the gut. 5 The total effect of a single oral dose of quinidine appears to be the same as the same dose given intravenously, even though only 70% of the oral dose reaches the systemic circulation as quinidine.
doi: 10.1111/j.1365-2125.1981.tb01124.xpmid: 7011349
1 The following four treatments were administered by constant intravenous infusion of four healthy volunteers in a balanced randomized study: 1) saline (30 min), salbutamol (0.15 micrograms kg‐1 min‐1 for 30 min) (sS), 2) saline, aminophylline (0.2 mg kg‐1 min‐1 for 30 min) (sA), 3) salbutamol, salbutamol (SS) and 4) aminophylline, salbutamol (AS). 2 Heart rate was recorded and venous blood taken for estimation of insulin, glucose, potassium and theophylline before and during the infusions (10, 20, 30, 40, 50 and 60 min). 3 The mean, peak heart rate increases from control, baseline values were 23.0 (sS), 3.5 (sA), 28.5 (SS) and 28.0 (AS) beats/min, the mean, peak insulin increases, 34.0 (sS), 0.5 (sA), 39.0 (SS) and 57.5 (AS) microU ml‐1, the mean, peak glucose increases, 1.4 (sS), 0.1 (sA), 2.6 (SS) and 2.0 (AS) mmol 1(‐1) and the mean, peak potassium changes, −0.45 (sS), 0.58 (sA), −0.78 (SS) and −0.68 (AS) mmol 1(‐1). 4 The mean, peak serum theophylline levels were 48.1 mumol 1(‐1) at 60 min in sA and 52.6 mumol 1(‐1) at 50 min in AS (39.1 mumol 1(‐1) at 30 min). 5 Salbutamol stimulated significant insulin release and produced hypokalaemia and glycogenolysis, whereas aminophylline induced no metabolic effect. 6 A comparison of sS and AS indicated a trend for aminophylline to potentiate the metabolic effects of salbutamol.
Barclay, J; Whiting, B; Meredith, PA; Addis, GJ
doi: 10.1111/j.1365-2125.1981.tb01125.xpmid: 7213523
1 The effect of inhaled salbutamol following a maximally effective dose of theophylline given by intravenous infusion was determined in 12 patients with chronic bronchitis. 2 An initial single intravenous dose study was performed to estimate each patient's theophylline kinetics and to identify those patients who would respond to theophylline. 3 Pulmonary function was assessed at hourly intervals during four to five incremental steady state theophylline infusions over the concentration range 5‐25 mg/l. 4 Inhaled salbutamol (400 micrograms) was administered after the maximum effect from theophylline had been achieved or when theophylline concentrations reached 25 mg/l without maximum effect: pulmonary function was again assessed. 5 Ten patients achieved a further significant improvement in pulmonary function after salbutamol: in five, predicted values for FVC were exceeded. 6 Patients with chronic bronchitis may benefit from the combination of theophylline and salbutamol if steady state theophylline concentrations of 15‐20 mg/l are achieved.
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