European Journal of Clinical Pharmacology

Leonetti, G.; Mazzola, C.; Boni, S.; Guffanti, E.; Meani, A.; Zanchetti, A.

doi: 10.1007/BF00608208pmid: 3533561

228 30 30 6 6 G. Leonetti C. Mazzola S. Boni E. Guffanti A. Meani A. Zanchetti Istituto di Clinica Medica Generale e Terapia Medica Università di Milano Milano Italy INRCA, Casatenovo Brianza Como Italy Ospedale Civile, Cassano d'Adda Milano Italy Summary The hypertensive effect of urapidil, a new antihypertensive agent that acts via central and peripheral alpha-adrenoceptors, has been compared with that of metoprolol in 40 patients with mild essential hypertension. Blood pressure was significantly reduced by both drugs, while the heart rate was reduced only after metoprolol. The increases in systolic blood pressure and heart rate caused by three progressive work loads of bicycle exercise were not affected during urapidil, whereas both were reduced by metoprolol. A slight reduction in forced expiratory volume was observed in some patients during treatment with the beta-blocker. There was no case of orthostatic hypotension during urapidil administration, despite its alpha 1 -blocking action. Side-effects were rare and negligible with both drugs.

Krusell, L.; Christensen, C.; Pedersen, O.

doi: 10.1007/BF00608209pmid: 2876898

228 30 30 6 6 L. R. Krusell C. K. Christensen O. Lederballe Pedersen Department of Internal Medicine I, Aarhus Amtssygehus Aarhus Denmark Second University Clinic of Internal Medicine, Kommunehospitalet Aarhus Denmark Summary The acute and chronic effects of pinacidil on blood pressure (BP) and renal function were investigated in 10 patients with moderate arterial hypertension insufficiently controlled by chronic beta-blockade. Acute i. v. administration of pinacidil caused a significant fall in BP of 29.9/18.3 mm Hg and, despite beta-blockade, a concomitant rise in heart rate (HR) of 21%. Renal vascular resistance (RVR) showed a marked reduction as a consequence of the fall in BP, and a transient rise in renal plasma flow (RPF). Diuresis and renal clearance of sodium and uric acid showed a parallel fall. The excretion rates of albumin and β 2 -microglobulin were also significantly reduced. Pharmacokinetic studies indicated that glomerular filtration was responsible for elimination of the parent drug, and that proximal tubular secretion was the pathway of excretion of the main metabolite, pinacidil pyridine-N-oxide. During therapy for 4 months there was no further significant reduction in BP, despite increases in the daily dose of pinacidil. The effects on HR were less conspicious after 4 months; renal haemodynamic parameters and body weight were not significantly changed. The initial level of RVR and the initial acute reduction in this parameter appeared to be major determinants of the long-term BP response. The drug was well tolerated apart from one patient who developed slight fluid retention. However, concomitant administration of a diuretic will probably be necessary during routine use of this therapeutic combination.

Johnston, G.; Finch, M.; Shanks, R.

doi: 10.1007/BF00608210pmid: 3533562

228 30 30 6 6 G. D. Johnston M. B. Finch R. G. Shanks Department of Therapeutics and Pharmacology The Queen's University of Belfast Belfast Northern Ireland the Belfast City Hospital Belfast Northern Ireland Summary In a double-blind, single oral dose, crossover study, the effects of bufuralol (60 mg) on heart rate, blood pressure, and peripheral vascular responses were compared with those of propranolol (160 mg), pindolol (10 mg), and placebo in a group of 12 healthy volunteers. All three beta-adrenoceptor antagonists reduced exercise tachycardia, but at the doses chosen the effects of bufuralol were less than those of propranolol. Forearm blood flow was reduced by propranolol and pindolol, but not by bufuralol. The antihypertensive and peripheral vascular effects of bufuralol (30–60 mg bd) were also compared with those of propranolol (40–80 mg bd) in a double-blind crossover study in 10 patients with mild hypertension. Propranolol and bufuralol produced comparable reductions in systemic blood pressure over a two-week period, but the decreases in forearm and finger blood flow were greater with propranolol. These studies suggest that bufuralol is a beta-adrenoceptor antagonist with antihypertensive properties, and that it produces less peripheral vasoconstriction than propranolol or pindolol.

Groth, S.; Tønnesen, P.; Asted, M.; Dirksen, H.; Sørensen, P.

doi: 10.1007/BF00608211pmid: 3533563

228 30 30 6 6 S. Groth P. Tønnesen M. Asted H. Dirksen P. G. Sørensen Department of Clinical Physiology The Finsen Institute Copenhagen Denmark the Department of Lung Medicine Lyngby Hospital Copenhagen Denmark Summary ICI 141,292 is a β-blocker with β 1 -selective partial agonist activity. To study its cardioselectivity in humans, comparable β-blocking doses of 200 mg ICI 141,292 and 100 mg atenolol were given to 12 patients with stable bronchial asthma. Both drugs significantly reduced the midexpiratory flow rate at 50% of vital capacity, whereas no significant reduction in FEV 1 or peak expiratory flow rate were observed. It is concluded that the cardioselectivity of ICI 141,292 did not differ significantly from that of atenolol. Since they both had a measurable effect on respiratory mechanics, they should probably not be prescribed in bronchial asthma, or only with the greatest possible caution.

Rehling, M.; Svendsen, T.; Maltbæk, N.; Tangø, M.; Trap-Jensen, J.

doi: 10.1007/BF00608212pmid: 3533564

228 30 30 6 6 M. Rehling T. L. Svendsen N. Maltbæk M. Tangø J. Trap-Jensen Department of Clinical Physiology and Department of Internal Medicine M Frederiksberg Hospital Frederiksberg Denmark Department of Medicine B Rigshospitalet Blegdamsvej 9 DK-2100 Copenhagen Denmark Summary In a double blind, cross over study the haemodynamic effects of an i.v. infusion of adrenaline during concomitant administration of atenolol, pindolol, propranolol or placebo were examined in 7 healthy volunteers. During coadministration with placebo, adrenaline caused an increase in systolic blood pressure (SBP) of 26 mm Hg and a decrease in diastolic blood pressure (DBP) of 20 mm Hg. Heart rate (HR) and stroke volume (SV) were increased by about 20–30%. Total peripheral resistance (TPR) fell significantly. When the subjects were pretreated with atenolol, the adrenaline increased SBP by 16 mm Hg, the DBP did not change, HR and SV increased by 19 and 30%, and TPR fell. During concomitant administration of the non-selective betablocker pindolol, which has strong intrinsic sympathomimetic activity (ISA), adrenaline increased SBP by 11 mm Hg and DBP by 17 mm Hg. This pure pressor response led to a significant reduction in HR and SV and an increase in TPR, probably mediated through the baroreceptors. The haemodynamic response to adrenaline during coadministration of propranolol was very similar to that seen after pindolol. It is concluded that a beta 1 -selective blocker interferes very little with the haemodynamic response to adrenaline, whereas it is changed to a pure pressor response during coadministration of a non-selective betablockers. ISA did not significantly modify the pressor response.

Frabetti, L.; Marchesini, B.; Capucci, A.; Cavallini, C.; Gubelli, S.; Ambrosioni, E.; Magnani, B.

doi: 10.1007/BF00608213pmid: 2429844

228 30 30 6 6 L. Frabetti B. Marchesini A. Capucci C. Cavallini S. Gubelli E. Ambrosioni B. Magnani Istituto di Malattie dell'Apparato Cardiovascolare Bologna Italy Cattedra e Servizio di Farmacologia Clinica Università degli Studi di Bologna Bologna Italy Summary In 11 patients with stable premature ventricular beats, the kinetics of single (150 and 300 mg) and multiple (150 mg t.i.d. and 300 mg t.i.d.) oral doses of propafenone were studied with reference to arrhythmia suppression. During the acute phase detectable plasma levels of the drug were achieved only with the higher dose. In 8 out of 10 patients the antiarrhythmic effect was obtained with the 300 mg dose, which was found to predict responsiveness at steady-state. During the chronic phase, antiarrhythmic efficacy was obtained with the lower dose regimen (150 mg t.i.d.) in half of those patients. A wide range of effective plasma levels was observed. The previously suggested therapeutic range (0.5–2.0 µg/ml) was not adequate in predicting either antiarrhythmic activity or adverse effects. The results show the role of propafenone metabolites in determining total antiarrhythmic action.

Quiding, H.; Anderson, P.; Bondesson, U.; Boréus, L.; Hynning, P.

doi: 10.1007/BF00608214pmid: 3770062

228 30 30 6 6 H. Quiding P. Anderson U. Bondesson L. O. Boréus P. -Å. Hynning Department of Clinical Pharmacology Karolinska Hospital Stockholm Sweden Summary Plasma concentrations of codeine and its demethylated metabolite, morphine, were determined after single and repeated oral administration of codeine. Twelve healthy volunteers received two doses of codeine 60 mg, 2.8 h apart. In order to achieve steady-state conditions codeine 60 mg was then taken every 8 h for a further five doses. The plasma concentrations of codeine and morphine after the first, second and seventh doses were analyzed by GC-MS. The maximum plasma concentrations of codeine and morphine were reached about 1 h after administration and this time interval did not change on repeated administration. The peak plasma codeine was higher after the second dose of codeine than after the first and the concentration resembled that at steady-state. For morphine, the plasma concentration did not increase significantly after the second dose. Both after a single dose and during steady-state the plasma concentration of morphine was only 2–3% of that of codeine. It seems unlikely that morphine plays a significant role in the analgesic efficacy of single or repeated doses of codeine.

Brøsen, K.; Klysner, R.; Gram, L.; Otton, S.; Bech, P.; Bertilsson, L.

doi: 10.1007/BF00608215pmid: 3533565

228 30 30 6 6 K. Brøsen R. Klysner L. F. Gram S. V. Otton P. Bech L. Bertilsson Department of Clinical Pharmacology Odense University Denmark Department of Psychiatry Hillerød General Hospital Denmark Department of Clinical Pharmacology, Karolinska Institute Huddinge Hospital Sweden Summary Thirty-five imipramine treated patients were phenotyped with regard to polymorphic drug oxidation using sparteine and/or debrisoquine. During treatment with 100 mg imipramine per day the mean steady-state concentrations and ratios in 28 extensive metabolizers were: imipramine 169 nmol/l; desipramine 212 nmol/l; 2-OH-imipramine/imipramine 0.25; 2-OH-desipramine/desipramine 0.57. The corresponding values in two poor metabolizers were: imipramine 455 and 302 nmol/l; desipramine 1148 and 1721 nmol/l; 2-OH-imipramine/imipramine 0.06 and 0.05; 2-OH-desipramine/desipramine: 0.09 and 0.04 respectively. The metabolic ratios (MR) sparteine/dehydrosparteine and debrisoquine/4-OH-debrisoquine (% of dose in 12-h urine samples) correlated poorly with the imipramine steady-state concentrations during administration of 100 mg per day, but quite well with the desipramine steady-state concentrations. Significant negative correlations were found between sparteine and debrisoquine MR and the 2-OH-imipramine/imipramine and 2-OH-desipramine/desipramine ratios. In most patients the initial dose was changed to obtain concentrations in the therapeutic range, and concentrations for imipramine + desipramine of (mean ± SD) 713±132 nmol/l were achieved in 33 patients. The therapeutic dose was 50 mg per day in one poor metabolizer and ranged from 50–400 mg per day in 32 extensive metabolizers. There was a weak negative correlation between sparteine MR and daily dose. Treatment with imipramine inhibited metabolism of both sparteine and debrisoquine (MR values about doubled), but did not affect the interpatient correlations.

Marées, H.; Welzel, D.; Marées, A.; Klotz, U.; Tiedjen, K.; Knaup, G.

doi: 10.1007/BF00608216pmid: 3533566

228 30 30 6 6 H. de Marées D. Welzel A. de Marées U. Klotz K. U. Tiedjen G. Knaup Institute of Sports Medicine of the Ruhr University of Bochum Bochum Federal Republic of Germany Department of Clinical Research of Sandoz AG Nürnberg Federal Republic of Germany Dr. Margarete-Fischer-Bosch Institute of Clinical Pharmacology Stuttgart Federal Republic of Germany Nuclear-Medical Division of the St. Elisabeth Hospital Bochum Federal Republic of Germany Summary In a double-blind, interindividual comparative study 30 healthy volunteers were randomly allocated to oral treatment with 5 or 10 mg of dihydroergotamine (DHE) or placebo once daily for 16 days. Regional basic venous blood volume (BBV), pressure dependent venous capacitance (C v ) of the calf, resting heart rate and blood pressure were determined on Days 1 and 15 of treatment. Plasma concentrations of DHE were monitored on Days 2 and 16. Due to spontaneous vasodilation BBV varied considerably, showing that it is an inappropriate parameter for investigating the venoconstrictor activity of DHE. C v remained unchanged after the first dose of DHE but it had declined significantly on both dosage regimens at the end of the treatment phase. In contrast, the blood concentration profiles of DHE were comparable at the beginning and the end of the trial. The discrepancy can best be explained by the existence of an effect compartment, e.g. smooth vascular musculature, which slowly becomes filled with DHE and/or its active metabolites. The venoconstrictor activity of DHE exhibited a significant dose-response relationship.

Staib, A.; Loew, D.; Harder, S.; Graul, E.; Pfab, R.

doi: 10.1007/BF00608217pmid: 3770063

228 30 30 6 6 A. H. Staib D. Loew S. Harder E. H. Graul R. Pfab Department of Clinical Pharmacology University of Frankfurt/Main Federal Republic of Germany Institute of Environtology and Nuclear Medicine University of Marburg Federal Republic of Germany Summary The absorption of a theophylline solution containing 80–120 mg doses delivered to different sites in the gastro-intestinal tract has been determined in 3 male volunteers using a remote controlled drug release system (HF-capsule). There was no difference between the stomach, ileum and the colon in the amount of theophylline absorbed (AUC). The T 1/2abs of theophylline absorbed via the colon was prolonged when compared with that entering via the upper gastro-intestinal tract. The results provide a rational basis for the further development of theophylline formulations and are indispensable for planned development and to account for variation in the bioavailability of retarded release drug preparations.