European Journal of Clinical Pharmacology

Karlsson, E.; Kinman, A.; Sonnhag, C.

doi: 10.1007/BF00561779pmid: 832652

228 11 11 1 1 E. Karlsson A. Kinman C. Sonnhag Division of Cardiology, Department of Internal Medicine and Department of Clinical Physiology University of Linköping Linköping Sweden Summary Ten patients with a persistent ventricular arrhythmia, but no other sign of heart disease, were studied by means of an exercise test performed 4 times with a fixed work load, over 30–40 min. No drug was given in the first exercise test and in the others phenytoin, procainamide or practolol were chosen at random for i. v. administration. Blood samples for determination of plasma concentration were frequently collected. The ECG was recorded continuously during the exercise test and was analysed minute by minute. Despite plasma levels within the suggested therapeutic range, only procainamide showed a statistically significant antiarrhythmic effect in this group of patients.

Pfister, B.; Imhof, P.

doi: 10.1007/BF00561780pmid: 832661

228 11 11 1 1 B. Pfister P. R. Imhof Research Department, Pharmaceuticals Division Ciba-Geigy Limited Basle Switzerland Summary In eight healthy volunteers pretreatment with phentolamine 40 mg p o inhibited platelet aggregation (1st and 2nd phases) induced by low concentrations of adrenaline (2, 1 and 0.5 µM) in plasma from blood sampled 30 min after administration of the compound. The lower the concentration of adrenaline used, the greater was the degree of inhibition elicited. These results are indicative of competitive inhibition of the action of adrenaline on the platelet membrane by phentolamine. Four to six hours after administration of the compound, the aggregation characteristics had reverted to normal. It is concluded that the increased tendency toward platelet aggregation associated with elevated blood levels of catecholamines can be prevented by therapeutic doses of phentolamine.

Boye, N.; Vale, J.

doi: 10.1007/BF00561781pmid: 319006

228 11 11 1 1 N. P. Boye J. R. Vale University Department of Lung Diseases, Rikshospitalet Oslo Norway Summary The bronchial effect of intravenous atenolol (ICI 66.082) has been studied in a doubleblind cross over trial in 10 patients with pronounced, labile bronchial asthma. A single i. v. dose of atenolol 3 mg, sufficient to cause a fall in heart rate and systolic blood pressure at rest, induced only a slight and clinically almost negligible impairment of ventilatory function. An ordinary therapeutic dose of salbutamol by inhalation far outweighed the bronchial effect of atenolol. The drug appears promising with regard to its cardio-selective properties.

Erle, G.; Basso, M.; Federspil, G.; Sicolo, N.; Scandellari, C.

doi: 10.1007/BF00561782pmid: 832653

228 11 11 1 1 G. Erle M. Basso G. Federspil N. Sicolo C. Scandellari Divisione di Malattie Metaboliche Ospedale Civile Vicenza Italy Istituto di Semeiotica Medica Università di Padova Padova Italy Summary In three groups of normal subjects and in one group of patients with latent diabetes mellitus a study has been made of the effects of chlorpromazine (CPZ) on blood glucose and plasma insulin. CPZ 75 mg/day for 7 days did not alter the plasma insulin response after oral glucose; nor did CPZ 50 mg/day for 7 days affect the glucose assimilation rate or insulin response to glucose injection. Infusion of CPZ 50 mg in 60 min slightly increased the basal blood glucose level but had no significant effect on basal plasma insulin. The insulin/glucose ratio after the end of the infusion was significantly higher than during the period of infusion of the drug. In latent diabetic patients CPZ infusion significantly diminished the insulin/glucose ratio during an intravenous glucose tolerance test. These results suggest that, whereas prolonged treatment with low doses of CPZ did not modify glucose tolerance and glucose-stimulated pancreatic response, higher acute doses of the drug may induce hyperglycaemia and can inhibit insulin secretion both in normal man and in patients with latent diabetes mellitus.

Balant, L.; Zahnd, G.; Weber, F.; Fabre, J.

doi: 10.1007/BF00561783pmid: 401739

228 11 11 1 1 L. Balant G. R. Zahnd F. Weber J. Fabre Policlinique de Médecine et Division de Diabétologie Clinique, Département de Médecine Université de Genève Genève Switzerland Summary Six maturity onset diabetic patients took glibenclamide 5 mg by mouth, every morning 10 min before a standard breakfast. Serum levels of immunoreactive glibenclamide, glucose and immunoreactive insulin were measured repeatedly on the first and 15th days of treatment. Measured glibenclamide blood levels were in close agreement with an analogue computer simulation of data obtained from healthy volunteers: there was no accumulation of drug in the blood, but there was strong evidence for the existence of a slowly equilibrating “deep” compartment. Considerable insulin release and correction of the breakfast-induced hyperglycaemia were observed immediately after administration of the drug, as well as 5 h later, at lunch time. The clinical significance of blood levels of glibenclamide, as well as the correlation of pharmacokinetics with pharmacodynamics, are discussed in the light of these results.

Belpaire, F.; Bogaert, M.; Mussche, M.

doi: 10.1007/BF00561784pmid: 832654

228 11 11 1 1 F. M. Belpaire M. G. Bogaert M. M. Mussche Heymans Institute of Pharmacology and Department of Nephrology University of Ghent, Medical School Ghent Belgium Summary Serum protein binding of phenylbutazone has been measured in the rat, guinea pig, cat, rabbit and dog, and the influence on it of renal failure induced by uranyl nitrate injection has been studied. In all species a clearcut decrease in binding was observed after the occurrence of renal failure; the time course of the fall in binding correlated well with development of renal failure. In further experiments, serum protein binding of two acidic drugs (phenylbutazone, warfarin), two basic drugs (papaverine, quinidine) and one neutral drug (digitoxin) was studied in rabbits with experimental renal failure, and the results compared with those obtained in patients with acute renal failure. In the rabbits, a decrease in the binding of phenylbutazone, warfarin, papaverine and quinidine was found, whereas protein binding of digitoxin was unchanged. In man, there was a definite fall in protein binding of phenylbutazone and digitoxin, a small decrease for warfarin and papaverine, and a slight increase for quinidine.

Talseth, T.; Landmark, K.

doi: 10.1007/BF00561785pmid: 832655

228 11 11 1 1 T. Talseth K. H. Landmark Medical Department B, Rikshospitalet University Hospital Oslo Norway Summary After oral administration of sulphadimidine (mean dose 3.33 g) to 21 volunteers it was possible to distinguish fast and slow acetylators by calculating the acetylated fraction (%acSDD) in a single serum sample obtained at any time between 1/2–24 h. There was a close correlation between %acSDD in serum and in urine collected from 0–8 h. Two groups of patients with chronic renal failure were studied. Four of the first 8 patients studied would have been designated as slow acetylators from their low %acSDD in 0–8 h urine, but as fast acetylators from their %acSDD in serum 6 h after drug administration. The next 18 patients were given a smaller dose of SDD (2 g) and they showed complete intra-individual correlation between %acSDD in 0–24 h urine and in a serum sample obtained at 24 h. The patients could be divided into 2 sub-groups on the basis of %acSDD in serum and urine, thus demonstrating the ability of this procedure to distinguish fast and slow acetylators, even in advanced chronic renal failure.

Ehrnebo, M.; Odar-Cederlöf, I.

doi: 10.1007/BF00561786pmid: 832656

228 11 11 1 1 M. Ehrnebo I. Odar-Cederlöf Karolinska Pharmacy, Department of Medicine and Department of Clinical Pharmacology Karolinska Hospital Stockholm Sweden Summary The binding of pentobarbital, diphenylhydantoin and salicylic acid to cells in blood was found to be independent of total drug concentration within therapeutic levels. Salicylic acid displaced pentobarbital and diphenylhydantoin from plasma protein binding sites, but high levels of salicylic acid had no effect on the distribution of the other two drugs to washed blood cells. Thus, in whole blood the presence of salicylic acid decreased the fraction of pentobarbital or diphenylhydantoin bound to plasma protiens and increased the fraction of the drug in plasma water and in blood cells. Diphenylhydantoin was shown not to be bound irreversibly to blood cells and equilibration in between the inside and outside of the cells was found to be rapid (within 5 min), even at high concentrations. Binding to washed blood cells was the same at 37°C and 25°C, in contrast to plasma protein binding. It is pointed out that these effects may cause certain analytical errors, resulting in changes in plasma concentration if plasma is separated at a low temperature.

Ackermann, E.; Richter, K.

doi: 10.1007/BF00561787pmid: 832657

228 11 11 1 1 E. Ackermann K. Richter Institute for Clinical Pharmacology “Carl Gustav Carus” Dresden German Democratic Republic Zentralinstitut für Krebsforschung Akademie der Wissenschaften der DDR Lindenberger Weg 80 DDR-1115 Berlin German Democratic Republic Summary Diazepam was metabolized by human foetal liver microsomes to N-desmethyldiazepam and N-methyloxazepam as early as the 13th week of gestation. The metabolic activity was lower than that of microsomes from adult human liver. Diazepam was shown mainly to be hydroxylated to N-methyloxazepam at substrate concentrations higher than 0.1 mM. Diazepam levels above 1.0 mM were inhibitory to the overall metabolic reaction. SKF 525-A inhibited diazepam metabolism by foetal liver microsomes at a concentration of 0.1 mM. The addition of diazepam to foetal and adult human liver microsomes resulted in a type II spectral change. Its inhibition by carbon monoxide indicated that biotransformation of diazepam was performed by the cytochrome P-450-linked mono-oxygenase system.

Moody, J.; Whyte, S.; MacDonald, A.; Naylor, G.

doi: 10.1007/BF00561788pmid: 832658

228 11 11 1 1 J. P. Moody S. F. Whyte A. J. MacDonald G. J. Naylor Biochemistry Department Royal Dundee Liff Hospital Dundee Scotland Summary Plasma levels of protriptyline have been determined in 30 depressed female patients undergoing antidepressant therapy. After 3 1/2 weeks treatment at dosage levels of 40 mg/day, protriptyline plasma levels ranged from 430 to 1430 nmol/l. During this period only two-thirds of the subjects had definitely achieved asymptotic concentrations. Single dose studies in 5 volunteers suggest that the volume of distribution of protriptyline shows little intersubject variation. The half life of the drug, however, may vary appreciably from subject to subject, ranging from 54 to 198 h. The effects of two sedatives on mean protriptyline plasma levels have been determined. Mean plasma levels for nitrazepam recipients are indistinguishable from those for patients receiving no night sedation. The mean plasma levels for a group of patients receiving sodium amylobarbitone were significantly reduced. The problem of choice and early adjustment of dosages in order to achieve satisfactory plasma levels is discussed. For practical purposes it is suggested that early values may be of predictive significance in allowing early dosage adjustments to be made.