European Journal of Clinical Pharmacology

Davies, P.; Franklyn, J.

doi: 10.1007/BF00315221pmid: 1884719

228 40 40 5 5 P. H. Davies J. A. Franklyn Department of Medicine University of Birmingham, Queen Elizabeth Hospital B15 2TH Edgbaston, Birmingham UK Summary Many drugs affect tests of thyroid function through alterations in the synthesis, transport and metabolism of thyroid hormones, as well as via influences on thyrotrophin (TSH) synthesis and secretion. Despite effects on circulating thyroid hormone and TSH levels, few drugs result in important changes in clinical thyroid state, but difficulty in interpretation of thyroid function tests often results. Commonly prescribed drugs including anti-convulsants, non-steroidal anti-inflammatory drugs, beta-adrenoceptor antagonists, steroid hormones and heparin may result in abnormal thyroid function tests in the absence of clinical features of thyroid dysfunction. In contrast, lithium and iodine containing drugs, including radiographic contrast agents and amiodarone, may result rarely in overt thyroid disease.

Dahlöf, C.; Hedner, T.; Thulin, T.; Gustafsson, S.; Olsson, S.

doi: 10.1007/BF00315222pmid: 1884720

228 40 40 5 5 C. Dahlöf T. Hedner T. Thulin S. Gustafsson S. -O. Olsson Gothenburg Medical Research Centre Sociala Huset Uppgång DII S-41117 Gothenburg Sweden Department of Clinical Pharmacology Sahlgrenska University Hospital S-41345 Gothenburg Sweden Department of Medicine University Hospital S-22185 Lund Sweden Sunne Hospital S-68600 Sunne Sweden Department of Clinical Research AB Ferrosan S-20180 Malmö Sweden Summary General well-being, adverse effects and antihypertensive efficacy have been investigated in a double blind, parallel-group, dose-response multicentre study of diltiazem and metoprolol monotherapy for hypertension. 128 patients with primary hypertension were included from 10 participating centres. The patients were randomized to receive oral diltiazem 120–240–360 mg/day or metoprolol 50–100–200 mg/day. Each dose was given for a 4-week period as a forced titration regime. In all 119 patients, 59 and 60, respectively, on diltiazem and metoprolol completed the study protocol. There were dose-dependent reductions in supine and standing blood pressures (BP) after both diltiazem and metoprolol therapy. In the diltiazem group, supine BP was reduced by 10 (11)/10 (6) mm Hg (SBP/DBP) at the highest dose level, and the corresponding values for the metoprolol group were 7 (16)/8 (9) mm Hg (SBP/DBP). Target pressures (DBP ≤ 90 mm Hg and/or a reduction in DBP of ≥ 10%) were reached in 63% and 48% of the patients, respectively. The incidence and severity of dose-dependent adverse effects, as evaluated by spontaneous reports or open and direct questioning, did not differ between treatments. Subjective well-being, evaluated by a self-administered questionnaire, the MSE-profile, did not differ significantly between diltiazem and metoprolol therapy. However, after an initial slight deterioration, contentment and vitality tended to improve with increasing doses of diltiazem, while a dose-related deterioration in these variables was observed on metoprolol therapy. At the highest dose levels, contentment and vitality tended to be better in the diltiazem than the metoprolol group. Thus, diltiazem and metoprolol in daily doses of 120–360 mg and 50–200 mg, respectively, produce comparable and parallel reductions in supine and standing BP. However, while subjective well-being tended to improve with increasing doses of diltiazem, there was a negative trend for metoprolol. It is concluded that diltiazem, given as monotherapy to hypertensive patients, does not impair subjective well-being.

Caponnetto, S.; Valvo, E.; Mocarelli, P.; Alberti, D.; Savonitto, S.

doi: 10.1007/BF00315223pmid: 1679390

228 40 40 5 5 S. Caponnetto E. Valvo P. Mocarelli D. Alberti S. Savonitto Medical Department Ciba-Geigy S.p.A. P.O. Box 88 I-21047 Saronno (VA) Italy Summary A randomized multicentre between-patient study comparison has been made of the efficacy and tolerability of cadralazine and prazosin, both administered for 6 weeks to hypertensive patients with a supine diastolic blood pressure (DBP) ≥ 95 mm Hg whilst on a beta-adrenoceptor-blocker. The doses of the beta-adrenoceptor-blocker (metoprolol SR 200 mg once daily) and cadralazine (10 mg once daily) were held constant during the study, while prazosin was individually titrated from 0.5 mg to a maximum of 2 mg tds. 108 patients (50 m and 58 f; mean age 54 y) were enrolled in 12 centres. Twelve patients withdrew due to adverse effects or poor efficacy (5 patients on prazosin and 7 on cadralazine). Both treatments induced a similar significant reduction in systolic blood pressure (SBP) and DBP, allowing normalization of BP in 58% of subjects on cadralazine and 55% on prazosin. Heart Rate (hR) increased significantly from 67 to 72 beats · min −1 in those on cadralazine and from 65 to 69 beats · min −1 on prazosin. Body weight was unchanged. Adverse effects were mild and typical of vasodilators, such as headache, flushing and dizziness. Physician evaluation of drug efficacy was not different between drugs, and cadralazine was rated better in terms of tolerability. Thus, in this multicentre study, cadralazine in the fixed dose of 10 mg once daily, as a second-step antihypertensive treatment in patients not satisfactorily controlled by a beta-adrenoceptor-blocker, was as effective and showed a similar side effect profile to prazosin given three times daily.

Lipworth, B.; Irvine, N.; McDevitt, D.

doi: 10.1007/BF00315224pmid: 1653143

228 40 40 5 5 B. J. Lipworth N. A. Irvine D. G. McDevitt Department of Clinical Pharmacology Ninewells Hospital and Medical School Dundee Scotland, UK Summary Six normal subjects were given once daily treatment for 15 days with placebo (PL), betaxolol 10 mg (B10), 40 mg (B40); atenolol 100 mg (A100); and nadolol 40 mg (N40). Measurements of β 1 -adrenoceptorblockade (reduction of exercise heart rate) and of β 2 -adrenoceptor-blockade (attenuation of isoprenaline induced finger tremor) were made after the first, eighth and fifteenth doses of each drug. Plasma concentrations showed dose related increases between 10 mg and 40 mg doses of betaxolol, and there was significant drug accumulation at steady state compared with after single dosing. The reduction in exercise heart rate (EHR) with B10 was less in comparison with all other treatments. There were no significant differences in effects between single and chronic-dosing for any of the treatments (% reduction EHR compared with placebo, on days 1 and 15): B10 (18.2, 19.0), B40 (28.6, 26.5); A100 (22.7, 23.1); N40 (26.6, 23.8). Dose-ratios for attenuation of isoprenaline-induced finger tremor (IT 100 ) were significantly greater with B40 compared with B10 or A100 (no dose-ratio for finger tremor could be calculated for N40). There were no differences between single and chronic-dosing (IT 100 dose-ratios on days 1 and 15): B10 (3.0, 2.5), B40 (4.4, 5.3); A100 (3.0, 3.0). The attenuation of isoprenaline-induced chronotropic response (IH 25 ) by N40 was significantly greater in comparison with all other treatments. IH 25 dose-ratios (on days 1 and 15) were as follows: B10 (2.8, 3.6), B40 (5.1, 5.8); A100 (3.6, 3.6); N40 (19.0, 17.4). Thus, despite drug accumulation after chronic-dosing, there was no evidence of any increase in either β 1 or β 2 -adrenoceptor antagonism at steady-state in comparison with after single-dosing. The apparent dissociation between plasma concentration and β-adrenoceptor antagonism after chronic-dosing my be a consequence of β-adrenoceptor up-regulation, resulting in partial attenuation of β-blockade.

Rolandi, E.; Franceschini, R.; Cataldi, A.; Cicchetti, V.; Carati, L.; Barreca, T.

doi: 10.1007/BF00315225pmid: 1679391

228 40 40 5 5 E. Rolandi R. Franceschini A. Cataldi V. Cicchetti L. Carati T. Barreca Department of Internal Medicine University of Genoa Genoa Italy Medical Department Zambon Group Milan Italy Summary The effects of ursodeoxycholic acid (UDCA, 450 mg daily) in patients with histologically proven chronic active hepatitis (CAH) have been evaluated in a randomized, double-blind, placebo-controlled study. Twenty-six patients with serum alanine aminotransferase (ALT) values at least twice the normal upper limit in two of three pre-treatment tests received UDCA or a placebo for twelve weeks. In all UDCA-treated patients, serum aspartate aminotransferase (AST), ALT, gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (AP) fell significantly after 4 weeks of treatment. There was a further decrease at the end of therapy, as well as a small but significant fall in total serum bilirubin. Conversely, 4 weeks aftersuspension of therapy, serum enzyme levels had increased, reaching values not much lower than those recorded before treatment. Total serum protein, albumin and γ-globulin did not change after UDCA treatment. In the placebo group no significant variation in the test results were found. The results indicate that UDCA therapy in CAH, as has been observed in primary biliary cirrhosis and primary sclerosing cholangitis, is able to improve several indices of liver damage, without producing any toxic adverse effects.

Lakhdar, A.; Farish, E.; Hillis, W.; Dunn, F.

doi: 10.1007/BF00315226pmid: 1884721

228 40 40 5 5 A. A. Lakhdar E. Farish W. S. Hillis F. G. Dunn Department of Medicine Stobhill General Hospital G21 3UW Glasgow UK Department of Biochemistry Stobhill General Hospital G21 3UW Glasgow UK Department of Materia Medica Stobhill General Hospital G21 3UW Glasgow UK Department of Cardiology Stobhill General Hospital G21 3UW Glasgow UK Summary Serum total cholesterol and triglyceride levels were measured in 12 patients before and 3, 6 and 9 months after treatment with amiodarone. In addition, we monitored serum T 4 , T 3 , reverse T 3 and TSH levels. Amiodarone and its desethyl metabolite levels were measured on each occasion. Serum total cholesterol and T 4 levels rose from 5.95 mmol/l, and 102.7 mmol/l respectively at baseline to 6.95 and 115.8 at 6 months and reverse T 3 increased at 3, 6 and 9 months from baseline. Serum triglycerides did not change. No relationship existed between cholesterol, T 4 and T 3 and amiodarone (or its metabolite) levels nor between cholesterol and thyroid hormone levels. These data demonstrate that amiodarone therapy is associated with an elevation in serum cholesterol. This may have clinical implications in view of the current widespread use of the drug.

Morris, R.; Kotasek, D.; Paltridge, G.

doi: 10.1007/BF00315227pmid: 1884722

228 40 40 5 5 R. G. Morris D. Kotasek G. Paltridge Department of Clinical Pharmacology The Queen Elizabeth Hospital 28 Woodville Road 5011 Woodville South South Australia Department of Haematology/Oncology The Queen Elizabeth Hospital 28 Woodville Road 5011 Woodville South South Australia Summary Thirteen cancer patients were studied following a total of 41 courses of epirubicin (EPI) (38–50 mg·m −2 , mean 49.2 mg·m −2 , administered by a 60 min infusion), together with other cancer chemotherapeutic agents. The aim was to consider the disposition of EPI and metabolites following subsequent courses as it has been reported that doxorubicin (the 4′-epimer parent of EPI) clearance is increased following the first administration. We have observed that EPI-glucuronide accounted for a mean 78.0%, epirubicinol 0.2% and epirubicinol-glucuronide 19.3% and that parent EPI accounted for only 2.4% of the EPI-compounds measured (mean of all patients and courses) for the 3 h period immediately following the infusion. These data confirm the rapid metabolism of EPI and the dominance of the glucuronidation metabolite pathway (which is not available to doxorubicin) and are compared with the metabolite profile observed in other reports. Large inter- and intra-individual variability in area under the plasma concentration/time curve were observed with no clear evidence of any consistent directional trend for such fluctuations, suggesting that factors contributing to EPI disposition are multivariate.

Persson, I.; Adami, H.; Norell, S.; Westerholm, B.; Wiholm, B.

doi: 10.1007/BF00315228pmid: 1884723

228 40 40 5 5 I. Persson H. -O. Adami S. E. Norell B. Westerholm B. -E. Wiholm Department of Obstetrics and Gynecology University Hospital Uppsala Sweden Department of Surgery University Hospital Uppsala Sweden Department of Epidemiology Institute of Environmental Medicine, Karolinska Institutet Sweden National Corporation of Pharmacies Stockholm Sweden Department of Drugs National Board of Health and Welfare Uppsala Sweden Summary The Department of Drugs of the Swedish National Board of Health and Welfare undertook a study of the possibilities of a new scheme for post-marketing surveillance by means of prescription and register based epidemiological studies, primarily of combined oral contraceptives (COC). Based on available data on COC usage patterns and incidence rates of the disease at study, it was estimated that study periods, including the necessary time periods for disease development and generation of a sufficient number of cases, would amount to at least 1 to 13 years for cardiovascular outcomes and 8 to 17 years for reproductive cancers. Prospective and unbiased exposure ascertainment would be the most important advantage. However, delay in follow up, the need for extensive individual questionnaire probing and fear of violation of personal integrity could adversely affect the feasibility of the scheme. Chiefly on the grounds of the extended study periods and magnitude of the necessary infrastructure, it was not judged cost-effective to pursue such a scheme for COC exposure only. It was, however, suggested that it would be considered for epidemiological surveillance of other drugs that are commonly used and for which short term and frequent serious side effects are expected, as for instance lipid lowering compounds, beta-blockers, bensodiazepines and other psychotropic drugs.

Wessling, A.; Bergman, U.; Westerholm, B.

doi: 10.1007/BF00315229pmid: 1884724

228 40 40 5 5 A. Wessling U. Bergman B. Westerholm National Corporation of Pharmacies Stockholm Sweden Department of Clinical Pharmacology of the Karolinska Institute Huddinge University Hospital Huddinge Sweden Summary Marked differences in the utilisation of psychotropic drugs between the three major urban areas in Sweden were recorded from four sources of information: drug supplies from wholesalers to pharmacies, drug supplies to hospitals for in-patient use, drugs sold on prescription for out-patient use, and out-patient consultation and drug prescribing as recorded by physicians. The total sales of psychotropics in the counties of Gothenburg (110,8 defined daily doses per 1000 inhabitants per day) and Malmö (102,1) were much higher than in the county of Stockholm (73,4), with about 25% of the difference being accounted for by diazepam. Differences in the total sales of psychotropics were not explained by any differences in hospital sales, which amounted to about 10% in all counties. Prescription sales differed due to the higher average number of DDD (defined daily doses) per prescription in Gothenburg and Malmö than in Stockholm (total psychotropics 8 and 15%, respectively), and especially because of the higher number of prescriptions per inhabitant (about 40 and 30–35%, respectively). There was no substantial difference in the pattern of diagnoses between areas, but there was a noticeable difference with regard to prescriber category, as psychiatrists accounted for more of the prescriptions in Stockholm than in Gothenburg and Malmö. The results raise questions about over- and under-treatment of mental disorders and about abuse of drugs. In order to explain the geographical differences in psychotropic drug sales morbidity patterns and prescribing practices should be further explored.

Karlson, B.; Emanuelsson, H.; Herlitz, J.; Nilsson, J.; Olsson, G.

doi: 10.1007/BF00315230pmid: 1884725

228 40 40 5 5 B. W. Karlson H. Emanuelsson J. Herlitz J. -E. Nilsson G. Olsson Division of Cardiology, Department of Medicine I Sahlgrenska Hospital Göteborg Sweden A. B. Hässle Mölndal Sweden Summary Nifedipine capsules t.d.s. and an extended release formulation of nifedipine, nifedipine-ER tablets, given once daily in corresponding daily doses, have been compared with placebo in a double-blind, three-way crossover study in 24 patients with stable angina pectoris. The objective was to study the influence on the antianginal effect of the different pharmacokinetics of several preparations of nifedipine. All patients received concomitant treatment with β-adrenoceptor blockers. Antianginal efficacy was assessed by a dynamic exercise test at the end of the dosage intervals, i.e. 8 and 24 h after nifedipine capsules and nifedipine-ER, respectively, as well as 6 h after dosing. Six h after dosing the time of onset of chest pain and total excercise time were longer and total work was significantly higher during both nifedipine-ER (plasma concentration 260 nmol/l) and placebo treatment than after nifedipine capsules (plasma concentration 78 nmol/l). Time to 1 mm ST depression was longer during nifedipine-ER than during nifedipine capsule treatment. No significant difference was seen between nifedipine-ER and placebo. At the end of the dosage interval (24 and 8 h after nifedipine-ER and nifedipine capsules, respectively), no significant difference was found between nifedipine-ER (plasma concentration 75 nmol/l) and the other two treatments. However, placebo was superior to nifedipine capsules (plasma concentration 58 nmol/l) both in the time to onset of chest pain and total exercise time. The lack of effect at the end of the dosage interval was probably due to the subtherapeutic plasma nifedipine level. Nifedipine capsules, but not the extended release formulation, were found to be significantly inferior to placebo both after 6 h and at the end of the dosage interval. This unexpected finding may have been induced by the rapid and extensive fluctuation in plasma levels, with a rapid decline from the peak value after the capsule formulation, since a similar deterioration was not seen with nifedipine-ER, despite similar plasma concentrations at the end of the dosage interval. This phenomenon merits further research.