European Journal of Clinical Pharmacology

Maggini, M.; Raschetti, R.; Traversa, G.

doi: 10.1007/BF00195926pmid: 8706765

228 49 49 6 6 M. Maggini R. Raschetti G. Traversa Department of Epidemiology and Biostatistics Istituto Superiore di Sanità Viale Regina Elena, 299 I-00161 Rome Italy Abstract Drug use in Italy in the period 1983–1991 has been analysed. The twenty most used substances accounted for about 20% of the sold packages. The effect of marketing of new drugs is worth noting: new and more expensive drugs are preferred even when effective, safe and less expensive alternatives are available. Prescribers have to face a highly dynamic pharmaceutical market in which 30% of substances (among the 300 most sold) changes every five years. Other than a more rational formulary, independent information and continuing education have to be considered as tools to improve a more rational prescribing.

Kubota, K.; Kubota, N.; Pearce, G.; Inman, W.

doi: 10.1007/BF00195927pmid: 8706766

228 49 49 6 6 K. Kubota N. Kubota G. L. Pearce W. H. W. Inman Drug Safety Research Unit Bursledon Hall SO31 1AA Southampton UK Abstract Objective : This study examines cough recorded in Prescription-Event Monitoring (PEM) of four ACE-inhibitors. Particular attention was paid to the study of enalapril because the drug was monitored before the causal relationship between cough and ACE-inhibitors had been widely accepted. Results : Several factors which had obscured the causal relationship in the individual cases were found to be also an obstacle in PEM. For example, cough was a common and non-serious event and was under-reported in the PEM study of enalapril and the rate was not strikingly different from that recorded for other drugs. Cough induced by ACE-inhibitors has several characteristics which reduce the chance of a recognis-able ‘signal’. The original questionnaires returned from doctors in the PEM study of enalapril have been reexamined. The observation that the rate of cough diminished after enalapril had been stopped rather than increased after starting, provided the best evidence of causality, because this was not affected by many biases such as the publicity that had occurred prior to doctors participating in PEM completed later reports.

Visser, L.; Stricker, B.; Vlug, A.; Lei, J.

doi: 10.1007/BF00195928pmid: 8706767

228 49 49 6 6 L. E. Visser B. H. Ch. Stricker A. E. Vlug J. van der Lei Department of Epidemiology and Biostatistics Erasmus University Medical School room Ee 2126 Dr. Molewaterplein 50 NL-3015 GE Rotterdam The Netherlands Drug Safety Unit Inspectorate for Health Care Rijswijk The Netherlands Department of Medical Informatics Erasmus University Rotterdam The Netherlands Abstract Objectives : To determine the risk of coughing as an adverse reaction to ACE inhibitors under everyday circumstances in a large population, and to study whether this adverse effect was duration or dose dependent. Design : A population-based case-control study. Setting : Ten general practices of 14 Dutch general practitioners (GP), in which all consultations, morbidity and medical interventions, including drugs prescribed, were registered over the 18 month period from 1st September, 1992 to 1st March, 1994. Subjects : 1458 patients with incident coughing and up to four controls per case were obtained (total 4182 controls), matched for GP. All cases and controls were 20 years or older and had no record of respiratory infection, influenza, tuberculosis, asthma, chronic bronchitis, emphysema, congestive heart failure, sinusitis, laryngitis, haemoptysis or respiratory neoplasms during the study period. Results : Cases were 2.1-times more likely than controls to have been exposed to ACE inhibitors (95% CI 1.5–3.1), but after adjustment the odds ratio was 1.4 (95% CI 0.9–2.1). The crude odds ratio for captopril was 1.3 (95% CI 0.7–2.5), for enalapril 2.6 (95% CI 1.6–4.2) and for lisinopril 2.0 (95% CI 0.5–9.3). The adjusted odds ratio for captopril was 0.9 (95% CI 0.4–1.7), for enalapril 1.7 (95% CI 1.03–2.8) and for lisinopril 1.7 (95% CI 0.4–7.9). For patients who had been on ACE inhibitor treatment for no longer than 2 months the odds ratio was 4.8 (95% CI 1.7–13.3). The odds ratio declined to 2.0 (95% CI 1.1–3.8) for those who had taken an ACE inhibitor for 2–6 months, and to 1.6 (95% CI 0.9–2.7) for those on ACE-inhibitors for more than 6 months. Conclusion : The risk of coughing was increased twofold among ACE inhibitor users, but the odds ratios were no longer significant after controlling for several confounding factors. The risk of developing cough due to ACE-inhibitors declines with the duration of treatment, possibly due to depletion of susceptible persons.

Avanzini, F.; Tognoni, G.; Colombo, F.; Alli, C.; Herxheimer, A.

doi: 10.1007/BF00195929pmid: 8706768

228 49 49 6 6 F. Avanzini G. Tognoni F. Colombo C. Alli A. Herxheimer Istituto di Ricerche Farmacologiche Mario Negri Via Eritrea, 62 I-20157 Milano Italy Ospedale Niguarda Milan Italy UK Cochrane Centre NHS R and D Programme OX2 7LG Oxford UK Abstract Objective : To determine whether general practitioners (GP) who are readers of independent drug bulletins can be used as an international epidemiological observatory of the criteria adopted by “well informed” doctors in various countries in the management of mild hypertension. Design : Questionnaire study of GPs' diagnostic criteria for mild hypertension, routine investigation and management of patients with this diagnosis. Participants : 206 GPs readers of independent drug bulletins in 7 countries, comprising 95 known systematic readers of a local bulletin and 111 randomly selected regular subscribers. Main outcome measures : Response rate to the questionaire. Diagnostic criteria, routine investigations, and treatment used for patients with mild hypertension. Results : The study required two months for planning and implementation. Four countries out of eleven had a response rate ≤50% and were excluded; the frequency of responses from other countries was 69%. The average diastolic blood pressure (DBP) considered diagnostic of mild hypertension range from 94 mm Hg (lower threshold) to 106 (upper threshold). A minority (17%) of GPs routinely request the minimum recommended laboratory tests to assess patients. GPs routinely advise non-drug measures before starting a drug. Most would not start drug treatment in patients without other risk factors and a DBP below 100 mmHg. The top first choice drugs were diuretics and β-adrenoceptor blockers. Half of the doctors were able to quote some published guide to the management of mild hypertension, and 18% cited a relevant trial. Attitudes in diagnosing and treating mild hypertension differed widely between GPs and countries. Conclusions : GP readers of drug bulletins can be used quickly and inexpensively to assess the extent to which recommended diagnostic and therapeutic practices are accepted by “well informed” doctors. The results suggest that attitudes in managing mild hypertension vary widely among GPs and countries and differ remarkably from the recommendations of published guidelines.

Antila, S.; Lehtonen, L.; Sandell, E.-P.; Eha, J.; Heinpalu, M.; Loogna, I.; Mesikepp, A.; Planken, U.

doi: 10.1007/BF00195930pmid: 8706769

228 49 49 6 6 S. Antila L. Lehtonen E.-P. Sandell J. Eha M. Heinpalu I. Loogna A. Mesikepp U. Planken Orion-Farmos, Orion Research P.O. Box 65 SF-02101 Espoo Finland Estonian Heart Center Tallinn Estonia Abstract Objective : Levosimendan in a new inodilator drug that sensitises troponin C in heart muscle cells to calcium, thus improving contractility. In previous studies, a single 2 mg intravenous dose of levosimendan increased cardiac output (CO) in healthy volunteers by about 40% and decreased pulmonary capillary wedge pressure in heart failure patients by 40–50%. The aim of the present, double-blind study was to evaluate the safety of concomitant use of levosimendan and an ACE-inhibiting drug. Methods : The haemodynamic effects of levosimendan, given with or without captopril, were evaluated by using 2-dimensional echocardiography, repeated blood pressure measurements and by ambulatory ECG recordings. Twenty-four male patients with stable NYHA II-III heart failure (EF<40%) after a previous myocardial infarct were given, in randomised order, a single IV infusion of levosimendan or placebo. The infusions were repeated after 2 weeks treatment with upto 50 mg b.i.d. of captopril. Twelve patients received levosimendan 1 mg and twelve received 2 mg. Results : Mean CO was increased from 6.0 to 6.81·min −1 in patients receiving 1 mg levosimendan compared to placebo, but only from 6.3 to 6.51·min −1 in patients receiving 2 mg. The increase in CO was statistically significant when all levosimendan patients were compared to placebo. Heart rate did not change after either dose. Mean stroke volume increased significantly after 1 mg but not after 2 mg of levosimendan. The addition of captopril did not change the effects of levosimendan. No additional decrease in systolic or diastolic blood pressure was observed when levosimendan and captopril were given concomitantly. Conclusion : It seems that concomitant treatment with captopril does not change the haemodynamic effects of levosimendan. No adverse haemodynamic interactions were seen.

Lönnebo, A.; Grahnén, A.; Jansson, B.; Brundin, R.; Ling-Andersson, A.; Eckernäs, S.-Å.

doi: 10.1007/BF00195931pmid: 8706770

228 49 49 6 6 A. Lönnebo A. Grahnén B. Jansson R. M. Brundin A. Ling-Andersson S.-Å. Eckernäs PMC Contract Research AB Islandgatan 2 S-753 18 Uppsala Sweden Abstract The systemic effects of single and multiple doses of inhaled fluticasone propionate (FP) and budesonide were examined in 24 healthy male volunteers (age range 18–29 years). The study was of an open, placebo-controlled, randomized, three-way crossover design. On each study day, multiple blood samples were taken over a 20 h period after drug administration (after a single dose and after the last of seven doses) and area under the curve (AUC 0–20 ) for plasma cortisol and white blood cell (WBC) counts was calculated. Results : The present study shows that multiple dosing with FP 1.0 mg b.i.d. for 3.5 days (seven doses) resulted in a marked cortisol suppression from placebo which, at 55%, was more than double that seen with a single dose (25% suppression). Multiple dosing with budesonide 0.8 mg b.i.d. resulted in a 34% suppression in plasma cortisol compared with a suppression of 26% with a single dose. The increase in systemic activity of FP after multiple dosing is confirmed by both the number of subjects with 0800 hours plasma cortisol values below normal limits and by the changes in WBC and differential counts. Conclusion : The results of the present study confirm previous findings with regard to the more marked systemic effect of FP following multiple dosing as compared with a single dose. This increase in systemic effect from single dosing to multiple dosing is significantly greater for FP than for budesonide.

Kravtzoff, R.; Ropars, C.; Desbois, I.; Chassaigne, M.; Lamagnere, J.; Colombat, Ph.; Muh, J.; Valat, Ch.

doi: 10.1007/BF00195932pmid: 8706771

228 49 49 6 6 R. Kravtzoff C. Ropars I. Desbois M. Chassaigne J. P. Lamagnere Ph. Colombat J. P. Muh Ch. Valat Laboratoire de Biopharmacologie Transfusionnelle INSERM U316, CRTS BP 2009 F-37020 Tours France Centre Régional de Transfusion Sanguine Tours France Service Oncologie Médicale et Maladies du Sang, CHRU Tours France Service de Biochimie, CHRU Tours France Service de Médecine Nucléaire, CHRU Tours France Abstract To evaluate the modification of pharmacodynamic parameters induced by the administration of l -asparaginase loaded into red blood cells, 13 patients received a single dose of l -asparaginase internalised into the carrier. The enzyme was loaded using a reversible lysis-resealing process. The dose per patient ranged from 30 to 200 IU·kg −1 . Considerable heterogeneity occurred between patients: the level of l -asparaginase circulating after 24 h represented 47% of the total injected dose as compared to 74.8% for red blood cells (RBCs). However, the half-life of the enzyme remaining in the circulation was very similar to that of the RBC carrier, i.e. 29 days and 27 days, respectively, compared with 8–24 h for the free enzyme. Sustained elimination of plasma l -asparagine occurred, the duration of which was dependent on the injected dose. A single injection of 30·IU·kg −1 was sufficient to eliminate plasma l -asparagine over 10 days. With 150–200 IU·kg −1 the elimination period was extended to 50 days. These data show that the use of RBCs as carriers of l -asparaginase greatly improves the pharmacodynamic parameters of the drug.

McElnay, J.; Al-Furaih, T.; Hughes, C.; Scott, M.; Nicholls, D.

doi: 10.1007/BF00195933pmid: 8706772

228 49 49 6 6 J. C. McElnay T. A. Al-Furaih C. M. Hughes M. G. Scott D. P. Nicholls Pharmacy Practice Research Group, School of Pharmacy The Queen's University of Belfast 97 Lisburn Road BT9 7BL Belfast N. Ireland, UK The Royal Victoria Hospital BT12 6BA UK Security Forces Hospital Riyadh Saudi Arabia Abstract Objective : The pharmacokinetics and pharmacodynamics of buffered sublingual captopril were assessed in patients with congestive heart failure (CHF). Methods : The study was carried out in a randomised single-blind cross-over fashion ( n =6, 4 males and 2 females) and involved two study days, at least 7 days apart. Baseline measurements were carried out for plasma renin activity (PRA), blood pressure (B.P.) and heart rate (H.R.). Captopril (12.5 mg) was administered sublingually with dibasic potassium phosphate which maintained salivary pH at 7, or perorally with 100 ml of water. Further B.P., H.R. measurements and venous blood samples were taken over a 3 hour period post-drug administration. Blood samples were analysed for captopril and PRA levels. Results : t max after buffered sublingual administration of captopril, which ranged from 40–60 min (median=40 min), was significantly shorter than after peroral administration (range 60–120 min, median=90 min). C max was slightly greater after buffered sublingual than after peroral administration with mean values of 108.2 vs. 94.0 ng·ml −1 . AUC values were similar after both routes of administration. Systolic and diastolic B.P. vs. time profiles for each administration method were significantly different i.e. sublingual administration produced an earlier reduction in B.P., however, HR did not differ significantly between the two routes. Conclusion : The data indicate that this novel administration method of captopril leads to an increased rate, but an unchanged extent of captopril absorption, suggesting a modest therapeutic advantage with the use of buffered sublingual captopril if a rapid reduction in blood pressure is required.

Lugo, R. A.; Nahata, M. C.; Menke, J. A.; McClead, E.

doi: 10.1007/bf00195934pmid: 8706773

Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population.Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days.Results: There was a strong relationship between clearance (4.96 ml·min−1·kg−1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min−1·kg−1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg−1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects.Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.

Lugo, R.; Nahata, M.; Menke, J.; McClead, E.

doi: 10.1007/BF00195934pmid: 8706773

228 49 49 6 6 R. A. Lugo M. C. Nahata J. A. Menke E. McClead The Wexner Institute for Pediatric Research, Children's Hospital College of Pharmacy, The Ohio State University 500 West 12th Avenue 43210 Columbus Ohio USA College of Pharmacy University of Utah Salt Lake City Utah USA Abstract Objective : Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods : We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results : There was a strong relationship between clearance (4.96 ml·min −1 ·kg −1 ) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min −1 ·kg −1 , respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg −1 , respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion : The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.