Interaction of diphenylhydantoin (DPH) and tolbutamide in man

Summary The influence of tolbutamide administration on the plasma concentrations of diphenylhydantoin (DPH) was investigated in seventeen long-stay patients with epilepsy. Tolbutamide, 0.5 g 2-3x daily, considerably increased the proportion of non-protein-bound DPH in plasma (mean: 44.6% of control values). The increase was transient, unlike the decrease found in total plasma DPH-concentration (approx. 10% of control values).In vitro experiments confirmed that the interaction between DPH and tolbutamide was due to displacement of DPH from plasma proteins. Some factors that limit the capacity to metabolise DPH in the liver are discussed; they may increase the risk of DPH-intoxication in patients who take sulphonylureas.     

Dynamics of beta-adrenoceptor blockade with cetamolol.

Cetamolol is a new beta-adrenoceptor blocking agent shown in animals to have moderate beta 1-adrenoceptor selectivity and partial agonist activity. In healthy normal volunteers, beta 1-adrenoceptor blockade was measured as the reduction of exercise-induced tachycardia, systolic blood pressure, and double product at 2, 8, and 24 h after a single oral dose of 10, 25, and 50 mg cetamolol. beta 1-adrenoceptor blockade was significantly linearly related to log serum cetamolol level, was maximal at 2 h, and was still clinically significant at 24 h. A crossover study of single 0, 10, and 25 mg doses confirmed these findings.     

Plasma level studies on different brands of sodium diphenylhydantoin (DPH) and primidone.

Comparative plasma level studies on different brands of sodium diphenylhydantoin (DPH) and primidone are described. Steady state plasma levels of both drugs were measured in epileptic patients who were chronically maintained on this medication. Simultaneous measurements of phenobarbital, primidone and diphenylhydantoin were carried out by gas chromatography. Drug product equivalence and clinical significance of plasma levels of DPH and primidone are discussed.     

Failure of indomethacin to modify beta-adrenoceptor blockade

Pretreatment of volunteers with indomethacin for 1 week did not influence the effect of a single dose of metoprolol on exercise-induced tachycardia.     

Persistent beta-adrenoceptor blockade with alkylating pindolol (BIM) in guinea-pig left atria and trachea

The actions of alkylating pindolol (N8-bromoacetyl-N1-3'-(4-indolyloxy)-2'-hydroxypropyl[z]-1,8- diamino-p-menthane; BIM) have been examined on beta-adrenoceptors in guinea-pig left atria and trachea. In organ bath experiments, addition of BIM (greater than or equal to 0.1 microM), followed by washout, produced concentration-dependent rightward shifts of the dose-response curve to cumulative additions of (-)-isoprenaline and oxymethylene-isoprenaline and reductions in the maximal response. The "apparent" pA2 value for BIM was 9.23 +/- 0.20 (slope = 0.98 +/- 0.20). Changes in the maximal density of beta-adrenoceptor binding sites were determined in guinea-pig left atrial membranes using [125I]-cyanopindolol. BIM (0.1, 1.0 and 10 microM) produced 14, 23 and 41% reductions in Bmax with no change in KD. The binding of [125I]-BIM to guinea-pig left atrial membranes had a high non-specific binding component and a pseudo-Hill coefficient less than unity. The "apparent" KD value of [125I]-BIM at beta-adrenoceptor binding sites was 85.7 +/- 57.9 pM.     

Effects of selective beta-adrenoceptor blockade on anxiety associated with flight phobia

The present study is aimed at studying the effects of selective beta-adrenoceptor blockade on anxiety in subjects with flight phobia. Using an incomplete block design subjects received a beta-1 (atenolol 2 x 50 mg), a beta-2 (ICI 118 551 3 x 50 mg) selective blocking drug, or placebo on three occasions over a 16 h period under double-blind conditions prior to a 1/2 h flight. The same procedure was repeated 4 weeks later. Thirty-four subjects completed this double-blind, two-period crossover study. Self-reporting by the Alderley Park State Anxiety Questionnaire, Global Flight Anxiety and Treatment Preference showed a moderate but significant effect of atenolol in alleviating especially somatic symptoms of flight anxiety in addition to an overall effect in the treatment of this entity (p<0.01). ICI 118 551 was ineffective in alleviating any of the important symptoms of flight phobia. These results may imply that the effect of beta-adrenoceptor blockade in reducing phobic anxiety may be more a result of beta-1 than of beta-2 blockade. Beta-1 adrenoceptor blockade may be an alternative treatment of flight phobia, particularly when the symptoms are of somatic character and when intellectual performance is expected shortly after the flight.     

Clinical use of beta-adrenoceptor blockade in systemic hypertension

beta-Blockers are effective in reducing the blood pressure of many patients with systemic hypertension. They differ in terms of the presence or absence of intrinsic sympathomimetic activity, membrane-stabilising activity, beta 1-selectivity, alpha-blocking properties, and relative potency and duration of action. All beta-blockers appear to have blood pressure lowering effects. The choice of which beta-blocker to use in an individual patient is determined by the pharmacodynamic and pharmacokinetic differences between the drugs in conjunction with the patient's other medical condition(s). This review discusses the practical use of beta-blockers and provides rational suggestions for which drug(s) to use in selected patient groups (Black, elderly, postinfarction, diabetes, renal disease, obstructive lung disease, elevated lipid levels, coexisting angina, and left ventricular hypertrophy).     

Effects of beta-adrenoceptor blockade on components of human decision-making

Rationale Converging evidence from studies with neurological patients and brain imaging studies with healthy volunteers suggests that the capacity to make choices between actions associated with probabilistic rewards and punishments depends upon a network of cortico-limbic systems including the orbitofrontal cortex, cingulate cortex, amygdala and striatum. The involvement of such structures highlights the emotional aspects of decision-making and suggests that decision-making may be sensitive to manipulations of the catecholamine systems that innervate these structures. In this study, we investigated the possible role of noradrenaline (NA).Objective We examined the effects of a single oral 80 mg dose of the beta-adrenoceptor blocker, propranolol, on the decision-making of healthy volunteers in a double-blind, placebo-controlled, between-subjects design.Methods Seventeen volunteers ingested a placebo while 15 volunteers ingested propranolol. Visual analogue scales, and self-reported positive and negative ratings, were used to assess subjective changes and mood. Vital signs were also monitored. Seventy-five minutes after treatment, volunteers were asked to make a series of choices between two simultaneously presented gambles, differing in the magnitude of possible gains (i.e. reward), the magnitude of possible losses (i.e. punishment), and the probabilities with which these outcomes were delivered. Volunteers also chose between gambles probing identified non-cognitive biases in human decision-making, namely, risk-aversion when choosing between gains and risk-seeking when choosing between losses.Results Propranolol treatment did not result in gross changes in subjective state or mood in comparison to placebo, but did slow heart rate significantly. Propranolol produced a selective change in volunteers decision-making; namely, it significantly reduced the discrimination between large and small possible losses when the probability of winning was relatively low and the probability of losing was high.Conclusions These results suggest that NA modulates the processing of punishment signals when choosing between probabilistic rewards and punishments under conditions of increased arousal.     

Quantitative assessment of bronchial beta-adrenoceptor blockade in man.

1. We describe a method for assessing bronchial beta-adrenoceptor blockade quantitatively in man. Specific airway conductance is measured after increasing doses of inhaled salbutamol and the extent to which the dose-response curve is displaced to the right after beta-adrenoceptor blocking drugs is used to assess bronchial beta-adrenoceptor blockade. 2. Salbutamol dose-response curves were plotted for six normal subjects by measuring sGaw 15 min after increasing doses of inhaled salbutamol. Salbutamol produced a 30-70% increase in sGaw. 3. Salbutamol dose response curves were obtained 2 h after oral practolol (100 mg and 200 mg) and oral propranolol (40 mg and 80 mg) on separate days and were displaced to the right. 4. The mean dose ratios for practolol 100 mg and 200 mg were 1.2 and 2.1 and for propranolol 40 mg and 80 mg they were 21 and 61 respectively.     

Plasma noradrenaline concentration in essential hypertension during long-term beta-adrenoceptor blockade with oxprenolol.

1. Chronic beta-adrenoceptor blockade with oxprenolol causes elevation of plasma noradrenaline levels, as compared with placebo, despite a significant fall in blood pressure and pulse rate. 2. The plasma noradrenaline concentration is not influenced by the frequency of administration or the formulation of the drug. 3. Plasma noradrenaline levels are not correlated with the plasma concentration of the drug. 4. The changes in plasma noradrenaline concentrations support a peripheral rather than central mechanism of action of beta-adrenoceptor blockers in man.     

Absence of excess peripheral muscle fatigue during beta-adrenoceptor blockade.

1. In eight normal volunteers, the adductor pollicis (AP) was fatigued using intermittent trains of programmed, supramaximal stimulation at 1, 10, 20, 50, 100 and 1 Hz. Activity protocols were performed both with and without circulatory occlusion, both without and during propranolol 80 mg thrice daily in order to investigate the effects of beta-adrenoceptor blockade on 'peripheral' fatigue mechanisms. 2. The degree of beta-adrenoceptor blockade was assessed by the reduction of exercise tachycardia during cycle ergometry, e.g. pulse rates at 210 watts were reduced from 190 +/- 15 to 127 +/- 5 beats min-1 (mean +/- 1 s.d.) indicating that beta-adrenoceptor blockade was substantial and highly significant (P less than 0.001). 3. Before, during and following fatiguing activity with circulatory occlusion force declines were identical during and without beta-adrenoceptor blockade. During and following activity without occlusion, there were slight declines in force which were questionably significantly different at 20 Hz (P less than 0.05). 4. The compound muscle action potential (CMAP) amplitude, measured from the skin surface over the muscle, was unaltered by beta-adrenoceptor blockade before, during or after activity whether with or without circulatory occlusion. 5. The maximal relaxation rate (MRR) was not significantly reduced in previously unfatigued muscle during beta-adrenoceptor blockade. During activity, both with and without circulatory occlusion, there was no evidence that MRR was reduced significantly more during beta-adrenoceptor blockade. 6. The absence of a convincing effect of beta-adrenoceptor blockade on peripheral fatigue mechanisms may indicate that central mechanisms are involved or that impairments of peripheral force production, of a specific nature or as a result of exacerbation of limitations of circulatory oxygen transport, though small are detected during voluntary exercise and give rise to increases in motor unit recruitment and/or firing rates, and hence increased perception of fatigue.     

The effect of acute beta-adrenoceptor blockade on examination performance.

Simple tests of verbal reasoning and mental arithmetic, taken under mildly stressful conditions, have been shown to give a reproducible test of intellectual function within groups of normal subjects. Using these tests, in two separate examinations, a double-blind cross-over study was performed on 35 medical students to assess the effects of acute beta-adrenoceptor blockade with propranolol on intellectual function. With placebo treatment, students recorded an average total score of 231.3 marks, with average scores of 108.9 marks on the mental arithmetic paper and 122.4 marks on the verbal reasoning paper. Treatment with propranolol was associated with an improvement in total score of 9.2 +/- 3.9 marks (P less than 0.05), an improvement in mental arithmetic score of 5.6 +/- 2.3 marks (P less than 0.05) and an improvement in verbal reasoning score of 3.6 +/- 2.4 marks (NS). Eighteen out of the 35 students said that they were mildly anxious before one examination and 13 students said they were anxious before both examinations. Those students who admitted anxiety seemed to benefit the most, in terms of improved examination performance, from treatment with propranolol.     

Adaptational responses to prolonged beta-adrenoceptor blockade in adult rabbits.

1 A method for measuring propranolol concentrations in plasma has been modified to permit estimations to be made on small volumes. The method has been used to correlate blockade of heart rate increases in response to intravenous isoprenaline, in both young and adult rabbits, with plasma concentrations of propranolol after subcutaneous injections of 2 or 4 mg/kg. It has been found that the relation between beta-adrenoceptor blockade and plasma concentrations is the same in rabbits as that determined by previous workers in man. 2 Adult Dutch dwarf rabbits were treated for 9 weeks twice daily subcutaneously with 2 mg/kg propranolol, or 10 mg/kg practolol, or with saline. 3 The treatment caused no change in heart weight in relation to body weight or in the water content of the hearts, in contrast to effects previously observed in young rabbits. 4 As in the young rabbits, treatment did cause a prolongation of action potential duration, as measured with intracellular electrodes in hearts of animals killed 24 h after the last dose of drug. 5 In another series of experiments, with a similar regime of treatment for 6 weeks, a significant reduction of diastolic blood pressure was observed in the propranolol group. 6 During the course of treatment and at the end, there was no change in the heart-rate increases observed in response to intravenous isoprenaline administered not less than 15 h after the previous dose of beta-blockers. Thus no functional alteration in sensitivity ot beta-adrenoceptor stimulation was apparent.     

Irreversible beta-adrenoceptor blockade of atrial rate and tension responses.

The competitive reversible beta-adrenoceptor antagonist activity of Ro 03-5255 [1-(5-acetylaminobenzfuran-2-yl)-2-isopropylaminoethanol] upon isoprenaline-induced increases of the rate and tension of guinea-pig isolated atria is described. The chlorinated derivative [Ro 03-7894; 1-[5-chloracetylaminobenzfuran-2-yl)-2-isopropyl-aminoethanol] in contrast exhibited concentration-dependent non-competitive irreversible blocking activity as measured by depression of the maximum responses which were not restored by a washout period that successfully reversed Ro 03-5255. When orciprenaline was used as a weak agonist of low efficacy, the maximum responses were depressed to a greater extent. The blockade by Ro 03-7894 was relatively specific for beta-adrenoceptors since it did not antagonize histamine or calcium chloride. The depression of the maximum responses to orciprenaline was reduced by the presence of sodium thiosulphate. Sodium thiosulphate was ineffective in reversing an established blockade. The blockade by Ro 03-7894 was therefore assumed to involve irreversible binding to the beta-adrenoceptor after conversion to an appropriate electrophilic ligand. The significance of this is discussed.     

Acute effects of combined vasodilation and beta-adrenoceptor blockade with prizidilol on renal function.

1 The effects of a single oral dose of 600 mg of prizidilol on renal function were studied 5 to 6 h after dosing in six normal subjects and eight patients with essential hypertension. 2 Mean arterial blood pressure was reduced to 92% of the control value in normal subjects and to 75% in hypertensive patients. Heart rate increased slightly. 3 In normal subjects, effective renal plasma flow was increased to 107% of control values while glomerular filtration rate (83%), filtration fraction (79%), sodium (84%) and potassium (50%) clearances were significantly decreased. 4 In hypertensive subjects, effective renal plasma flow was increased to 120% of control values, while glomerular filtration rate (67%), filtration fraction (57%), sodium (27%) and potassium (72%) clearances were significantly decreased. 5 Plasma noradrenaline increased significantly in normal subjects (150%) and in patients (173%). Plasma renin activity, aldosterone and epinephrine levels did not change consistently. 6 The results indicate that the acute effects of prizidilol on blood pressure and renal function are more marked in hypertensive than in normotensive subjects. Prizidilol increases renal plasma flow like hydralazine and depresses glomerular filtration rate and fractional sodium excretion like endralazine. In addition to the fall in arterial pressure, efferent vasodilation and/or a specific effect on the glomerular ultrafiltration coefficient Kf may account for the striking decrease in filtration fraction.     

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.