European Journal of Clinical Pharmacology

Eggers, R.; Bircher, J.

doi: 10.1007/BF00542430pmid: 3402517

228 34 34 4 4 R. H. Eggers J. Bircher Division of Clinical Pharmacology Georg-August-University of Göttingen Göttingen Federal Republic of Germany Summary Quality control parameters were surveyed in the clinical pharmacological literature of 1984 and 1985, as published by the European Journal of Clinical Pharmacology, the British Journal of Clinical Pharmacology, and Clinical Pharmacology and Therapeutics. Papers which included newly developed methods gave details about precision and sensitivity in more than 60% and about accuracy and specificity in nearly 30%. Fewer than one-third of all articles containing analytical methods, described by citation only, gave information about precision and sensitivity in the originating laboratory, and accuracy and specificity were reported by less than 10% of them. These data represent an important deficiency in laboratory information in the clinical pharmacological literature.

Mulligan, I.; Fraser, A.; Tirlapur, V.; Lewis, M.; Newcombe, R.; Henderson, A.

doi: 10.1007/BF00542431pmid: 2841136

228 34 34 4 4 I. P. Mulligan A. G. Fraser V. Tirlapur M. J. Lewis R. G. Newcombe A. H. Henderson Department of Cardiology University of Wales College of Medicine Cardiff Wales, UK Department of Pharmacology University of Wales College of Medicine Cardiff Wales, UK Department of Medical Computing & Statistics University of Wales College of Medicine Cardiff Wales, UK Summary We performed a randomized double-blind placebo controlled cross-over study of enalapril in 16 patients with chronic congestive heart failure, to assess haemodynamic and hormonal effects at rest and on exercise. Acute effects were measured 4 h after enalapril 10 mg, and chronic effects after 6 weeks treatment with enalapril 10–20 mg per day. Exercise tolerance, assessed by the duration of a maximal bicycle ergometer test, was not altered by enalapril. Mean blood pressure was reduced after enalapril, at rest and on exercise, acutely by 7% and 8% respectively, and chronically by 14% and 16%. Systemic vascular resistance was reduced by 16% at rest both acutely (NS) and chronically ( p <0.05). The resting pulmonary capillary wedge pressure was reduced by 28% with chronic treatment. In the acute study, total body oxygen consumption on exercise was 26% higher after enalapril. Chronically, resting oxygen consumption was reduced by 13% after enalapril, with mixed venous oxygen saturation increasing by 16%. In the acute study enalapril increased plasma renin activity at rest and on exercise by 181% and by 189%, and reduced aldosterone by 49% (NS) and 39% ( p <0.05), and these effects were sustained after 6 weeks. Enalapril increased antidiuretic hormone concentrations at rest acutely by 73% (NS) and chronically by 34% ( p <0.05) but not on exercise; the increase in the acute study correlated with plasma enalaprilat levels ( r =0.66, p <0.05). Enalapril did not alter plasma catecholamine concentrations. Patients preferred enalapril to placebo, and radiographic heart size was reduced during chronic treatment. There were no serious adverse effects. We conclude that enalapril is an effective angiotensin converting enzyme inhibitor of clinical value in chronic heart failure, but study design and methods of assessment of benefit can have a major influence on the results of pharmacological studies in such patients.

Whyte, K.; Whitesmith, R.; Reid, J.

doi: 10.1007/BF00542432pmid: 3402518

228 34 34 4 4 K. F. Whyte R. Whitesmith J. L. Reid Department of Material Medica University of Glasgow Glasgow UK Department of Biochemistry Stobhill General Hospital Glasgow UK Department of Respiratory Medicine City Hospital Sreenbank Drive EH10 5SB Edinburgh UK Summary We have examined the interaction between the administration of bendrofluazide, frusemide, spironolactone, and placebo and increased plasma adrenaline concentrations in a double-blind, placebo-controlled, cross over study. We studied healthy subjects on the fourteenth day of each treatment period and after a two hour infusion of adrenaline (0.06 µg·kg −1 ·min −1 {0.33 nmol·kg −1 ·min −1 }) we measured their heart rates, blood pressures, and plasma potassium and magnesium concentrations. There were no differences in heart rates or blood pressures for all four treatments. Baseline potassium concentrations were not significantly different compared to placebo, and plasma potassium fell during the period of the infusion on all study days. this fall was significantly greater on frusemide (0.5 mmol·l −1 ) and bendrofluazide (0.4 mmol·l −1 ) compared with both placebo and spironolactone. Baseline plasma magnesium concentration were not different and similar falls in plasma magnesium were seen on all four treatments during and after the adrenaline infusion. We conclude that chronic diuretic therapy with a thiazide diuretic or frusemide may increase the severity of hypokalaemia during short-term rises in plasma adrenaline. Pretreatment with spironolactone had no effect on adrenaline-induced hypokalaemia. None of the diuretics studied altered adrenaline-induced hypomagnesaemia.

Kraemer, R.; Birrer, P.; Sennhauser, F.; Schöni, M.

doi: 10.1007/BF00542433pmid: 3402519

228 34 34 4 4 R. Kraemer P. Birrer F. H. Sennhauser M. H. Schöni Department of Pediatrics University of Berne Berne Switzerland Alpine Children's Hospital “Pro Juventute” Davos Switzerland Summary The effects of salbutamol 0.225 mg/kg given systemically on lung function in infants have been measured by whole-body plethysmography in 60 children with broncho-pulmonary diseases (24 after respiratory distress syndrome, 21 with wheezy bronchitis and 15 with cystic fibrosis). A therapeutic action was demonstrated in 74% of the tests, taking into account changes in end-expiratory resting level (state of inflation) and associated changes in airway resistance. There was a significant decrease in thoracic gas volume as an estimate of pulmonary hyperinflation, which was due to improved alveolar ventilation and to a consequential decrease in end-expiratory resting level. The improvement in airway resistence, as an estimate of airway obstruction, reflects a substantial relaxation of bronchial smooth muscle increasing the diameter of the airways. The extent to which similar results may be achieved by topical administration of nebulised beta agonists remains to be determined.

Lehmann, K.; Reichling, U.; Wirtz, R.

doi: 10.1007/BF00542434pmid: 3402520

228 34 34 4 4 K. A. Lehmann U. Reichling R. Wirtz Institut für Anaesthesiologie der Universität zu Köln Köln FRG Summary Eighty patients recovering from major operations were investigated to evaluate the influence of naloxone on the analgesic and respiratory depressant properties of buprenorphine. They were randomly assigned to two groups to self-administer either buprenorphine (Group B) or a mixture of buprenorphine and naloxone (fraction 60%; Group BN) in the early postoperative period by means of the On-Demand Analgesia Computer (ODAC). The duration of patient-controlled analgesia (PCA) was 21.0 h (B) or 23.5 h (BN), during which 12.2 (B) and 18.2 (BN) demands per patient were recorded, representing significantly different consumption of buprenorphine 0.80 (B) and 1.07 (BN) µg·kg −1 ·h −1 . Retrospective pain scores were significantly better in Group B, and respiratory rate was significantly higher in Group BN. The analgesia was judged superior by 81% (B) and 88% (BN) of the patients compared to conventional postoperative pain treatment. The minimum effective buprenorphine concentration (MEC) varied greatly in both groups with no significant differences between them (median 0.4 ng·ml −1 , range 0.1–8.6 ng·ml −1 ); intra-individual variability was lower (67.9% B, and 58.2% BN) than inter-individual variability (107.3% B and 84.0% BN). Accumulation in plasma and acute tolerance did not occur. Thus, admixture of 60% naloxone decreased both the analgesic and respiratory depressant effects of buprenorphine which were generally independent of plasma concentrations. The analgesia achieved with the buprenorphine/naloxone mixture under patient-controlled conditions was comparable to that of other narcotic analgesics. Accordingly, this drug combination may be expected to give clinically adequate analgesia without notable impairement of spontaneous respiration, whilst withdrawal symptoms would probably arise in drug addicts abusing other opiates.

Wolff, J.; Bigler, D.; Christensen, C.; Rasmussen, S.; Andersen, H.; Tønnesen, K.

doi: 10.1007/BF00542435pmid: 3402521

228 34 34 4 4 J. Wolff D. Bigler C. Broen Christensen S. N. Rasmussen H. B. Andersen K. H. Tønnesen Departments of Anaesthesia, Pain Clinic, and Clinical Physiology Bispebjerg Hospital Copenhagen Denmark Department of Pharmacology University of Copenhagen Copenhagen Denmark Department of Pharmacology The Royal Danish School of Pharmacy Copenhagen Denmark Summary The influence of renal function, measured by 51 Cr-EDTA clearance, on morphine and morphine glucuronide kinetics has been studied in 13 patients after a single i.v. injection of morphine. Unconjugated morphine and morphine glucuronides were measured by a sensitive, specific RIA after extraction from plasma. No significant correlation was found between total body clearance of unconjugated morphine and 51 Cr-EDTA clearance. However, patients with renal insufficiency had impaired elimination of morphine glucuronides, and the apparent clearance was significantly correlated with the 51 Cr-EDTA clearance ( r =0.94, p <0.001). A relatively long terminal elimination half-life of morphine was found in all patients (mean±SD: 9.2±2.5 h), irrespective of glomerular function.

Fitscha, P.; Meisner, W.; Tiso, B.

doi: 10.1007/BF00542436pmid: 2900143

228 34 34 4 4 P. Fitscha W. Meisner B. Tiso 2nd Department of Internal Medicine Policlinic Vienna Austria Summary The acute cardiovascular effects of two beta-adrenoceptor blocking agents, bopindolol and propranolol, were compared in a randomized study in 16 male patients with coronary heart disease. All patients had had an uncomplicated acute myocardial infarction at least 8 weeks earlier. The two drugs reduced the arterial blood pressure to the same extent, both at rest and during exercise. As heart rate and stroke volume were also decreased, cardiac output was reduced, whereas systemic vascular resistance was increased at rest and during exercise. Left ventricular filling pressure was increased. No statistically significant differences in these variables were seen between the two groups.

Joubert, P.; Venter, C.; Wellstein, A.

doi: 10.1007/BF00542437pmid: 2900144

228 34 34 4 4 P. H. Joubert C. P. Venter A. Wellstein Department of Pharmacology and Therapeutics Medical University of Southern Africa (MEDUNSA) South Africa Zentrum der Pharmakologie Klinikum der J. W. Goethe-Universität Frankfurt am Main Federal Republic of Germany Summary A randomized, double-blind, placebo-controlled study was performed in 8 white and 8 black volunteers matched for sex, age and mass. The effect of 3 intravenous doses of a new, cardiose-lective beta-adrenergic blocker, bisoprolol, on the heart rate increase after standardized exercise was compared to that of 3 doses of propranolol. As described previously for propranolol, black volunteers showed less response than whites to beta-blockade assessed in terms of the reduction in exercise-induced tachycardia. The effects of the two beta-blockers were similar and the apparent ethnic difference was seen with both drugs. It has previously been shown that black volunteers have a higher intrinsic heart rate (i.e. heart rate after parasympathetic and beta-adrenergic blockade of the heart) than whites, but their resting heart rates are similar because of greater parasympathetic tone in blacks. When exercise-load was calculated as increase in heart rate above that after atropinization, no ethnic differences were seen. It is suggested that in populations that are heterogenous in terms of the heart rate increase after atropine, work load should be standardized in terms of the increase in heart rate over the atropine heart rate rather than on absolute heart rate. The apparent ethnic difference represents a flaw in methodology as applied to a heterogenous volunteer population.

Zysset, T.; Wietholtz, H.

doi: 10.1007/BF00542438pmid: 3402522

228 34 34 4 4 T. Zysset H. Wietholtz Department of Clinical Pharmacology University of Berne Berne Switzerland Department of Internal Medicine Neues Klinikum Aachen Federal Republic of Germany Regionalspital Biel Hospital Pharmacy CH-2502 Biel Switzerland Summary As the influence of diabetes on drug metabolism in patients is controversial, a study was performed to assess antipyrine (AP) disposition in controlled Type I and Type II diabetics and 2 age-and sex-matched control groups. In Type I diabetics, the half-life of AP was significantly reduced from 12.0 (controls) to 7.9 h, and the volume of distribution (V) was lowered from 733 to 569 ml·kg −1 . The resulting plasma clearance and cumulative urinary excretion of AP and its metabolites over 24 h did not differ from controls. In Type II diabetics, the AP half-life (14.5 h) and V (568 ml·kg −1 ) did not differ from their age- and sex-matched controls (11.1 h and 643 ml·kg −1 , respectively), but the plasma clearance of AP was significantly reduced by 30%, and urinary excretion was significantly reduced to 44% of controls. The differential effects of Types I and II diabetes on AP metabolism may explain, at least in part, the controversial data in the literature.

Klimowicz, A.; Nowak, A.; Kadyków, M.

doi: 10.1007/BF00542439pmid: 3402523

228 34 34 4 4 A. Klimowicz A. Nowak M. Kadyków Dermatological Clinic Pomeranian Medical Academy Szczecin Poland Summary Plasma and skin blister fluid concentration-time curves following a single oral dose of trimethoprim have been evaluated. Skin blisters were produced by the cantharides technique, using patches with cantharidin ointment. Trimethoprim concentrations in plasma following multiple doses of 200 mg were also determined. The maximal concentration in plasma after a single oral dose of 400 mg trimethoprim was 3.95±1.08 mg/l, and it was observed after 2 h, whereas in skin blister fluid the level was 2.21±0.62 mg/l, and it was delayed for up to 6 h. This means that a certain time is required for drug transfer from the capillaries via the basal membrane into blister fluid. Penetration of the drug into blister fluid, defined as the ratio of the areas under the trimethoprim level time curve in skin blister fluid to that of plasma, was 0.826±0.096. The steady-state concentration of trimethoprim in plasma during routine treatment with 200-mg doses ranged between 2 and 3.5 mg/l.