European Journal of Clinical Pharmacology

Hallas, J.; Harvald, B.; Worm, J.; Beck-Nielsen, J.; Gram, L.; Grodum, E.; Damsbo, N.; Schou, J.; Kromann-Andersen, H.; Frølund, F.

doi: 10.1007/BF00315383pmid: 8276041

228 45 45 3 3 J. Hallas B. Harvald J. Worm J. Beck-Nielsen L. F. Gram E. Grodum N. Damsbo J. Schou H. Kromann-Andersen F. Frølund Department of Clinical Pharmacology Institute of Medical Biology Odense Denmark Medical Department C Odense University Hospital Odense Denmark Geriatric Department Q Odense University Hospital Odense Denmark Department of General Medicine, ISH Odense University Hospital Odense Denmark Danish Committee on Adverse Drug Reactions National Health Board Copenhagen Denmark Summary As part of a high-intensity monitoring study of drug events as the cause of admission to departments of internal medicine, the effect of an educational intervention programme was studied. Two departments were included, one specialising in geriatrics and one that received patients by non-selected referral. The series consisted of 607 consecutive admissions studied before and 703 after the intervention. The drug events considered were adverse drug reactions and dose-related therapeutic failures, mainly due to non-compliance. A modest, statistically non-significant decrease in drug related hospital admissions (DRH) was seen, from 14% before to 13% after the intervention period. However, DRHs classified as definitely avoidable showed the significant decrease of 83%. There was no apparent relationship between the topics selected for the intervention programme and changes in the pattern of DRHs. No relationship between alterations in sales data and hospital admissions caused by a given drug could be demonstrated. A blinded external evaluation of case abstracts did not disclose any significant shift in the investigators' assessments. The intervention may have had an non-specific effect on avoidable DRHs.

Matthews, K.; Eagles, J.; Matthews, C.

doi: 10.1007/BF00315384pmid: 8276042

228 45 45 3 3 K. Matthews J. M. Eagles C. A. Matthews Department of Mental Health University of Aberdeen Scotland, UK The Ross Clinic Royal Cornhill Hospital Aberdeen Scotland, UK The Clinical Trials Unit Royal Cornhill Hospital Aberdeen Scotland, UK Summary The aim of this study was to examine the antidepressant drug prescribing preferences and habits of a population of general practitioners. The method used was that of a questionnaire survey, including case vignettes. The response rate exceeded 70% Data are presented outlining the attitudes of the respondents to the use of antidepressant drugs in the management of common psychiatric presentations in the primary care setting. The majority of general practitioners (G.P.'s) had received little or no post-graduate education in psychiatry. The antidepressants most frequently prescribed were amitriptyline, clomipramine, trazodone and lofepramine. Despite recognition of the alarming frequency of serious self-poisoning incidents with some of these compounds, 26% of respondents confessed to an inability to make an informed choice of antidepressant drug, with 14% using the same drug with every patient with no attempt to select according to individual patient requirements. The management of depressive neurosis generates considerable clinical confusion with a variety of interventions favoured. The use of a sedating antidepressant is popular. There is greater accord for the management of endogenomorphic depression. The use of the benzodiazepine drugs in the management of anxiety disorders is infrequent, with appropriate recognition of the merits of behavioural approaches. However, the role for antidepressant drugs in the management of anxiety disorders is under-recognized. We conclude that general practitioners are required to undertake a significant body of work for which they may be inadequately trained.

Kruse, W.; Nikolaus, T.; Rampmaier, J.; Weber, E.; Schlierf, G.

doi: 10.1007/BF00315385pmid: 8276043

228 45 45 3 3 W. Kruse T. Nikolaus J. Rampmaier E. Weber G. Schlierf Klinisches Institut für Herzinfarktforschung an der Medizinischen Universitätsklinik Heidelberg Germany Abteilung für Klinische Pharmakologie, Medizinische Universitätsklinik Heidelberg Germany Summary The objective of the study was to compare compliance with and the hypocholesterolaemic effect of lovastatin given once daily as a morning or an evening dose. Twenty-four out-patients with familial hypercholesterolaemia were randomly assigned to receive placebo first, then lovastatin 20 mg, to be taken once daily for 4 weeks, either with the breakfast or evening meal, in a single-blind fashion. Drug compliance was assessed by pill counts and continuous electronic monitoring. Two compliance parameters were evaluated, consumption, defined as percentage of prescribed doses taken, and time compliance, the percentage of total dosing events recorded within defined intervals (6.00–10.00 h, and 17.00–21.00 h), for the morning and evening regimes. Both regimes satisfactorily reduced the total and LDL-cholesterol concentrations, and there was no significant difference in the extent of the reductions. Pill counts overestimated compliance, as revealed by the monitoring method. The times of actual consumption of doses by the patients often differed from that prescribed, predominantly in patients who were told to take the evening dose. Partial time compliance may have confounded the efficacy of the drugs. Electronic compliance monitoring appears to be particularly useful in chronopharmacological studies.

Abe, K.; Fujino, Y.; Sakakibara, T.

doi: 10.1007/BF00315386pmid: 8276044

228 45 45 3 3 K. Abe Y. Fujino T. Sakakibara Department of Anaesthesiaand Cardiovascular Surgery Osaka Police Hospital Tennoujiku Osaka Japan Summary We have evaluated the effect of prostaglandin E 1 (PGE 1 ) on renal function after cardiac surgery with cardiopulmonary bypass in 20 patients, ten of whom received 0.02 μg·kg −1 ·min −1 of PGE 1 by infusion into the oxygenator during bypass; ten patients served as controls. Serum β 2 -microglobulin fell significantly and urine β 2 -microglobulin increased significantly after surgery in both groups. Urine N -acetyl-β- D -glucosaminidase was high after surgery in both groups, but it was significantly lower in the PGE 1 group. Free water clearance fell significantly on the 1st, 3rd, and 5th postoperative days compared with preoperative values in the control but not in the PGE 1 group. These results suggest that PGE 1 may prevent renal dysfunction after cardiopulmonary bypass.

Güldütuna, S.; Leuschner, M.; Wunderlich, N.; Nickel, A.; Bhatti, S.; Hübner, K.; Leuschner, U.

doi: 10.1007/BF00315387pmid: 8276045

228 45 45 3 3 S. Güldütuna M. Leuschner N. Wunderlich A. Nickel S. Bhatti K. Hübner U. Leuschner Centre of Internal Medicine, Department of Gastroenterology Johann Wolfgang Goethe University Frankfurt am Main Germany Centre of Pathology Johann Wolfgang Goethe University Frankfurt am Main Germany Summary We treated 6 patients with Stage II primary biliary cirrhosis with cholic acid (CA) 10 mg · kg −1 per day for 3 months and then with the same dose of ursodeoxycholic acid (UDCA). A matching group of 6 patients was observed for 3 months without any therapy. Liver function tests and serum and stool bile acids were investigated before, during and at the end of CA and UDCA therapy. The results of liver function tests deteriorated after 6–8 weeks of CA therapy and the changes were correlated ( r =0.92) with an increase in α-dihydroxy-bile acids (chenodeoxycholic acid and deoxycholic acid) in the serum. The 24 h excretion of DCA in 24 h faeces was markedly increased. Ursodeoxycholic acid treatment improved liver function tests; after 4 weeks glutamate dehydrogenase (GLDH) had decreased. After 8–12 weeks of therapy ursodeoxycholic acid had increased to 50–60% of the total serum bile acids whereas the more apolar bile acids were significantly decreased. No changes in liver function tests or bile acid metabolism were found in the untreated group. Since CA and UDCA are non-toxic in man, this trial indicates that the apolar bile acids chenodeoxycholic acid and deoxycholic acid may be responsible for the deterioration of liver function in primary biliary cirrhosis. However, the therapeutic effect of UDCA cannot be explained merely by the decrease in α-dihydroxy-bile acids in the serum, since the laboratory results had improved prior to the decrease in the serum apolar bile acids.

Foster, R.; Jubber, A.; Hassan, N.; Franke, B.; Vernillet, L.; Denouel, J.; Carpenter, J.; Small, R.

doi: 10.1007/BF00315388pmid: 8276046

228 45 45 3 3 R. W. Foster A. S. Jubber N. A. G. M. Hassan B. Franke L. Vernillet J. Denouel J. R. Carpenter R. C. Small Smooth Muscle Research Group, Department of Physiological Sciences, Medical School University of Manchester UK Sandoz Pharma Ltd. Basel Switzerland Human Pharmacokinetic Department Pharmaceutical Research Centre, Sandoz Laboratories Rueil-Malmaison France Summary An approximately steady-state reduction of specific airway conductance was induced in healthy human subjects by means of an individualized inhaled methacholine loading dose followed by a maintenance dose regime. Tested against this background bronchoconstriction, the xanthine analogue SDZ MKS 492, when administered as a single oral dose of 40 mg, showed a significant bronchodilator action, which lasted for up to 5.5 h. Bronchodilatation was not seen after administration of 10 or 20 mg doses. SDZ MKS 492 inhaled as a dry powder had a bronchodilator action that was small, most evident with the 12 mg dose and transient. The peak relief of imposed bronchoconstriction was 29% and the apparent half-time of removal of SDZ MKS 492 from its site of action was 5–6 min. Inhaled SDZ 492 had a bitter taste that was not masked by inclusion of menthol and aspartame in the formulation. The bronchodilatation seen in laboratory animals can also be produced by SDZ MKS 492 in man when administered orally or by inhalation. Its magnitude correlates better with the plasma concentration of parent drug than with that of either of the identified metabolites. Dispositional processes in the lung abbreviate its action after administration by inhalation.

Ingum, J.; Beylich, K.-M.; Mørland, J.

doi: 10.1007/BF00315389pmid: 8276047

228 45 45 3 3 J. Ingum K.-M. Beylich J. Mørland National Institute of Forensic Toxicology Gaustad, Oslo Norway Summary Flunitrazepam (1 mg) or placebo was administered once daily over a treatment period of 8 days to healthy, male volunteers to study the time course of the effects on memory functions and on subjective ratings of alertness and tension. The plasma level of flunitrazepam increased by approximately 40% ( P <0.05) during the treatment period. The mean pre-dose level of flunitrazepam on day 4 and day 8 was approximately 0.005 ώM, and no residual effects on memory functions were observed. Intake of flunitrazepam decreased the number of freely recalled words by about 85% ( P <0.05) and significantly affected the subjects' rating of attention when tested during the first few hours after drug intake on day 1 of treatment. However, no significant effect on the subjects' rating of relaxation was observed. When tested similarly after 8 days treatment, flunitrazepam significantly affected the subjects' rating of relaxation ( P <0.01). Furthermore, no tolerance developed for the effect of flunitrazepam on free recall ( P >0.3) and the subjects' rating of attention ( P >0.7), and these effects had nearly equal time courses during the treatment period. This may indicate that the amnesic effect of benzodiazepines is at least partially mediated through the effects on attention or general arousal. Two of the subjects in the active drug group reported adverse reactions or incidents of discomfort during the 1st week following the treatment period, whereas none in the placebo group reported such reactions.

Beermann, B.; Nyquist, O.; Höglund, C.; Jacobsson, K.-A.; Näslund, U.; Jensen-Urstad, M.

doi: 10.1007/BF00315390pmid: 8276048

228 45 45 3 3 B. Beermann O. Nyquist C. Höglund K.-A. Jacobsson U. Näslund M. Jensen-Urstad Medical Products Agency Uppsala Sweden Institution of Medicine, Karolinska Institute Huddinge University Hospital Huddinge Sweden Department of Medicine Södersjukhuset Stockholm Sweden Department of Medicine Norrland University Hospital Ume» Sweden Department of Clinical Physiology Södersjukhuset Stockholm Sweden Summary The aim of the present study was primarily to evaluate the haemodynamic effects of the ACE-inhibitor ramipril which is active via its metabolite ramiprilat. Ramipril 1.25, 2.5 and 5 mg and placebo was administered orally to 4 groups of 12 patients with heart failure (NYHA III) in a double-blind randomised, parallel study. Haemodynamics were monitored for 24 h and blood was sampled and urine collected for up to 96 h. In the placebo-treated group the cardiac index (CI) was significantly increased (15.8%) and right atrial pressure decreased (26.6%). Ramipril 1.25 mg had insignificant haemodynamic effects compared to placebo and the 2.5 mg dose had significant effects on some haemodynamic variables. Ramipril 5 mg had pronounced and sustained effects on pulmonary artery pressure, which fell by 43.7%, and pulmonary capillary wedge pressure (PCWP; −59.1%); systemic vascular resistance was also decreased 21%. A significant effect on CI was only seen after 2.5 mg ramipril (+7.4%). The mean maximal degree of ACE inhibition was 73.2, 90.4 and 98.5%, respectively, after the three doses of ramipril. Complete inhibition of ACE-activity was seen at a mean plasma concentration of ramiprilat of 4.7 ng·ml −1 . The degree of inhibition declined with a half life of about 75 h. There was a significant relation between the degree of ACE-inhibition and change in PCWP but not with the change in SVR. Ramipril was mainly eliminated in the form of ramiprilat and inactive metabolites.

Krähenbühl, S.; Grass, P.; Surve, A.; Kutz, K.; Reichen, J.

doi: 10.1007/BF00315391pmid: 8276049

228 45 45 3 3 S. Krähenbühl P. Grass A. Surve K. Kutz J. Reichen Department of Clinical Pharmacology University of Berne Switzerland Human Pharmacology Department Drug Safety Assessment Sandoz Pharma Basle Switzerland Sandoz Research Institute East Hanover NJ USA Summary The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis ( n =10), in patients with chronic, non-cirrhotic liver disease ( n =8) and in a control group of healthy subjects ( n =16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 μg·h·l −1 , 923 μg·h·l −1 and 1300 μg·h·l −1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h −1 in patients vs. 2.00 h −1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.

Griensven, J.; Seibert-Grafe, M.; Schoemaker, H.; Frölich, M.; Cohen, A.

doi: 10.1007/BF00315392pmid: 8276050

228 45 45 3 3 J. M. T. van Griensven M. Seibert-Grafe H. C. Schoemaker M. Frölich A. F. Cohen Centre for Human Drug Research University Hospital Leiden The Netherlands Hoechst Aktiengesellschaft Klinische Forschung Frankfurt am Main Germany Laboratory of Pathological Chemistry University Hospital Leiden The Netherlands Summary We have studied the pharmacodynamic effects of ramipril, propranolol, and their combination, as well as the effect of propranolol on the pharmacokinetics of ramipril in 12 healthy men (age 24 (SD 6) y, weight 72 (7) kg). Propranolol and placebo, ramipril and placebo, or propranolol and ramipril were given orally for four days in a crossover, double-blind fashion. The pharmacokinetics of ramipril and ramiprilat were investigated on day 4. Effects on plasma renin activity, ACE activity, and heart rate and blood pressure both before and after a standardized exercise test were measured on days 1 and 4. On day 4 the combination reduced the mean arterial pressure by 2.8 mmHg compared with propranolol alone and by 3.7 mmHg compared with ramipril alone. Ramipril had no effect on the bradycardia induced by propranolol. Propranolol reduced exercise mean arterial pressure by 9 mmHg (day 4) and heart rate by 7 beats.min −1 (day 4) compared with ramipril; this was not affected by co-administration of ramipril. On day 4 the average plasma renin activity was not significantly higher than after the combination. ACE activity was not affected by propranolol. The pharmacokinetics of ramipril and ramiprilat were not influenced by propranolol. The combination of ramipril and propranolol has additive pharmacodynamic effects that may be useful in the treatment of hypertension.