European Journal of Clinical Pharmacology

Miremont, G.; Haramburu, F.; Bégaud, B.; Péré, J.; Dangoumau, J.

doi: 10.1007/BF00194392pmid: 7957509

228 46 46 4 4 G. Miremont F. Haramburu B. Bégaud J. C. Péré J. Dangoumau Centre de Pharmacovigilance, Hôpital Pellegrin Université Bordeaux II Bordeaux France Centre de Pharmacovigilance Hôpital Pellegrin F-33076 Bordeaux Cedex France Abstract Since spontaneous reporting of adverse drug reactions depends on the physician's opinion of the relationship between the drug and the adverse event, we compared physicians' opinions with the scores obtained by the causality assessment method used in France. During a 2 month period, all physicians who reported adverse drug reactions (ADRs) to our pharmacovigilance centre expressed their opinions on the causal link by means of visual analogue scales. ADR reports were then assessed with the French causality assessment method by a clinical pharmacologist who was blind to physicians' opinions. The assessment by both physicians and the standardized method was performed for 75 ADR cases involving 120 drugs. Physicians used a wide range of assessments, with a preponderance of extreme scores, resulting in a U-shaped distribution, while the standardized method gave generally low scores. Scores given by physicians were very high (causality considered very likely or likely) in 60% of cases and very low (causality considered unlikely or dubious/possible) in 32% of cases. Scores obtained using the causality assessment method were low (causality dubious/possible) in 89% of cases and causality considered likely in only 11 cases, essentially in cases with positive rechallenge. Complete agreement occurred in only 6% of cases. Adding complete agreement and minor discrepancies raised the percentage to 49%.

Malmvik, J.; Löwenhielm, C.; Melander, A.

doi: 10.1007/BF00194393pmid: 7957510

228 46 46 4 4 J. Malmvik C. G. P. Löwenhielm A. Melander Department of Forensic Medicine University of Lund Lund Sweden Department of Clinical Pharmacology University of Lund Lund Sweden Department of Community Health Sciences University of Lund Malmö Sweden Department of Clinical Pharmacology Lund University, Malmö General Hospital S-214 01 Malmö Sweden Abstract All forensic autopsy cases in southern Sweden in 1986–89 in which antidepressant drugs were found in the blood were assessed and the findings related to the sales of antidepressants as expressed as defined daily doses per 1,000 inhabitants per day. There was a total of 272 antidepressant-positive cases, which were divided in three groups: 1. suicide or possible suicide caused by antidepressant drugs, 2. suicide or possible suicide caused by other means (including other drugs and other toxic agents), and 3. other deaths. Amitriptyline was the agent most commonly involved in suicide or possible suicide caused by antidepressants, and it was also the most commonly sold antidepressant. When corrected for sales, trimipramine was most frequently involved as the causal agent. Conversely, despite frequent sales, lofepramine appeared only rarely to be involved. This may be related to lower toxicity of lofepramine, reduced lofepramine absorption at overdose and/or to differences in the administration of various antidepressant drugs to patients with differing degrees of risk of suicide.

Mey, C.; Breithaupt, K.; Seibert-Grafe, M.; Belz, G.

doi: 10.1007/BF00194394pmid: 7957511

228 46 46 4 4 C. de Mey K. Breithaupt M. Seibert-Grafe G. G. Belz Centre for Cardiovascular Pharmacology Mainz-Wiesbaden Germany Division of Clinical Pharmacology Hoechst AG Frankfurt/Main Germany Centre for Cardiovascular Pharmacology Alwinenstrasse 16 D-65189 Wiesbaden Germany Abstract Sixteen healthy male subjects were investigated on four occasions when they received either placebo, 10 mg isosorbide dinitrate (ISDN), or 2.5 or 10 mg pirsidomine, a novel NO-donating drug. A constant-rate iv. infusion of a subsystemic dose (average 42 ng·min -1 , SD 20.5) of noradrenaline in a dorsal hand vein was begun 1 h before drug treatment. It did not cause systemic changes but reduced the venous hand vein diameter by about 50%. This venoconstrictor response was approximately halved by 10 mg ISDN. Pirsidomine, in contrast, did not affect the in situ venoconstrictor responses to noradrenaline. ISDN and pirsidomine reduced systemic resting blood pressure. ISDN and 10 mg pirsidomine were approximately equipotent in reducing systolic blood pressure, both in terms of the duration and the extent of the effect (maximum average reduction of ISDN -6.7, 95% CI -10.3 to -3.0; and 10 mg pirsidomine -7.6, 95% CI -11.3 to -4.0 mmHg, respectively); 2.5 mg pirsidomine was less effective (-4.1, 95% CI -7.8 to -0.5). ISDN and 10 mg pirsidomine were also similarly effective in reducing diastolic blood pressure (ISDN -8.4 mmHg, 95% CI -10.5 to -6.2; 10 mg pirsidomine -6.0 mmHg, 95% CI -8.2 to -3.9; 2.5 mg pirsidomine -2.8 mmHg, 95% CI -5.0 to -0.6) but the effects of ISDN were longer lasting. Although similar with regard to their putative mechanism(s) of action and likely arterial/arteriolar effects, pirsidomine and ISDN seem to affect the venous vascular bed in distinctly different ways.

Behne, M.; Bremerich, D.; Heinrich, J.; Schumacher, H.; Scherer, M.

doi: 10.1007/BF00194395pmid: 7957512

228 46 46 4 4 M. Behne D. Bremerich J. Heinrich H. Schumacher M. Scherer Zentrum der Anaesthesiologie und Wiederbelebung Klinikum der Johann Wolfgang Goethe-Universität D-60596 Frankfurt Germany Boehringer Ingelheim Deutschland GmbH D-55216 Ingelheim Germany Zentrum der Anaesthesiologie und Wiederbelebung Klinikum der Johann Wolfgang Goethe-Universität Theodor-Stern-Kai 7 D-60596 Frankfurt Germany Abstract In this double-blind, randomised, placebo-controlled cross-over study the respiratory effects of Mr 2264 Cl2 × 5 mg IV, a new partial opiate receptor agonist, were investigated and compared with the respiratory effects of morphine 2 × 10 mg IV and placebo. As primary end-points, the slope of the rebreathing curve (dV'/dPCO 2 ET) and V 55 (ventilation at PCO 2 ET=55 mm Hg) were determined by Read's rebreathing method. The incidence of adverse events was also documented and compared. The respiratory depression after the intravenous administration of 5 mg and 10 mg Mr 2264 Cl was comparable to the decreased sensitivity of the respiratory centre after the 20 mg morphine IV. In contrast to morphine, a ceiling effect of Mr 2264 Cl was found. The tolerability of Mr 2264 Cl was comparable to that of morphine.

Stappaerts, I.; Schil, L.; Veken, J.

doi: 10.1007/BF00194396pmid: 7957513

228 46 46 4 4 I. Stappaerts L. Van Schil J. Van der Veken Department of Pneumology St. Vincentiusziekenhuis Antwerp Belgium Boehringer Ingelheim Belgium Kerkelei 32 B-2610 Wilrijk Belgium Abstract Twelve patients suffering from partially reversible chronic obstructive pulmonary disease (COPD) took past in a single blind, randomised, 4-way cross-over trial to determine the optimal dose and duration of action of the anticholinergic agent oxitropium bromide (OTB) inhaled as a nebulised solution. Single doses of 500, 1000, 1500 and 2000 μg nebulised OTB were compared during a 6 hour-observation period. Lung function test results indicated that 500 and 100 μg OTB only induced slight bronchodilatation, whereas 1500 and 2000 μg OTB produced a significantly greater increase in mean FEV1 compared to 500 μg. There was a trend for 2000 μg to be superior to 1000 μg, but 2000 μg and 1500 μg were not significantly different. Significant bronchodilatation (>15% rise in FEV1 from baseline) persisted for 6 h after 1500 μg. A significant decrease in airway resistance (Raw) was observed following inhalation of 2000 μg. The mean decrease in Raw was 33% after 30 min, 20% after 4 h and 12% after 6 h. In this trial, 2000 μg OTB administered by an ultrasonic nebuliser was the optimal dose, but a satisfactory result was also obtained with 1500 μg.

Konishi, H.; Morita, K.; Yamaji, A.

doi: 10.1007/BF00194397pmid: 7957514

228 46 46 4 4 H. Konishi K. Morita A. Yamaji Department of Hospital Pharmacy Shiga University of Medical Science Ohtsu Japan Department of Hospital Pharmacy Shiga University of Medical Science Seta 520-21 Ohtsu Japan Abstract The effect of fluconazole, an antimycotic that inhibits cytochrome P-450-mediated drug metabolism, on theophylline kinetics and the production of its metabolites were compared with those of enoxacin in 5 healthy subjects. All subjects received a single oral dose of 240 mg theophylline (aminophylline, 300 mg) after they had been given oral fluconazole 100 mg every 12 h or enoxacin 200 mg every 8 h for three consecutive days. Pretreatment with enoxacin decreased the total clearance (CL T ) and elimination rate constant (K el ) of theophylline by 50% and 46%, respectively, without changing the volume of distribution (V d ), but there were no significant change in any pharmacokinetic parameter when fluconazole was administered. Enoxacin led to a 50% reduction in the metabolic clearance (CL M ) of theophylline and to decreases of 69%, 59% and 38% in the formation clearance of the three theophylline metabolites, 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU), respectively, accompanied by significant changes in the urinary recovery of theophylline and its metabolites. In contrast, treatment with fluconazole led only to a slight decrease in the CL M of theophylline (16%) and in the formation clearance of its metabolites (15%–18%), and there was no change in the renal clearance (CL R ) of theophylline. The results indicate that fluconazole is a minor inhibitor of theophylline disposition compared with enoxacin, and they suggest that the inhibitory action of fluconazole is selective for certain cytochrome P-450 isozymes, but not for the cytochrome P-4501A involved in theophylline metabolism.

Laaksonen, R.; Ojala, J.; Tikkanen, M.; Himberg, J.

doi: 10.1007/BF00194398pmid: 7957515

228 46 46 4 4 R. Laaksonen J. -P. Ojala M. J. Tikkanen J. -J. Himberg Department of Clinical Pharmacology University of Helsinki Finland Third Department of Medicine University of Helsinki Finland First Department of Medicine University of Helsinki Finland Department of Clinical Pharmacology University of Helsinki Paasikivenkatu 4 SF-00250 Helsinki Finland Abstract Serum ubiquinone levels were studied during long- and short-term treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in 17 men with primary non-familial hypercholesterolaemia. The serum ubiquinone levels were determined after the patients had received simvastatin (20–40 mg per day) for 4.7 years, after a 4 week treatment pause and again after they had resumed treatment with lovastatin (20–40 mg per day) for 12 weeks. During the treatment pause the average serum ubiquinone levels increased by 32%; resumption of treatment caused a reduction of 25%. The changes in the levels of ubiquinone and serum total cholesterol as well as those of ubiquinone and low-density lipoprotein cholesterol were closely parallel. This suggested that changes in serum ubiquinone reflected changes in cholesterol-containing serum lipoproteins which could serve as carrier vehicles for ubiquinone. After long-term simvastain treatment and after short-term lovastatin treatment, average serum ubiquinone levels (1.16 and 1.22 mg·l -1 , respectively) were similar to that observed in a group of apparently healthy middle-aged men (1.16 mg·l -1 ).

Vogt, D.; Trenk, D.; Bonn, R.; Jähnchen, E.

doi: 10.1007/BF00194399pmid: 7957516

228 46 46 4 4 D. Vogt D. Trenk R. Bonn E. Jähnchen Abteilung für Klinische Pharmakologie, Herz-Zentrum Bad Krozingen Germany Schwarz Pharma AG Monheim Germany Abteilung für Klinische Pharmakologie, Herz-Zentrum Südring 15 D-79189 Bad Krozingen Germany Abstract The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers. After the sublingual spray C max was higher (39.0 ng·ml -1 ) and t max was shorter (3.9 min) than after the sublingual (22.8 ng·ml -1 and 13.8 min) and peroral (16.9 ng·ml -1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml -1 ·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively. The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (e max =130%) and the time to e max (t emax ) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.

Björkman, S.; Carlsson, M.; Berntorp, E.

doi: 10.1007/BF00194400pmid: 7957517

228 46 46 4 4 S. Björkman M. Carlsson E. Berntorp Hospital Pharmacy Malmö General Hospital Malmö Sweden Department of Community Health Sciences Malmö General Hospital Malmö Sweden Department for Coagulation Disorders Malmö General Hospital Malmö Sweden Hospital Pharmacy Malmö General Hospital S-21401 Malmö Sweden Abstract The aims of this study were to investigate the influence of total blood sampling time on the estimated pharmacokinetic parameters of Factor IX procoagulant activity (FIX:C) and to relate the pharmacokinetics of FIX:C to the putative physiological disposition of Factor IX (FIX). Six patients with severe haemophilia B each received 2 infusions of FIX and on both occasions blood samples were collected for 104 h. Each FIX:C decay curve was processed with successive deletion of the last (remaining) datapoint. The fitted terminal half-life (t 1/2β ) and the calculated model-independent mean residence time (MRT MI ), elimination clearance (CL MI ) and volume of distribution at steady state (V ss ) stabilised close to their final values when FIX:C data corresponding to at least 56 h of sampling were used. The final mean values were t 1/2β =34 h, MRT MI =37 h, CL MI =4.0 ml · h -1 · kg -1 and V ss =0.15 l · kg -1 . The disposition of FIX could be characterised by a two-compartment pharmacokinetic model. On average, FIX molecules spent 44% of their total MRT in the second (or “extravascular”) compartment. The distribution clearance was comparable to estimated total lymph flow. The volume of the central compartment was twice the estimated plasma volume, which may reflect the rapid and reversible binding of FIX to vascular endothelium. This explains the common clinical finding that the peak activity of FIX:C is less than the injected dose divided by the estimated plasma volume of the patient.

Jensen, J.; Jensen, L.; Madsen, J.

doi: 10.1007/BF00194401pmid: 7957518

228 46 46 4 4 J. D. Jensen L. W. Jensen J. K. Madsen Department of Nephrology and Medicine C, Skejby Hospital University Hospital in Aarhus Aarhus Denmark Department of Nephrology and Medicine C, Skejby Hospital University Hospital in Aarhus DK-8200 Aarhus Denmark Abstract The pharmacokinetics of recombinant human erythropoietin (RhEPO) were investigated after subcutaneous (s.c.) injection in the thigh and in the abdominal wall. Eleven healthy subjects, age 24.4 years (median), were studied. Each subject received two s.c. injections of 100 U·kg -1 RhEPO dissolved in 1 ml water: one injection in the thigh and another in the abdomen. Serum erythropoietin was measured regularly by radioimmunoassay until 144 h after each injection. The mean residence time was significantly longer after injection in the thigh than in the abdomen (32.7 vs 26.2 h). The estimated half-life of absorption was significantly longer after injection in the thigh than after abdominal application (14.9 vs 12.3 h). The estimated half-life of elimination was not significantly different (4.4 vs 4.8 h). The relative difference in the area under the curve between injection in the abdomen and the thigh in the same subject ranged from -36% to +68% but there was no significant difference in bioavailability. The peak concentration was not significantly different and appeared at around 10 h (C max thigh, 175 U·l -1 vs C max abdomen, 216 U·l -1 ). A twin-peak configuration of the concentration vs time curve with a significant second peak at 24 h was found after injection in the thigh but not after abdominal injection. In conclusion, the mean residence time was longer after administration in the thigh, probably due to delayed absorption, but bioavailability was not significantly different. Following injection in the thigh the concentration curve had two peaks. The differences may be due to regional variations in lymph flow and to physical activity. The overall differences in pharmacokinetics appeared to be too small to recommend a general preference of the injection site.