European Journal of Clinical Pharmacology

Brubakk, A.; Bathen, J.

doi: 10.1007/BF00609868pmid: 436922

228 15 15 2 2 A. O. Brubakk J. Bathen Section of Cardiology, Department of Medicine Regional Hospital Trondheim Norway Summary The acute haemodynamic effects of injected diazoxide (Hyperstat ® Schering) have been studied in 8 hypertensive subjects. Aortic blood pressure was measured and cardiac output and peripheral conductance were assessed continuously using a simulation model. In six of the patients pulmonary artery end-diastolic pressure was also measured. Blood pressure fell in all subjects 5–10 min after injection of the drug cardiac output increased in all patients studied. However, the initial change in cardiac output differed, as it decreased in two subjects and did not change in one. The largest initial increases in cardiac output were seen in the subjects with the highest pulmonary artery end-diastolic pressure. Patients with an initial decrease in cardiac output were those with the least compliant (stiffest) aortas. We consider that the responsiveness of the baroreceptors determines the size of the increase in cardiac output immediately after reduction of blood pressure by diazoxide. Thus in a patient with a stiff aorta, particularly at low cardiac filling pressure, diazoxide might cause a fall in blood pressure to an unacceptable level.

Gaillard, J.; Kafi, Sarah

doi: 10.1007/BF00609869pmid: 220059

228 15 15 2 2 J. M. Gaillard Sarah Kafi Clinique Psychiatrique de l'Université de Genève Bel-Air Switzerland Summary In an attempt to clarify the roles of pre-and postsynaptic catecholaminergic (CA) receptors in the regulation of paradoxical sleep (PS) in man, the effects of various doses of chlorpromazine (CPZ) and clonidine (CLN) have been investigated. The action of CPZ was biphasic, small doses enhancing and larger doses depressing the production of PS. However, the effect of CLN was monophasic, showing no modification after small doses, and a decrease in production of PS after moderate doses. In addition, a small dose of CLN, ineffective by itself, completely abolished the effect of a small dose of CPZ. These observations can be explained by preferential blockade of presynaptic alpha-receptors by a small dose of CPZ. They show, too, that it is possible to investigate in man the functional consequences of pharmacological manipulation of pre-synaptic receptors on cerebral CA neurons.

Oh, V.; Taylor, Elizabeth; Wadsworth, Jane; Turner, P.

doi: 10.1007/BF00609870pmid: 436923

228 15 15 2 2 V. M. S. Oh Elizabeth A. Taylor Jane Wadsworth P. Turner Department of Clinical Pharmacology St. Bartholomew's Hospital West Smithfield EC1A 7BE London England Computing Unit for Medical Sciences St. Bartholomew's Hospital West Smithfield EC1A 7BE London England Summary A double-blind, balanced and randomised study in 8 healthy volunteers examined the effects of relatively high versus low single doses of practolol on heart rate and ventilation at rest and during standardised exercise. Practolol 1 and 4 mg/kg, a typically non-selective drug propranolol 0.2 mg/kg, and placebo were given intravenously at weekly intervals. Cardiac beta-adrenoceptor blockade was measured by the reduction in exercise heart rate >160 beats/min, and bronchial beta-adrenoceptor blockade by the reduction in exercise peak expiratory flow rate (PEFR) up to 4 h after each treatment. Results were assessed by analysis of co-variance. All three active treatments reduced exercise heart rate markedly, practolol 4 mg/kg causing most reduction. Exercise PEFR was significantly reduced by propranolol 0.2 mg/kg compared with both practolol 1 mg/kg and placebo at all times of measurement, and by practolol 4 mg/kg compared with practolol 1 mg/kg and placebo at most times. Mean plasma concentrations after practolol 4 mg/kg were 3.5 to 4.5 times higher than after 1 mg/kg. Practolol may lose its ‘cardioselectivity’ and cause airflow obstruction at relatively high plasma concentrations above about 2 µg/ml.

Quarterman, C.; Kendall, M.; Welling, P.

doi: 10.1007/BF00609871pmid: 436924

228 15 15 2 2 C. P. Quarterman M. J. Kendall P. G. Welling Department of Therapeutics and Clinical Pharmacology The Medical School B15 2TJ Birmingham UK Summary Plasma levels and associated reduction in exercise-induced tachycardia have been examined following the administration of single doses of metoprolol in conventional and slow-release tablets at different times to six healthy male subjects. The study was carried out in two parts. Initially, the tablets were given at 9 a. m. and the subjects were studied up to 14 h and then at 24 h. Subsequently, the same doses were given at 9 p. m. and the subjects were studied 12–24 h after drug administration (i. e. 9 a. m.–9 p. m. the next day). After giving the slow-release tablets the peak plasma levels were significantly lower but the drug persisted in the plasma at higher levels than after the conventional tablet. However, the beta-blocking effect was comparable from the two dosages. The results obtained for the period 12–24 h after the evening dose differed from the corresponding values after morning administration in that the plasma levels were higher and the betablocking effects more marked. Furthermore, the half-life values calculated from these data were significantly longer.

Brørs, O.; Jacobsen, S.; Arnesen, E.

doi: 10.1007/BF00609872pmid: 436918

228 15 15 2 2 O. Brørs S. Jacobsen E. Arnesen Institute of Pharmacology University of Oslo Oslo Norway Medical Department 7 Ullevål Hospital Oslo Norway Summary The pharmacokinetics of a new “high ceiling” diuretic, muzolimine (Bay g 2821), were investigated after a single oral dose of 40 mg in 7 patients with cardiac failure (Stages I–IV, New York Heart Association classification), and in 2 healthy subjects. Plasma concentrations peaked 1–3 h after administration and declined according to a two-compartment model. The α-phase (distribution phase) lasted until 12–16 h after administration and the mean t 1/2α was 3.6 h (range 2.3–4.7) in patients, and 2.6 h (range 2.3–2.9) in healthy subjects. The mean t 1/2β was 13.5 h (range 7.4–22.4) in the patients and 14.0 h (range 12.4–14.6) in healthy subjects. T 1/2β was not correlated with the degree of heart failure or with the area beneath the plasma concentration curve, which varied three-fold. The renal clearance of muzolimine was in the range 2.7–15.3 ml · min −1 in 5 subjects in whom it was investigated. The pharmacokinetics of muzolimine appear not to be significantly altered by cardiac failure. The prolonged half-lives of the drug are probably responsible for the longer duration of diuretic action reported for muzolimine than for furosemide and bumetamide.

Heinz, N.; Rietbrock, N.

doi: 10.1007/BF00609873pmid: 436919

228 15 15 2 2 N. Heinz N. Rietbrock Pharmaforschung Beiersdorf AG, Hamburg and Zentrum für Pharmakologie/Klinische Pharmakologie Frankfurt/Main Federal Republic of Germany Summary The correlation between the daily dose of digoxin, its plasma level and clinical characteristics of 213 patients receiving β-acetyldigoxin treatment has been evaluated. After logarithmic transformation of lognormally distributed variables multiple linear regression analysis was performed. Eight predictor variables were chosen: sex, age, height, weight, glycoside dose, creatinine and potassium level in serum and dose of spironolactone. The resulting correlation coefficient was 0.46, i. e. only 100×r 2 =21.4% of the variance of the steady state digoxin plasma level could be interpreted with the aid of these variables. For only 4 of the 8 variables (age, glycoside dose, serum level of creatinine, and spironolactone dose) were partial coefficients of regression and of correlation significantly different from zero. Almost 80% of the variance could not be accounted for. This finding is in accordance with conclusions in the literature.

Ohnhaus, E.; Vozeh, S.; Nuesch, E.

doi: 10.1007/BF00609874pmid: 374088

228 15 15 2 2 E. E. Ohnhaus S. Vozeh E. Nuesch Department of Medicine University of Berne Berne Switzerland Summary The absorption of digoxin has been investigated in 8 patients before and after successful treatment of severe right heart failure. 3 H-digoxin 0.1 mg as a solution, and un-labelled digoxin 0.25 mg as a tablet, were given to fasted patients. Blood samples were taken at various time intervals up to 120 hours and urine was collected over the same period. The concentrations of labelled digoxin in plasma and urine were measured in a liquid scintillation counter, unlabelled digoxin was estimated by radioimmunoassay, and various pharmacokinetic parameters were calculated. There was no significant difference in the plasma concentration curves in severe right heart failure and after its successful treatment, nor did any of the calculated pharmacokinetic parameters change significantly. Therefore, inhibition of the absorption of digoxin appears unlikely. In an additional study to estimate absolute bioavailability two different groups of patients in severe right heart failure were given 3 H-digoxin 0.1 mg or unlabelled digoxin 0.25 mg i. v. and the pharmacokinetic parameters were compared with those from the previous study. The bioavailability of the 3 H-digoxin solution and of the digoxin tablet were in the same range as values previously published for healthy volunteers, and patients both with and without cardiac failure.

Hengstmann, J.; Falkner, F.

doi: 10.1007/BF00609875pmid: 374089

228 15 15 2 2 J. H. Hengstmann F. C. Falkner Department of Internal Medicine University of Bonn Germany Division of Clinical Pharmacology Vanderbilt University Medical School Nashville Tennessee USA Drug Metabolism Pfizer, Inc. Groton Conneticut USA Summary The plasma level and urinary excretion rate of guanethidine have been measured in 30 patients during oral maintenance therapy, and in 5 patients following discontinuation of therapy. A significant correlation was found between the daily average urinary excretion and the maintenance dose, although wide interindividual variation was noted among patients maintained on the same dose. A statistically significant correlation was also observed between the area under the plasma level curve during the dose interval and the oral maintenance dose. After discontinuation of chronic therapy, the half-life of 1.5 days of the initial phase of elimination was essentially in agreement with the half-life of almost 2 days determined in acute studies. In addition, a second phase of elimination with a half-life of 4 to 8 days was observed.

Gómez, J.; Erill, S.

doi: 10.1007/BF00609876pmid: 436920

228 15 15 2 2 J. Gómez S. Erill Hospital de la Santa Cruz y San Pablo, and Universidad Autónoma de Barcelona Barcelona Spain Department of Internal Medicine Ciudad Sanitaria “Virgen de la Arrixaca” Murcia Spain Department of Pharmacology University of Bilbao Medical School Lejona Spain Summary A survey among hospital staff physicians was conducted in order to evaluate their attitudes towards systemic antimicrobial agents. Direct questions about the value of different agents and choice within pairs of antimicrobial drugs, stating the reasons for the preference, were included in the questionnaire used. Gentamicin, penicillin G and ampicillin were the most popular antibiotics among respondents. On the other hand, ampicillin, penicillin G, sulfonamides, tetracycline and aminoglycosides were the agents perceived as most often associated with side-effects. Low toxicity, bactericidal effect, diffusion in the body and familiarity with the drug were acknowledged as the most important attributes in choice of a systemic antimicrobial agent, but a broad spectrum of antibacterial activity appeared as a major determinant in the choice of these drugs when physicians were asked to select one substance from members of several pairs listed. The results suggest that certain important misconceptions may have played a substantial role in the prescribing habits of the physicians surveyed.

Driessen, O.; Sorgedrager, N.; Michel, M.; Kerrebijn, K.; Hermans, J.

doi: 10.1007/BF00609877pmid: 436921

228 15 15 2 2 O. M. J. Driessen N. Sorgedrager M. F. Michel K. F. Kerrebijn J. Hermans Department of Pharmacology University of Leiden The Netherlands Department of Pediatrics Erasmus University Rotterdam The Netherlands Department of Medical Microbiology Erasmus University Rotterdam The Netherlands Department of Medical Statistics University of Leiden The Netherlands Summary The variability and predictability of the plasma concentration of ampicillin and kanamycin in new-born infants being treated for infections are discussed. For kanamycin a standard dose regimen of 7.5 mg/kg/12 h is recommended.