European Journal of Clinical Pharmacology

Hansson, B.; Hökfelt, B.

doi: 10.1007/BF00558323pmid: N/A

228 10 10 3 4 B. -G. Hansson B. Hökfelt Dept. of Internal Medicine and Endocrinology General Hospital Malmö Sweden Summary Studies in seven patients with moderate hypertension were done to explore the effect of the non-selective beta-receptor blocking agent penbutolol on blood glucose and plasma insulin levels under fasting conditions, and following a glucose load. Oral penbutolol 20–30 mg, twice daily for 3–8 months, produced no change in fasting levels of blood glucose and plasma insulin, or in the blood glucose response following an oral or iv glucose load. The initial insulin response to intravenous glucose was similar before and during penbutolol treatment. The total integrated insulin response following iv glucose increased slightly during treatment when measured from insulin zero level, but was unaltered when calculated from the initial basal insulin level. Following oral glucose the total integrated insulin response was not affected by treatment with penbutolol.

Thiringer, G.; Svedmyr, N.

doi: 10.1007/BF00558324pmid: N/A

228 10 10 3 4 G. Thiringer N. Svedmyr Clinical Pharmacology Laboratory University Lung Clinic, Renströmska Hospital Göteborg Sweden Summary In a single-blind study eight patients with asthma received on five different days, in randomized order, doses of: propranolol 40 mg, metoprolol 50 mg and 100 mg (a new selective beta 1 -blocking agent with no intrinsic activity), practolol 200 mg or placebo. The beta 1 -blocking potency of the selective drugs at these dose levels was higher than or equal to that of propranolol. The effects on heart rate, blood pressure, ventilatory capacity (FEV 1 ) and skeletal muscle tremor were studied at rest and during infusion of increasing doses of isoprenaline. There was a slight decrease in FEV 1 after propranolol and both doses of metoprolol. After the placebo, isoprenaline produced a dose-dependent increase in heart rate, systolic blood pressure, FEV 1 and tremor, and lowered the diastolic blood pressure. Propranolol almost completely blocked the effects of all doses of isoprenaline on heart rate, FEV 1 and tremor, and, to a lesser extent, any change in systolic and diastolic pressure. The two doses of metoprolol and practolol did not inhibit the effect of isoprenaline on FEV 1 . The effect of metoprolol and practolol on the isoprenaline-induced increase of heart rate indicated their selectivity for beta 1 -receptors. The increase in tremor during infusion of isoprenaline was blocked by propranolol, but not by the selective beta 1 -blockers, which implies that the induction of tremor was a beta 2 -effect. The effect of isoprenaline on FEV 1 was not inhibited by selective beta 1 -blocking agents, and so, when combined with beta 2 -stimulators, they may be given to asthmatic patients.

Lorier, J.; Elias, G.

doi: 10.1007/BF00558325pmid: N/A

228 10 10 3 4 J. Le Lorier G. Elias Department de pharmacologie Faculté de Médecine Université de Montréal Montreal Canada Department de médecine, Faculté de Médecine Université de Montréal Montreal Canada Summary A clinical trial of 7 months duration was carried out on 18 patients with angina pectoris. The study was divided in 4 stages: A 4-week single blind stage on placebo, a six-week single blind, dose finding stage divided in 3 periods of 2 weeks each during which the patients received daily doses of 400, 800 and 1,200 mg of practolol respectively. Physician evaluation based on anginal episodes counts, nitroglycerin consumption and exercise stress testing at the end of each dose period were used to select the optimal dose for each patient. Subsequently and after a 2-week single-blind stage on placebo (wash-out) the patients moved to a fourth stage where the optimal dose of practolol was tested against placebo using a double-blind double cross-over design consisting of 4 periods of 4 weeks each. The patients received practolol during two of these periods and placebo during the other two. No difference between practolol and placebo was seen in the frequency of anginal episodes, the nitroglycerin consumption, the blood pressure level and the exercise performance. A significant difference was observed in the resting heart rate and the exercise heart rate. Thus, although the doses used produced beta-blockade they did not lead to objectively demonstrable antianginal effects.

Berglund, G.; Andersson, O.

doi: 10.1007/BF00558326pmid: N/A

228 10 10 3 4 G. Berglund O. Andersson Medical Department I, Sahlgrenska Hospital University of Göteborg Göteborg Sweden Summary The antihypertensive activity and side effects of three doses of hydrochlorothiazide combined with a potassium supplement (Esidrex ® -K novum, Ciba) were determined in 40 hypertensive subjects in a double-blind, cross-over study. The lowest daily dose (12.5 mg) gave almost the same blood pressure reduction as the doses in common use (25 mg and 50 mg) and as the adrenergic beta-blocking agents previously employed. Metabolic side effects in the form of decreased serum potassium and increased fasting blood sugar and serum uric acid were observed in patients on the lower dose and, with the exception of serum uric acid, were only slightly more pronounced with the higher doses. The frequency of subjective side effects, on the other hand, increased with increasing dose. No changes were noted in total body potassium at any dose level. It is suggested that hydrochlorothiazide in low dose, alone or in combination with other antihypertensive agents, is a useful therapeutic regimen in mild hypertension.

Talseth, T.

doi: 10.1007/BF00558327pmid: N/A

228 10 10 3 4 T. Talseth Medical Department B, Rikshospitalet University Hospital Oslo Norway Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline ® ), the serum half-life (T1/2) and bioavailability (AUC 0−∞ ) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC 0−∞ was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml −1 , compared to 0.66±0.12 µg·hour·ml −1 in the fast acetylators (p<0.025). Treatment with Apresoline ® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml −1 and 33.4±4.2 ng·ml −1 in 8 slow and 5 fast acetylators, respectively (p<0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml −1 and 147.6±15.0 ng·ml −1 in slow and fast acetylators, respectively (p<0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.

Davidson, C.; Thadani, U.; Taylor, S.; Hess, H.; Riess, W.

doi: 10.1007/BF00558328pmid: N/A

228 10 10 3 4 C. Davidson U. Thadani S. H. Taylor H. Hess W. Riess University Departments of Medicine and Cardiovascular Studies, The General Infirmary Leeds England Research Department, Pharmaceuticals Division Ciba-Geigy Ltd. Basle Switzerland Summary 1.) Circulatory effects of standard commercial and two slow-release preparations of oxprenolol, each containing 80 mg were compared with placebo in a double-blind randomized cross-over study in six normal subjects. 2.) After both slow-release preparations, the concentration of oxprenolol in blood was significantly less at one hour but significantly greater at 4, 8 and 12 hours than after the standard preparation. Variability of blood oxprenolol concentration between individuals was similar after all three formulations. 3.) Blood oxprenolol concentration was linearly related to the suppression of isoprenaline tachycardia and logarithmically related to the reduction in maximum exercise heart rate. 4.) The reduced maximum, but more sustained, blood oxprenolol concentration after the slow release preparations had no significant effect on the reduction of exercise tachycardia at one hour but significantly extended the duration of its activity compared with the commercial preparation. 5.) These results indicate that the pharmacological activity of beta-adrenoceptor antagonists with a relatively short duration of action may be usefully extended by slow-release formulation.

Planz, G.; Planz, R.; Rahn, K.

doi: 10.1007/BF00558329pmid: N/A

228 10 10 3 4 G. Planz R. Planz K. H. Rahn Abteilung Innere Medizin II der Rheinisch-Westfälischen Technischen Hochschule Aachen Germany Summary In order to study the function of dopamine-β-hydroxylase (DBH) in human plasma, dopamine, its natural substrate, was infused intravenously in 22 healthy volunteers. Their plasma DBH activities showed great interindividual variations (31–301 units/ml). The infusion rates of dopamine required to increase systolic blood pressure (BP) by 30 mm Hg differed considerably between the subjects, and ranged from 3,0 to 11,6 µg/kg/min. No correlation could be shown between the various dopamine doses and individual plasma levels of DBH. It was concluded, therefore, that plasma DBH in the blood stream was enzymatically inactive. Experiments with human plasma DBH in vitro also support this interpretation. Consequently, interindividual differences in the effects on BP during dopamine infusion cannot be due to pressor effects of noradrenaline synthesized by plasma DBH.

Vastag, E.; Nagy, L.; Miskovits, G.

doi: 10.1007/BF00558330pmid: N/A

228 10 10 3 4 E. Vastag L. Nagy G. Miskovits Department of Chest Diseases Semmelweis University Medical School Budapest Hungary Summary Anticholinergic agents have proved to be powerful bronchodilating drugs in various types of chronic obstructive pulmonary disease. Atropine given as an aerosol had a stronger bronchodilating effect, even in low doses not producing side-effects, than after peroral or intramuscular administration. Sch 1000, a new quater-nized atropine derivative had a stronger and more prolonged bronchodilator effect, even in significantly lower doses, and no side effects were observed. Because of its adventageous characteristics, Sch 1000 seems to be the anticholinergic agent to be preferred in clinical practice. It shows a wider therapeutic range than the beta adrenergic agent orciprenaline. A vagus-mediated reflex mechanism may be involved in histamine-induced bronchoconstriction. Experimental results show that a cholinergic mechanism and increased parasympathetic tone are important factors in the pathological mechanism of chronic airways obstruction.

Husted, S.; Andreasen, F.; Foged, L.

doi: 10.1007/BF00558331pmid: N/A

228 10 10 3 4 S. Husted F. Andreasen L. Foged Institute of Pharmacology University of Aarhus Aarhus Denmark Summary Abnormal sensitivity to phenprocoumon in a castrated male who was receiving substitution therapy with methyltestosterone, has been studied and compared with pharmacokinetic data obtained from six control subjects, all of whom had cardiac disorders. The concentration-effect relationship for phenprocoumon in the castrated patient was evaluated by the mathematical model described by Nagashima et al. (1969). The possible mechanisms involved in sensitization by methyltestosterone of the response to phenprocoumon are discussed. It is suggested that methyltestosterone increases the affinity of the receptor sites in the liver for phenprocoumon, an effect which has previously been attributed to other C17-alkyl-substituted androgens.

Hepsö, H.; Lökken, P.; Björnson, J.; Godal, H.

doi: 10.1007/BF00558332pmid: N/A

228 10 10 3 4 H. U. Hepsö P. Lökken J. Björnson H. C. Godal Department of Oral Surgery and Oral Medicine, Institute of Pharmacology University of Oslo Oslo Norway Haematological Research Laboratory Ullevål Hospital Oslo Norway Summary Acetylsalicylic acid (ASA) was tested against placebo in a double-blind crossover study, in which essentially the same operation was performed twice on 23 healthy patients who required surgical removal of bilateral “identically” impacted wisdom teeth. On the evening before one operation they received ASA 1.0 g (Globentyl ® ) followed by ASA 2.0 g daily for the next 3 days, and at the other operation placebo tablets. A number of objective and subjective parameters were recorded for paired comparison of the pre-, per-, and post-operative courses, including bleeding, pain, wound-healing, and preference. Tests of platelet aggregation before each operation indicated whether or not ASA had been taken. Pre-operative bleeding time was significantly increased (from 4.4 to 6.9 min) by ASA, as well as the per-operative blood loss (about 30%), and the post-operative bleeding tendency. Episodes of profuse post-operative haemorrhage were reported by 5 patients, always after the operation for which ASA had been given. ASA also significantly promoted the occurrence of ecchymosis and haematoma. The pre-operative bleeding time was not a reliable predictor for these complications. The drug was very well tolerated with respect to side effects such as abdominal discomfort. The post-operative pain scores were neither reduced nor increased significantly by ASA, and the preference scores were not in favour of the drug. The present patients were all young and denied any previous bleeding disorders; nevertheless, ASA resulted in post-operative haemorrhage, ecchymosis and haematoma formation in several cases.